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Sample records for involving substandard antimalarial

  1. Substandard anti-malarial drugs in Burkina Faso

    Directory of Open Access Journals (Sweden)

    Sie Ali

    2008-05-01

    Full Text Available Abstract Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers and illicit (market and street vendors, shops sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50% chloroquine, 10/77 (13% pyrimethamine-sulphadoxine, 9/77 (12% quinine, 6/77 (8% amodiaquine, 9/77 (12% artesunate, and 4/77 (5% artemether-lumefantrine. 32/77 (42% drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6% and 27/30 (90.0% samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the

  2. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

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    Bertocchi Paola

    2007-02-01

    Full Text Available Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. Results The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date; low content of active substance (in one sample; different, non-declared, active substance (in one sample; sub-standard technological properties and very low dissolution profiles (in about 50% of samples. This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. Conclusion This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution

  3. Substandard/counterfeit antimicrobial drugs.

    Science.gov (United States)

    Kelesidis, Theodoros; Falagas, Matthew E

    2015-04-01

    Substandard/counterfeit antimicrobial drugs are a growing global problem. The most common substandard/counterfeit antimicrobials include beta-lactams (among antibiotics) and chloroquine and artemisin derivatives (among antimalarials). The most common type of substandard/counterfeit antimicrobial drugs have a reduced amount of the active drug, and the majority of them are manufactured in Southeast Asia and Africa. Counterfeit antimicrobial drugs may cause increased mortality and morbidity and pose a danger to patients. Here we review the literature with regard to the issue of substandard/counterfeit antimicrobials and describe the prevalence of this problem, the different types of substandard/counterfeit antimicrobial drugs, and the consequences for the individuals and global public health. Local, national, and international initiatives are required to combat this very important public health issue. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  4. Substandard and counterfeit medicines: a systematic review of the literature

    Science.gov (United States)

    Almuzaini, Tariq; Choonara, Imti; Sammons, Helen

    2013-01-01

    Objective To explore the evidence available of poor-quality (counterfeit and substandard) medicines in the literature. Design Systematic review. Data sources Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (pcounterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials. Conclusions The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active

  5. 7 CFR 983.30 - Substandard pistachios.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Substandard pistachios. 983.30 Section 983.30... Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE PISTACHIOS GROWN IN CALIFORNIA, ARIZONA, AND NEW MEXICO Definitions § 983.30 Substandard pistachios. Substandard pistachios means...

  6. 7 CFR 983.57 - Substandard pistachios.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Substandard pistachios. 983.57 Section 983.57... Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE PISTACHIOS GROWN IN CALIFORNIA, ARIZONA, AND NEW MEXICO Regulations § 983.57 Substandard pistachios. The committee shall, with the...

  7. Antimalarial drug quality in Africa.

    Science.gov (United States)

    Amin, A A; Kokwaro, G O

    2007-10-01

    There are several reports of sub-standard and counterfeit antimalarial drugs circulating in the markets of developing countries; we aimed to review the literature for the African continent. A search was conducted in PubMed in English using the medical subject headings (MeSH) terms: 'Antimalarials/analysis'[MeSH] OR 'Antimalarials/standards'[MeSH] AND 'Africa'[MeSH]' to include articles published up to and including 26 February 2007. Data were augmented with reports on the quality of antimalarial drugs in Africa obtained from colleagues in the World Health Organization. We summarized the data under the following themes: content and dissolution; relative bioavailability of antimalarial products; antimalarial stability and shelf life; general tests on pharmaceutical dosage forms; and the presence of degradation or unidentifiable impurities in formulations. The search yielded 21 relevant peer-reviewed articles and three reports on the quality of antimalarial drugs in Africa. The literature was varied in the quality and breadth of data presented, with most bioavailability studies poorly designed and executed. The review highlights the common finding in drug quality studies that (i) most antimalarial products pass the basic tests for pharmaceutical dosage forms, such as the uniformity of weight for tablets, (ii) most antimalarial drugs pass the content test and (iii) in vitro product dissolution is the main problem area where most drugs fail to meet required pharmacopoeial specifications, especially with regard to sulfadoxine-pyrimethamine products. In addition, there are worryingly high quality failure rates for artemisinin monotherapies such as dihydroartemisinin (DHA); for instance all five DHA sampled products in one study in Nairobi, Kenya, were reported to have failed the requisite tests. There is an urgent need to strengthen pharmaceutical management systems such as post-marketing surveillance and the broader health systems in Africa to ensure populations in the

  8. Substandard and Counterfeit Antimicrobials: Recent Trends and ...

    African Journals Online (AJOL)

    ... trends in the availability of substandard and counterfeit antimicrobials in the global market ... Literature search using PubMed and Medline databases and Google search engine was conducted to identify related publications on the subject.

  9. Fighting trafficking of falsified and substandard medicinal products in Russia.

    Science.gov (United States)

    Fayzrakhmanov, N F

    2015-01-01

    , which was attended by more than 750 professionals in the field of law and pharmacy from different countries, including USA, China, countries of the European Council and the Commonwealth of Independent States. At the end of the conference the Convention on the counterfeiting of medicinal products and similar crimes involving threats to public health, was signed, which was called Medicrime [2]. The Convention was signed by representatives of Austria, Germany, Israel, Iceland, Italy, Cyprus, Portugal, Russian Federation, Finland, France, Ukraine, Switzerland. The Medicrime Convention is the first legal agreement in the field of criminal law aimed at criminalizing the trafficking of falsified and substandard medicinal products, as well as aimed at providing legal support for the investigation of these crimes at the international level. The positive side of the Convention of the Council of Europe Medicrime is that it is open for signature not only by member States of the Council of Europe and the European Union, but also by States that are not members of the Council of Europe, but participated in the elaboration of a Convention or have observer status with the Council of Europe. In addition, the Convention is open for signature by any other state at the invitation of the Committee of Ministers of the Council of Europe. The Convention introduces the responsibility for the production, storage and distribution of falsified medicinal products, active substances, excipients, components, materials and supplies; the use of falsified documents related to the trafficking of medicinal products (Articles 5, 6, 7). This legal act regulates the cooperation between the health authorities, customs, police and other competent authorities at international and national level (Articles 17, 21, 22).One of the results of the legal implementation of the rules of the Convention Medicrime in the Russian legislation was the adoption of the Federal law of the Russian Federation dated 31.12.2014 No

  10. Surveillance for falsified and substandard medicines in Africa and Asia by local organizations using the low-cost GPHF Minilab.

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    Albert Petersen

    Full Text Available Substandard and falsified medical products present a serious threat to public health, especially in low- and middle-income countries. Their identification using pharmacopeial analysis is expensive and requires sophisticated equipment and highly trained personnel. Simple, low-cost technologies are required in addition to full pharmacopeial analysis in order to accomplish widespread routine surveillance for poor-quality medicines in low- and middle-income countries.Ten faith-based drug supply organizations in seven countries of Africa and Asia were each equipped with a Minilab of the Global Pharma Health Fund (GPHF, Frankfurt, Germany, suitable for the analysis of about 85 different essential medicines by thin-layer chromatography. Each organization was asked to collect approximately 100 medicine samples from private local medicine outlets, especially from the informal sector. The medicine samples were tested locally according to the Minilab protocols. Medicines which failed Minilab testing were subjected to confirmatory analysis in a WHO-prequalified medicine quality control laboratory in Kenya.Out of 869 medicine samples, 21 were confirmed to be substandard or falsified medical products. Twelve did not contain the stated active pharmaceutical ingredient (API, six contained insufficient amounts of the API, and three showed insufficient dissolution of the API. The highest proportion of substandard and falsified medicines was found in Cameroon (7.1%, followed by the Democratic Republic of Congo (2.7% and Nigeria (1.1%. Antimalarial medicines were most frequently found to be substandard or falsified (9.5% of all antimalarials. Thin-layer chromatography according to the Minilab protocols was found to be specific and reproducible in the identification of medicines which did not contain the stated API. Since only samples which failed Minilab testing were subjected to confirmatory testing using pharmacopeial methods, this study did not assess the

  11. Problems Associated With Substandard And Counterfeit Drugs In ...

    African Journals Online (AJOL)

    Problems Associated With Substandard And Counterfeit Drugs In Developing Countries: A Review Article On Global Implications Of Counterfeit Drugs In The Era Of Anti-Retroviral (ARVS) Drugs In A Free Market Economy.

  12. Estimated Under-Five Deaths Associated with Poor-Quality Antimalarials in Sub-Saharan Africa

    Science.gov (United States)

    Renschler, John P.; Walters, Kelsey M.; Newton, Paul N.; Laxminarayan, Ramanan

    2015-01-01

    Many antimalarials sold in sub-Saharan Africa are poor-quality (falsified, substandard, or degraded), and the burden of disease caused by this problem is inadequately quantified. In this article, we estimate the number of under-five deaths caused by ineffective treatment of malaria associated with consumption of poor-quality antimalarials in 39 sub-Saharan countries. Using Latin hypercube sampling our estimates were calculated as the product of the number of private sector antimalarials consumed by malaria-positive children in 2013; the proportion of private sector antimalarials consumed that were of poor-quality; and the case fatality rate (CFR) of under-five malaria-positive children who did not receive appropriate treatment. An estimated 122,350 (interquartile range [IQR]: 91,577–154,736) under-five malaria deaths were associated with consumption of poor-quality antimalarials, representing 3.75% (IQR: 2.81–4.75%) of all under-five deaths in our sample of 39 countries. There is considerable uncertainty surrounding our results because of gaps in data on case fatality rates and prevalence of poor-quality antimalarials. Our analysis highlights the need for further investigation into the distribution of poor-quality antimalarials and the need for stronger surveillance and regulatory efforts to prevent the sale of poor-quality antimalarials. PMID:25897068

  13. Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

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    Aleisha R. Brock

    2017-05-01

    Full Text Available Background: The use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s can theoretically promote the emergence and transmission of drug resistant parasites. Methods: We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant and both poor quality and good quality (artemether-lumefantrine antimalarial use. Findings: The model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy. Interpretation: Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria. Keywords: Deterministic compartmental model, Falsified antimalarial medicine, Substandard antimalarial treatments, Antimalarial quality, Plasmodium falciparum malaria, Drug resistance

  14. Substandard drugs: a potential crisis for public health

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    Johnston, Atholl; Holt, David W

    2014-01-01

    Poor-quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article reviews the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs, incorrect drug quantity and presence of impurities). The possible means of addressing substandard manufacturing practices are also discussed. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient. PMID:24286459

  15. Problems associated with substandard and counterfeit drugs in developing countries: a review article on global implications of counterfeit drugs in the era of antiretroviral (ARVs) drugs in a free market economy.

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    Nsimba, Stephen E D

    2008-12-01

    To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs. Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper. When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients. Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more

  16. Strengthening of national capacity in implementation of antimalarial drug quality assurance in Thailand.

    Science.gov (United States)

    Vijaykadga, Saowanit; Cholpol, Sawat; Sitthimongkol, Saipin; Pawaphutanan, Anusorn; Pinyoratanachot, Arunya; Rojanawatsirivet, Chaiporn; Kovithvattanapong, Rojana; Thimasarn, Krongthong

    2006-01-01

    Substandard and counterfeit pharmaceutical products, including antimalarial drugs, appear to be widespread internationally and affect both the developing and developed countries. The aim of the study was to investigate the quality of antimalarial drugs, ie, artesunate (ART), chloroquine (CHL), mefloquine (MEF), quinine (QUI), sulfadoxine/pyrimethamine (S/P) and tetracycline (TT) obtained from the government sector and private pharmacies in 4 Thai provinces: Mae Hong Son, Kanchanaburi, Ranong, and Chanthaburi. Three hundred sixty-nine samples of 6 antimalarial drugs from 27 government hospitals, 27 malaria clinics, and 53 drugstores, were collected. Drug quality was assessed by simple disintegration test and semi-quantitative thin-layer chromatography in each province; 10% passed, 100% failed and doubtful samples were sent to be verified by high performance liquid chromatography (HPLC) at the Thai National Drug Analysis Laboratory, (NL). Fifteen point four percent of ART, 11.1% of CHL and 29.4% of QUI were substandard. Based on the finding, drug regulatory authorities in the country took appropriate action against violators to ensure that antimalarial drugs consumed by malaria patients are of good quality.

  17. On peroxide antimalarials

    Directory of Open Access Journals (Sweden)

    IGOR OPSENICA

    2007-12-01

    Full Text Available Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

  18. Poisoning by anti-malarial drugs

    African Journals Online (AJOL)

    had taken chloroquine: no other anti-malarial drugs were involved [1]. ... and angio-oedema have been described. Itching without a ... 15mg/L the risk of permanent visual damage and cardiac dysrhythmias is ... to use an alternative method.

  19. The counterfeit anti-malarial is a crime against humanity: a systematic review of the scientific evidence.

    Science.gov (United States)

    Karunamoorthi, Kaliyaperumal

    2014-06-02

    The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change. Further, responsible stakeholders in

  20. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

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    Newton Paul N

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

  1. A nationwide survey of the quality of antimalarials in retail outlets in Tanzania.

    Science.gov (United States)

    Kaur, Harparkash; Goodman, Catherine; Thompson, Eloise; Thompson, Katy-Anne; Masanja, Irene; Kachur, S Patrick; Abdulla, Salim

    2008-01-01

    Retail pharmaceutical products are commonly used to treat fever and malaria in sub-Saharan African countries. Small scale studies have suggested that poor quality antimalarials are widespread throughout the region, but nationwide data are not available that could lead to generalizable conclusions about the extent to which poor quality drugs are available in African communities. This study aimed to assess the quality of antimalarials available from retail outlets across mainland Tanzania. We systematically purchased samples of oral antimalarial tablets from retail outlets across 21 districts in mainland Tanzania in 2005. A total of 1080 antimalarial formulations were collected including 679 antifol antimalarial samples (394 sulfadoxine/pyrimethamine and 285 sulfamethoxypyrazine/pyrimethamine), 260 amodiaquine samples, 63 quinine samples, and 51 artemisinin derivative samples. A systematic subsample of 304 products was assessed for quality by laboratory based analysis to determine the amount of the active ingredient and dissolution profile by following the published United States Pharmacopoeia (USP) monogram for the particular tablet being tested. Products for which a published analytical monogram did not exist were assessed on amount of active ingredient alone. Overall 38 or 12.2% of the samples were found to be of poor quality. Of the antifolate antimalarial drugs tested 13.4% were found to be of poor quality by dissolution and content analysis using high-performance liquid chromatography (HPLC). Nearly one quarter (23.8%) of quinine tablets did not comply within the tolerance limits of the dissolution and quantification analysis. Quality of amodiaquine drugs was relatively better but still unacceptable as 7.5% did not comply within the tolerance limits of the dissolution analysis. Formulations of the artemisinin derivatives all contained the stated amount of active ingredient when analysed using HPLC alone. Substandard antimalarial formulations were widely

  2. A nationwide survey of the quality of antimalarials in retail outlets in Tanzania.

    Directory of Open Access Journals (Sweden)

    Harparkash Kaur

    Full Text Available Retail pharmaceutical products are commonly used to treat fever and malaria in sub-Saharan African countries. Small scale studies have suggested that poor quality antimalarials are widespread throughout the region, but nationwide data are not available that could lead to generalizable conclusions about the extent to which poor quality drugs are available in African communities. This study aimed to assess the quality of antimalarials available from retail outlets across mainland Tanzania.We systematically purchased samples of oral antimalarial tablets from retail outlets across 21 districts in mainland Tanzania in 2005. A total of 1080 antimalarial formulations were collected including 679 antifol antimalarial samples (394 sulfadoxine/pyrimethamine and 285 sulfamethoxypyrazine/pyrimethamine, 260 amodiaquine samples, 63 quinine samples, and 51 artemisinin derivative samples. A systematic subsample of 304 products was assessed for quality by laboratory based analysis to determine the amount of the active ingredient and dissolution profile by following the published United States Pharmacopoeia (USP monogram for the particular tablet being tested. Products for which a published analytical monogram did not exist were assessed on amount of active ingredient alone. Overall 38 or 12.2% of the samples were found to be of poor quality. Of the antifolate antimalarial drugs tested 13.4% were found to be of poor quality by dissolution and content analysis using high-performance liquid chromatography (HPLC. Nearly one quarter (23.8% of quinine tablets did not comply within the tolerance limits of the dissolution and quantification analysis. Quality of amodiaquine drugs was relatively better but still unacceptable as 7.5% did not comply within the tolerance limits of the dissolution analysis. Formulations of the artemisinin derivatives all contained the stated amount of active ingredient when analysed using HPLC alone.Substandard antimalarial formulations were

  3. Safeguarding against substandard/counterfeit drugs: mitigating a macroeconomic pandemic.

    Science.gov (United States)

    Wertheimer, Albert I; Norris, Jeremiah

    2009-03-01

    Counterfeiting and the sale of substandard pharmaceutical products can no longer be ignored. At 10% of global trade, counterfeiting is affecting many countries, causing serious downstream expenses and resource shortages. To describe the nature and impact of drug product counterfeiting and substandard product sale and to present strategies that may have value in ameliorating these phenomena. A literature review was conducted, supplemented by interviews of key leaders/experts in the field and the search of relevant web sites. All of the data were combined, integrated, and coordinated to present the complete picture of this problem. In addition to known corruption in some of the least developed countries, the trail through developed countries was detected. This report identifies means to detect faulty products and describes efforts toward resisting and ending these corrupt practices. Counterfeit drugs, if not stopped, can be responsible for a macroeconomic pandemic where major portions of some populations may be too ill to work and where the health sector resources are completely overwhelmed, as with the case of HIV/AIDS.

  4. Substandard factors in perinatal care in The Netherlands : a regional audit of perinatal deaths

    NARCIS (Netherlands)

    Wolleswinkel-van den Bosch, JH; Vredevoogd, CB; Borkent-Polet, M; van Eyck, J; Fetter, WPF; Lagro-Janssen, TLM; Rosink, IH; Treffers, PE; Amelink, M; Richardus, JH; Verloove-Vanhorick, P; Mackenbach, JP

    Background. To determine: 1) whether substandard factors were present in cases of perinatal death, and to what extent another course of action might have resulted in a better outcome, and 2) whether there were differences in the frequency of substandard factors by level of care, particularly between

  5. Substandard emergency obstetric care - a confidential enquiry into maternal deaths at a regional hospital in Tanzania

    DEFF Research Database (Denmark)

    Sorensen, Bjarke Lund; Elsass, Peter; Nielsen, Brigitte Bruun

    2010-01-01

    for major substandard care. Hospital based maternal deaths between 2006 and 2008 (35 months) were included. Of 68 registered maternal deaths sufficient information for reviewing was retrieved for 62 cases (91%). As a supplement, in-depth interviews with staff about the underlying causes of substandard care...... in 46 (74%) of the 62 cases reviewed. During the same time period MDA identified substandard care in 18 cases. Staff perceived poor organization of work and lack of training as important causes for substandard care. Local MDA was considered useful although time-consuming and sometimes threatening......, and staff dedication to the process was questioned. CONCLUSION: Quality assurance of emergency obstetric care might be strengthened by supplementing internal MDA with external CE....

  6. Antimalarial Activity of Azadipeptide Nitriles

    OpenAIRE

    Löser, Reik; Gut, Jiri; Rosenthal, Philip J.; Frizler, Maxim; Gütschow, Michael; Andrews, Katherine T.

    2009-01-01

    Azadipeptide nitriles – novel cysteine protease inhibitors – display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s haemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of...

  7. Antimalarial Activity of Plant Metabolites.

    Science.gov (United States)

    Pan, Wen-Hui; Xu, Xin-Ya; Shi, Ni; Tsang, Siu Wai; Zhang, Hong-Jie

    2018-05-06

    Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum . As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

  8. Antimalarial Activity of Plant Metabolites

    Directory of Open Access Journals (Sweden)

    Wen-Hui Pan

    2018-05-01

    Full Text Available Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002 reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

  9. Antimalarial drug induced decrease in creatinine clearance

    NARCIS (Netherlands)

    Landewé, R. B.; Vergouwen, M. S.; Goeei The, S. G.; van Rijthoven, A. W.; Breedveld, F. C.; Dijkmans, B. A.

    1995-01-01

    To confirm the antimalarial drug induced increase of creatinine to determine the factors contributing to this effect. Patients with rheumatoid arthritis (RA) (n = 118) who have used or still use antimalarials (chloroquine or hydroxychloroquine). Serum creatinines prior to antimalarials and serum

  10. Pyrimidines in antimalarial drug design

    CSIR Research Space (South Africa)

    Moleele, SS

    2008-09-01

    Full Text Available of the routes attempted are shown in Scheme 1. Pyrimidines In Antimalarial Drug Design S S Moleele1, D Gravestock1, A L Rousseau1, R L Van Zyl2 1Discovery Chemistry, CSIR, Biosciences, Private Bag X2, Modderfontein, 1645, South Africa; SMoleele@csir.co.za 2...

  11. Substandard care in maternal mortality due to hypertensive disease in pregnancy in the Netherlands

    NARCIS (Netherlands)

    Schutte, J. M.; Schuitemaker, N. W. E.; van Roosmalen, J.; Steegers, E. A. P.

    Objective To review the standard of care in cases of maternal mortality due to hypertensive diseases in pregnancy and to make recommendations for its improvement. Design Care given to women with hypertensive disease in pregnancy was audited and substandard care factors identified. Setting

  12. Antimalarial drugs in pregnancy: a review

    NARCIS (Netherlands)

    Nosten, François; McGready, Rose; d'Alessandro, Umberto; Bonell, Ana; Verhoeff, Francine; Menendez, Clara; Mutabingwa, Thenonest; Brabin, Bernard

    2006-01-01

    In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine,

  13. Some Pharmacological Aspects of Antimalarial Drugs

    African Journals Online (AJOL)

    1974-06-15

    Jun 15, 1974 ... Some Pharmacological Aspects of Antimalarial. Drugs. D.BOTHA. SUMMARY. A short review is given of antimalarial drugs currently in use. S. Air. Med. l., 48, 1263 (1974). CLASSIFICATION. The chemotherapy of malaria may be conveniently classi- fied as (i) casual prophylaxis; (ii) suppressive treatment;.

  14. Antimalarial natural products: a review

    Directory of Open Access Journals (Sweden)

    Faraz Mojab

    2012-03-01

    Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

  15. Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector--Results from a Nationally Representative Outlet Survey.

    Science.gov (United States)

    Act Consortium Drug Quality Project Team And The Impact Study Team

    2015-06-01

    Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. © The American Society of Tropical Medicine and Hygiene.

  16. Substandard, Spurious, Falsely-Labelled, Falsified and Counterfeit (SSFFC Drugs: Time to Take a Bitter Pill

    Directory of Open Access Journals (Sweden)

    Geetha Mani

    2016-10-01

    Full Text Available Substandard, Spurious, Falsely-Labelled, Falsified and Counterfeit (SSFFC drugs are an emerging public health concern in India. With one of the huge pharmaceutical sectors in the world, India has a varied prevalence of SSSFC drugs ranging from 0.04% to 34% according to various studies. Apart from severe health consequences, SSSFC drugs also weaken community's trust in the health care system. India is tackling the epidemic of SSSFC drugs through various existing and new regulatory measures. Considering the calamitous consequences of this silent epidemic, it is time to prescribe a bitter pill.

  17. Interactions of DB75, a Novel Antimalarial Agent, with Other Antimalarial Drugs In Vitro▿

    OpenAIRE

    Purfield, Anne E.; Tidwell, Richard R.; Meshnick, Steven R.

    2008-01-01

    Pafuramidine is a novel orally active antimalarial. To identify a combination partner, we measured the in vitro antimalarial activities of the active metabolite, DB75, with amodiaquine, artemisinin, atovaquone, azithromycin, chloroquine, clindamycin, mefloquine, piperaquine, pyronaridine, tafenoquine, and tetracycline. None of the drugs tested demonstrated antagonistic or synergistic activity in combination with pafuramidine.

  18. Clinical implications for substandard, nonproprietary medicines in multiple sclerosis: focus on fingolimod

    Science.gov (United States)

    Correale, Jorge; Chiquete, Erwin; Boyko, Alexey; Beran, Roy G; Strauch, Jorge Barahona; Milojevic, Snezana; Frider, Nadina

    2016-01-01

    Both proprietary and nonproprietary medicines are expected to undergo rigorous preapproval testing and both should meet stringent health authority regulatory requirements related to quality to obtain approval. Nonproprietary (also known as copy, or generic) medicines, which base their authorization and use on the proprietary documentation and label, are often viewed as a means to help lower the cost and, thus, increase patient access. If these medicines fail to meet quality standards, such as good manufacturing practice and bioequivalence (in humans), they are then defined as substandard copies and can pose serious risks to patients in terms of safety and efficacy. Potentially noncontrolled or different manufacturing process and excipients in nonproprietary medicines may result in poor batch-to-batch reproducibility (accurate and consistent quantity of each ingredient in each capsule/tablet) and lower quality. Substandard, nonproprietary copies of medicines that are immunomodulatory or immunosuppressive are of concern to patients due to their possible untoward safety and lack of efficacy events. This article reviews the potential risks associated with nonproprietary medicines that do not meet the regulatory requirements of the United States Food and Drug Administration, the European Medicines Agency, or the World Health Organization. The clinical implications for patients are described. This article focuses on nonproprietary medicines for multiple sclerosis, particularly fingolimod, that are not identical to proprietary versions and could thus fail to meet efficacy expectations or have different impact on the safety of patients with multiple sclerosis. PMID:27418809

  19. Synthesis and Evaluation of Some New Isoquine Analogues for Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Chandra Nath Saha

    2009-01-01

    Full Text Available Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI, which binds to cellular macromolecules leading to hepatotoxicity and agranulocytosis. Interchange of the 3ʼ hydroxyl and the 4ʼ Mannich side-chain function of amodiaquine provides an amodiaquine regioisomer (isoquine that cannot form toxic quinoneimine metabolites. By a simple two-step procedure, four isoquine analogues were synthesized and subsequently evaluated against the chloroquine sensitive RKL-2 strain of Plasmodium falciparum in vitro. All synthesized analogues demonstrated differential level of antimalarial activity against the test strain. However, no compound was found to exhibit better antimalarial property as compared to chloroquine.

  20. Clinical implications for substandard, nonproprietary medicines in multiple sclerosis: focus on fingolimod

    Directory of Open Access Journals (Sweden)

    Correale J

    2016-06-01

    Full Text Available Jorge Correale,1 Erwin Chiquete,2 Alexey Boyko,3 Roy G Beran,4–6 Jorge Barahona Strauch,7,8 Snezana Milojevic,9 Nadina Frider101Department of Neurology, Raúl Carrea Institute for Neurological Research, Foundation for the Fight against Infant Neurological Illnesses (FLENI, Buenos Aires, Argentina; 2Department of Neurology and Psychiatry, Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City, Mexico; 3Clinical and Research Center “MS and Other Demyelinating Diseases” at the Neuroclinical Hospital, Department of Neurology, Neurosurgery and Medical Genetics of the Pirogov Russian National Research Medical University, Moscow, Russia; 4South Western Clinical School, University of New South Wales, Liverpool, 5Department of Neurology, Liverpool Hospital, Sydney, NSW, 6School of Medicine, Griffith University, Southport, QLD, Australia; 7Department of Neurology, Clínica Alemana de Santiago, 8School of Medicine, Universidad del Desarrollo, Santiago, Chile; 9Novartis Pharma AG, Basel, Switzerland; 10Novartis Latin America and Canada Region, Buenos Aires, ArgentinaAbstract: Both proprietary and nonproprietary medicines are expected to undergo rigorous preapproval testing and both should meet stringent health authority regulatory requirements related to quality to obtain approval. Nonproprietary (also known as copy, or generic medicines, which base their authorization and use on the proprietary documentation and label, are often viewed as a means to help lower the cost and, thus, increase patient access. If these medicines fail to meet quality standards, such as good manufacturing practice and bioequivalence (in humans, they are then defined as substandard copies and can pose serious risks to patients in terms of safety and efficacy. Potentially noncontrolled or different manufacturing process and excipients in nonproprietary medicines may result in poor batch-to-batch reproducibility (accurate and consistent quantity of

  1. Synergistic In Vitro Antimalarial Activity of Omeprazole and Quinine

    OpenAIRE

    Skinner-Adams, T.; Davis, T. M. E.

    1999-01-01

    Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.

  2. Anticancer Effect of AntiMalarial Artemisinin Compounds | Das ...

    African Journals Online (AJOL)

    A PubMed search of about 127 papers on anti‑cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. ... Keywords: Anticancer agents, Antimalarials, Antitumor activity, Artemisinins, Novel chemotherapy ...

  3. Local health workers’ perceptions of substandard care in the management of obstetric hemorrhage in rural Malawi

    Directory of Open Access Journals (Sweden)

    Beltman Jogchum Jan

    2013-02-01

    Full Text Available Abstract Background To identify factors contributing to the high incidence of facility-based obstetric hemorrhage in Thyolo District, Malawi, according to local health workers. Methods Three focus group discussions among 29 health workers, including nurse-midwives and non-physician clinicians (‘medical assistants’ and ‘clinical officers’. Results Factors contributing to facility-based obstetric hemorrhage mentioned by participants were categorized into four major areas: (1 limited availability of basic supplies, (2 lack of human resources, (3 inadequate clinical skills of available health workers and (4 substandard referrals by traditional birth attendants and lack of timely self-referrals of patients. Conclusion Health workers in this district mentioned important community, system and provider related factors that need to be addressed in order to reduce the impact of obstetric hemorrhage.

  4. Giardia duodenalis infection: risk factors for children living in sub-standard settlements in Brazil

    Directory of Open Access Journals (Sweden)

    Júlio César Teixeira

    2007-06-01

    Full Text Available The objective of the present study was to characterize Giardia duodenalis infection among children living in sub-standard settlement areas in the municipality of Juiz de Fora, Minas Gerais State, Brazil. The cross-sectional epidemiological study included 590 children from 1 to 5 years of age. Data were collected from one child per selected family through home interviews with the parent or guardian and parasitological examination of stool samples. Thirty-one putative risk factors concerning family structure, socioeconomic status, and environmental factors were analyzed by multivariate logistic regression. Prevalence of G. duodenalis infection was 18% (106 children. Four potential risk factors were heavily associated with G. duodenalis infection: number of under-five children in the same household, index child's birth order, existence of a bathroom in the home, and drinking water source.

  5. Antimalarial Drug: From its Development to Deface.

    Science.gov (United States)

    Barik, Tapan Kumar

    2015-01-01

    Wiping out malaria is now the global concern as about three billion people are at risk of malaria infection globally. Despite of extensive research in the field of vaccine development for malaria, till now, no effective vaccine is available for use and hence only antimalarial drugs remain our best hope for both treatment and prevention of malaria. However, emergence and spread of drug resistance has been a major obstacle for the success of malaria elimination globally. This review will summarize the information related to antimalarial drugs, drug development strategies, drug delivery through nanoparticles, few current issues like adverse side effects of most antimalarial drugs, non availability of drugs in the market and use of fake/poor quality drugs that are hurdles to malaria control. As we don't have any other option in the present scenario, we have to take care of the existing tools and make them available to almost all malaria affected area.

  6. Acetone-butanol-ethanol production from substandard and surplus dates by Egyptian native Clostridium strains.

    Science.gov (United States)

    Abd-Alla, Mohamed Hemida; Zohri, Abdel-Naser Ahmed; El-Enany, Abdel-Wahab Elsadek; Ali, Shimaa Mohamed

    2015-04-01

    One hundred and seven mesophilic isolates of Clostridium were isolated from agricultural soils cultivated with different plants in Assuit Governorate, Egypt. Eighty isolates (out of 107) showed the ability to produce ABE (Acetone, butanol and ethanol) on T6 medium ranging from 0.036 to 31.89 g/L. The highest numbers of ABE producing isolates were obtained from soil samples of potato contributing 27 isolates, followed by 18 isolates from wheat and 10 isolates from onion. On the other hand, there were three native isolates that produced ABE more than those produced by the reference isolate Clostridium acetobutylicum ATCC 824 (11.543 g/L). The three isolates were identified based on phenotypic and gene encoding 16S rRNA as Clostridium beijerinckii ASU10 (KF372577), Clostridium chauvoei ASU55 (KF372580) and Clostridium roseum ASU58 (KF372581). The highest ABE level from substandard and surplus dates was produced by C. beijerinckii ASU10 (24.07 g/L) comprising butanol 67.15% (16.16 g/L), acetone 30.73% (7.4 g/L) and ethanol 2.12% (0.51 g/L), while C. roseum ASU58 and C. chauvoei ASU55 produced ABE contributing 20.20 and 13.79 g/L, respectively. ABE production by C. acetobutylicum ATCC 824 was 15.01 g/L. This study proved that the native strains C. beijerinckii ASU10 and C. roseum ASU58 have high competitive efficacy on ABE production from economical substrate as substandard and surplus date fruits. Additionally, using this substrate without any nutritional components is considered to be a commercial substrate for desired ABE production. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Stating Values through Denial of Substance: Implementation of One Cognitive Mechanism in the Russian Substandard

    Directory of Open Access Journals (Sweden)

    Tatiana V. Ukhanova

    2017-11-01

    Full Text Available The article is devoted to the study of objectification in the substandard forms of Russian language concerning the conceptual norm of possession, which represents the axiological aspect of the world picture by sociolect holders. The relevance of the work is determined by the belonging of the indicated problem to the field of the interest intersection from the theory of nomination, cognitive linguistics and social linguistics, and at the same time, by an insufficient knowledge of the implementation means in the mechanism language of value marking concerning socially separate groups of Russian mentality bearers. In Russian language, the cognitive mechanism of value assertion through the negation of a substance is realized through the word-formation category "an attribute for the lack of substance", which belongs to the number of productive nominative categories. Our task was a complex structural and functional description of sub-standard derivatives of this category with the aim to their further comprehension from onomasiologic and cognitive positions. This conditioned the use of word-formation and component analysis methods. Basing on the works by E.S. Kubryakova and N.D. Arutunova, we determined the essence of the Russian mental norm of possession. The model of field organization proposed by us concerning the mental norm of possession made it possible to draw the conclusion about the complexity of the value basis organization concerning the Russian national worldview, determining the role in which the spiritual and moral guidelines play an important role, and the material values located on the periphery are less significant. The results of the research can be applied in the field of linguistic didactics, especially in the practice of teaching Russian as a foreign language, as well as in the organization of associative and social linguistic experiments.

  8. Understanding heterogeneity in metropolitan India: the added value of remote sensing data for analyzing sub-standard residential areas

    NARCIS (Netherlands)

    Baud, I.; Kuffer, M.; Pfeffer, K.; Sliuzas, R.; Karuppannan, S.

    2010-01-01

    Analyzing the heterogeneity in metropolitan areas of India utilizing remote sensing data can help to identify more precise patterns of sub-standard residential areas. Earlier work analyzing inequalities in Indian cities employed a constructed index of multiple deprivations (IMDs) utilizing data from

  9. A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides.

    Science.gov (United States)

    Bachi, Mario D; Korshin, Edward E; Hoos, Roland; Szpilman, Alex M; Ploypradith, Poonsakdi; Xie, Suji; Shapiro, Theresa A; Posner, Gary H

    2003-06-05

    The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of beta-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

  10. Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies.

    Science.gov (United States)

    Ashok, Penta; Ganguly, Swastika; Murugesan, Sankaranarayanan

    2014-11-01

    The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of β-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and -resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity.

    Science.gov (United States)

    Giannangelo, Carlo; Stingelin, Lukas; Yang, Tuo; Tilley, Leann; Charman, Susan A; Creek, Darren J

    2018-03-01

    The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (∼90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia. Copyright © 2018 American Society for Microbiology.

  12. Antimalarial Drugs for Pediatrics - Prescribing and Dispensing ...

    African Journals Online (AJOL)

    Purpose: To assess dispensing and prescribing practices with regard to antimalarial drugs for pediatrics in private pharmacies and public hospitals in Dar es Salaam, Tanzania. Methods: This was a cross-sectional, descriptive study that assessed the knowledge and practice of 200 drug dispensers in the private community ...

  13. Antimalarial sesquiterpene lactones from oncosiphon piluliferum

    CSIR Research Space (South Africa)

    Pillay, P

    2006-02-01

    Full Text Available for the treatment of malaria. Through this consortium, an indigenous plant, Oncosiphon piluliferum, was identified as a potential source of new antimalarial drugs. Bio-assay-guided fractionation based on in vitro antiplasmodial activity led to the isolation of five...

  14. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.(G.mangostana)(pericarp)in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry(LC/MS/MS).Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.(pericarp)at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control(non-exposed),while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.(pericarp).

  15. Are all prey created equal? A review and synthesis of differential predation on prey in substandard condition

    Science.gov (United States)

    Mesa, Matthew G.; Poe, Thomas P.; Gadomski, Dena M.; Petersen, James H.

    1994-01-01

    Our understanding of predator-prey interactions in fishes has been influenced largely by research assuming that the condition of the participants is normal. However, fish populations today often reside in anthropogenically altered environments and are subjected to many kinds of stressors, which may reduce their ecological performance by adversely affecting their morphology, physiology, or behaviour. One consequence is that either the predator or prey, or both, may be in a substandard condition at the time of an interaction. We reviewed the literature on predator-prey interactions in fishes where substandard prey were used as experimental groups. Although most of this research indicates that such prey are significantly more vulnerable to predation, prey condition has rarely been considered in ecological theory regarding predator-prey interactions. The causal mechanisms for increased vulnerability of substandard prey to predation include a failure to detect predators, lapses in decision-making, poor fast-start performance, inability to shoal effectively, and increased prey conspicuousness. Despite some problems associated with empirical predator-prey studies using substandard prey, their results can have theoretical and applied uses, such as in ecological modelling or justification of corrective measures to be implemented in the wild. There is a need for more corroborative field experimentation, a better understanding of the causal mechanisms behind differential predation, and increased incorporation of prey condition into the research of predator-prey modellers and theoreticians. If the concept of prey condition is considered in predator-prey interactions, our understanding of how such interactions influence the structure and dynamics of fish communities is likely to change, which should prove beneficial to aquatic ecosystems.

  16. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

    Directory of Open Access Journals (Sweden)

    Birgit Viira

    2016-06-01

    Full Text Available Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  17. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

    Science.gov (United States)

    Viira, Birgit; Gendron, Thibault; Lanfranchi, Don Antoine; Cojean, Sandrine; Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre; Maes, Louis; Maran, Uko; Loiseau, Philippe M; Davioud-Charvet, Elisabeth

    2016-06-29

    Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  18. Modelling the effects of transglutaminase and L-ascorbic acid on substandard quality wheat flour by response surface methodology

    Directory of Open Access Journals (Sweden)

    Šimurina Olivera D.

    2014-01-01

    Full Text Available In recent decade, there have been observed extreme variations in climatic conditions which in combination with inadequate agro techniques lead to decreased quality of mercantile wheat, actally flour. The application of improvers can optimise the quality of substandard wheat flour. This paper focuses to systematic analysis of individual and interaction effects of ascorbic acid and transglutaminase as dough strengthening improvers. The effects were investigated using the Response Surface Methodology. Transglutaminase had much higher linear effect on the rheological and fermentative properties of dough from substandard flour than L-ascorbic acid. Both transglutaminase and L-ascorbic acid additions had a significant linear effect on the increase of bread specific volume. Effects of transglutaminase and ascorbic acid are dependent on the applied concentrations and it is necessary to determine the optimal concentration in order to achieve the maximum quality of the dough and bread. Optimal levels of tested improvers were determined using appropriate statistical techniques which applied the desirability function. It was found that the combination of 30 mg/kg of transglutaminase and 75.8 mg/kg of L-ascorbic acid achieved positive synergistic effect on rheological and fermentative wheat dough properties, as well on textural properties and specific volume of bread made from substandard quality flour.

  19. Synthetic Antimalarial Maculopathy: A Case Report

    Directory of Open Access Journals (Sweden)

    Aziz El Ouaf

    2017-04-01

    Full Text Available Antimalarial drug-induced retinopathy was first described in the 1950s. Screening for preclinical poisoning prevents evolution to irreversible maculopathy. We discuss, through the case of maculopathy with antimalarial (AM revealed by progressive bilateral decrease in vision in a patient with lupus, the modalities of monitoring patients treated with AM and the management of a potential intoxication. All authors stress the need for clinical and paraclinical ophthalmological monitoring regularly to detect early signs of impaired retinal function at a reversible stage. Indeed, at a more severe retinal intoxication, impaired visual function remains irreversible and can lead to blindness. A full ophthalmologic assessment is necessary before starting long course treatment with AM, possibly coupled with additional tests (central visual field, colour vision and/or electrophysiological examinations.

  20. Abstract 20854: A Tale of Self-Fulfilling Prophecies in Out-of-Hospital Cardiac Arrest: Emergency Medical Technicians Deliberately Perform Substandard CPR When Anticipating Poor Prognosis

    DEFF Research Database (Denmark)

    Bødtker, Henrik; Klausen, Troels M; Lauridsen, Kasper G

    2017-01-01

    ) if they believe resuscitation to be futile. Furthermore, to investigate if different patient and resuscitation attempt characteristics result in EMTs deliberately performing substandard CPR.Methods: This was a cross-sectional questionnaire survey study conducted in 2016 through 2017 including EMTs from a Danish...... and compressions). Overall, 22% and 51% would perform substandard CPR if the patient were 80 or 90 years old respectively, 46% if the patient was living in a nursing home and up to 31% due to comorbidity such as cancer. EMTs (51%) would deliberately perform substandard CPR in case of on-going bystander CPR >20...... minutes. EMTs (72%) felt competent to terminate resuscitation, but only 9% knew international termination guidelines.Conclusion: EMTs delay start of resuscitation if they anticipate resuscitation to be futile. Furthermore, they deliberately perform substandard CPR based on controversial patient...

  1. Lead optimization of antimalarial propafenone analogues.

    Science.gov (United States)

    Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

    2012-07-12

    Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

  2. Short synthesis and antimalarial activity of fagaronine

    OpenAIRE

    Rivaud, M.; Mendoza, A.; Sauvain, Michel; Valentin, A.; Jullian, Valérie

    2012-01-01

    Herein, we report a new synthesis of fagaronine 1, inspired by the synthesis reported by Luo for nornitidine. The in vitro biological activity of fagaronine against malaria on several chloroquine-sensitive and resistant Plasmodium falciparum strains was confirmed, and the selectivity index compared to mammalian cells was calculated. Fagaronine was found to have very good antimalarial activity in vivo, comparable to the activity of the reference compound chloroquine. Therefore, fagaronine appe...

  3. Naturally occurring cobalamins have antimalarial activity.

    Science.gov (United States)

    Chemaly, Susan M; Chen, Chien-Teng; van Zyl, Robyn L

    2007-05-01

    The acquisition of resistance by malaria parasites towards existing antimalarials has necessitated the development of new chemotherapeutic agents. The effect of vitamin B(12) derivatives on the formation of beta-haematin (synthetic haemozoin) was determined under conditions similar to those in the parasitic food vacuole (using chloroquine, a known inhibitor of haemozoin formation for comparison). Adenosylcobalamin (Ado-cbl), methylcobalamin (CH(3)-cbl) and aquocobalamin (H(2)O-cbl) were approximately forty times more effective inhibitors of beta-haematin formation than chloroquine, cyanocobalamin (CN-cbl) was slightly more inhibitory than chloroquine, while dicyanocobinamide had no effect. It is proposed that the cobalamins exert their inhibitory effect on beta-haematin formation by pi-interactions of their corrin ring with the Fe(III)-protoporphyrin ring and by hydrogen-bonding using their 5,6-dimethylbenzimidazole/ribose/sugar side-chain. The antimalarial activity for the cobalamins (Ado-cbl>CH(3)-cbl>H(2)O-cbl>CN-cbl) was found to be less than that for chloroquine or quinine. Ado-cbl, CH(3)-cbl and CN-cbl do not accumulate in the parasite food vacuole by pH trapping, but H(2)O-cbl does. Unlike humans, the malaria parasite has only one enzyme that uses cobalamin as a cofactor, namely methionine synthase, which is important for growth and metabolism. Thus cobalamins in very small amounts are necessary for Plasmodium falciparum growth but in larger amounts they display antimalarial properties.

  4. Aspidosperma species as sources of antimalarials. Part III. A review of traditional use and antimalarial activity.

    Science.gov (United States)

    de Paula, Renata Cristina; Dolabela, Maria Fâni; de Oliveira, Alaíde Braga

    2014-03-01

    Several plant species belonging to the genus Aspidosperma are traditionally used in Brazil and other Meso- and South American countries for the treatment of malaria and fevers. These traditional uses were motivation for this review. A literature survey completed for this review has identified scientific bibliographical references to the use of 24 Aspidosperma species to treat malaria/fevers and to 19 species that have had their extracts and/or alkaloids evaluated, with good results, for in vitro and/or in vivo antimalarial activity. Indole alkaloids are typical constituents of Aspidosperma species. However, only 20 out of more than 200 known indole alkaloids isolated from this genus have been assayed for antimalarial activity. These data support the potential of Aspidosperma species as sources of antimalarials and the importance of research aimed at validating their use in the treatment of human malaria. Georg Thieme Verlag KG Stuttgart · New York.

  5. Antiplasmodial and antimalarial activities of quinolone derivatives: An overview.

    Science.gov (United States)

    Fan, Yi-Lei; Cheng, Xiang-Wei; Wu, Jian-Bing; Liu, Min; Zhang, Feng-Zhi; Xu, Zhi; Feng, Lian-Shun

    2018-02-25

    Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. 'It's good enough': Swedish general dental practitioners on reasons for accepting substandard root filling quality.

    Science.gov (United States)

    Dahlström, L; Lindwall, O; Rystedt, H; Reit, C

    2018-04-01

    The concept of 'good enough' is central and necessary in the assessment of root filling quality. The aim was to explore the concept by analysing reasons and arguments for the acceptance or rejection of substandard root filling quality as reported by general dental practitioners (GDPs) in Sweden. The study was designed as a qualitative and exploratory study based on seven videotaped focus group interviews analysed by means of qualitative content analysis. Thirty-three GDPs employed in the Public Dental Health Service in Gothenburg, Sweden, participated (4-6 GDPs/interview). In all, nine predetermined questions were followed. Before each focus group, the participants received radiographs of 37 root fillings and were asked to assess the root filling quality. The three cases representing the most divergent assessments served as a basis for the discussion. The cases were presented without clinical information; the dentists would relate to the cases as being just root filled by themselves. The radiographs did not provide a sufficient basis for decisions on whether or not to accept the root filling. This study emphasized that dentists did not primarily look for these arguments in the technical details of the root filling per se, but instead, they considered selected features of the contextual situation. The GDPs constantly introduced relevant 'ad hoc considerations' to account for the decisions they made. These contextual considerations were related to aspects of pulpal and periapical disease, risks (e.g. technical complications) or to consumed resources (personal and/or economic). It was obvious that the concept of 'good enough' does not exist as a general formula ready to be applied in particular situations. Instead, it is necessarily and irremediably tied to contextual properties that emerge from case to case. © 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  7. Antimalarial Anthrone and Chromone from the Leaf Latex of Aloe ...

    African Journals Online (AJOL)

    In Ethiopian traditional medicine, the leaf latex of Aloe debranan Chrstian is used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the leaf latex of A. debrana was tested for its in vivo antimalarial activity, in a 4-day suppressive assay ...

  8. Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.

    OpenAIRE

    Rosenthal, P J; Olson, J E; Lee, G K; Palmer, J T; Klaus, J L; Rasnick, D

    1996-01-01

    We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or...

  9. In vivo Antimalarial Activity of Methanol and Water Extracts of ...

    African Journals Online (AJOL)

    Conclusions: The possible active compounds responsible for the observed chemosupression may be flavonoids, terpeneoids and anthraquinones which are present in the extract. This is the first report on the in vivo antimalarial activity of E. thorifolium. Keywords: Antimalarial, Eryngium thorifolium, Plasmodium berghei, ...

  10. Terahertz absorption spectra of commonly used antimalarial drugs

    Science.gov (United States)

    Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

    2018-03-01

    Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

  11. Terahertz absorption spectra of commonly used antimalarial drugs

    Science.gov (United States)

    Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

    2018-06-01

    Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

  12. QSAR modeling and chemical space analysis of antimalarial compounds

    Science.gov (United States)

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-05-01

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  13. The Antimalarial Effect of Curcumin Is Mediated by the Inhibition of Glycogen Synthase Kinase-3β.

    Science.gov (United States)

    Ali, Amatul Hamizah; Sudi, Suhaini; Basir, Rusliza; Embi, Noor; Sidek, Hasidah Mohd

    2017-02-01

    Curcumin, a bioactive compound in Curcuma longa, exhibits various pharmacological activities, including antimalarial effects. In silico docking simulation studies suggest that curcumin possesses glycogen synthase kinase-3β (GSK3β)-inhibitory properties. The involvement of GSK3 in the antimalarial effects in vivo is yet to be demonstrated. In this study, we aimed to evaluate whether the antimalarial effects of curcumin involve phosphorylation of host GSK3β. Intraperitoneal administration of curcumin into Plasmodium berghei NK65-infected mice resulted in dose-dependent chemosuppression of parasitemia development. At the highest dose tested (30 mg/kg body weight), both therapeutic and prophylactic administrations of curcumin resulted in suppression exceeding 50% and improved median survival time of infected mice compared to control. Western analysis revealed a 5.5-fold (therapeutic group) and 1.8-fold (prophylactic group) increase in phosphorylation of Ser 9 GSK3β and 1.6-fold (therapeutic group) and 1.7-fold (prophylactic group) increase in Ser 473 Akt in liver of curcumin-treated infected animals. Following P. berghei infection, levels of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, and IL-4 were elevated by 7.5-, 35.0-, 33.0-, and 2.2-fold, respectively. Curcumin treatment (therapeutic) caused a significant decrease (by 6.0- and 2.0-fold, respectively) in serum TNF-α and IFN-γ level, while IL-10 and IL-4 were elevated (by 1.4- and 1.8-fold). Findings from the present study demonstrate for the first time that the antimalarial action of curcumin involved inhibition of GSK3β.

  14. Anticancer properties of distinct antimalarial drug classes.

    Directory of Open Access Journals (Sweden)

    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  15. Antimalarial properties of imipramine and amitriptyline

    International Nuclear Information System (INIS)

    Dutta, P.; Siegel, L.; Pinto, J.; Meshnick, S.

    1986-01-01

    This laboratory has previously demonstrated that imipramine (IM) and amitriptyline (AM), inhibit the conversion of riboflavin to its coenzymic derivatives. Several other laboratories have shown that dietary riboflavin deficiency is protective against malarial infection. In the present investigation, the authors determined whether IM and AM exert antimalarial effects similar to that of riboflavin deficiency, as they have hypothesized. In addition, they evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of P. falciparum (FCR3) in the absence or presence of these drugs (80 μM) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring ( 3 H)hypoxanthine uptake. With no drug, parasitemia was 20.3 +/- 5.3%, whereas in the presence of IM and AM, parasitemia was reduced to 7.3 +/- 0.8% and 13.6 +/- 2.8%, respectively. The uptake of ( 3 H)hypoxanthine was reduced to 47 +/- 3.6% and 54 +/- 2.9% of control by IM and AM, respectively. Assays of hemolysis were conducted by incubating 0.5% RBC suspension in NaCl-Tris buffer for 3 h at 37 0 C with variable concentrations of drugs and/or FP (1-7 μM). Both drugs at 10 to 100 μM significantly enhanced hemolysis induced by FP. No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, IM and AM, possess substantial antimalarial properties, thereby supporting the hypothesis that drugs which interfere with riboflavin metabolism should also provide protection against malaria

  16. Anticancer Properties of Distinct Antimalarial Drug Classes

    Science.gov (United States)

    Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

    2013-01-01

    We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

  17. Antimalarial Activity of Ultra-Short Peptides

    Directory of Open Access Journals (Sweden)

    María Yolanda Rios

    2009-12-01

    Full Text Available Ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. On the basis of the IC50 data for these compounds, the effects of nature, polarity, and amino acid sequence on Plasmodium berghei schizont cultures were analyzed too. Tetrapeptides Phe-Orn-Phe-Orn (4 and Lys-Phe-Phe-Orn (5 showed a very important activity with IC50 values of 3.31 and 2.57 μM, respectively. These two tetrapeptides are candidates for subsequent in vivo assays and SARS investigations.

  18. Understanding heterogeneity in metropolitan India: The added value of remote sensing data for analyzing sub-standard residential areas

    Science.gov (United States)

    Baud, Isa; Kuffer, Monika; Pfeffer, Karin; Sliuzas, Richard; Karuppannan, Sadasivam

    2010-10-01

    Analyzing the heterogeneity in metropolitan areas of India utilizing remote sensing data can help to identify more precise patterns of sub-standard residential areas. Earlier work analyzing inequalities in Indian cities employed a constructed index of multiple deprivations (IMDs) utilizing data from the Census of India 2001 ( http://censusindia.gov.in). While that index, described in an earlier paper, provided a first approach to identify heterogeneity at the citywide scale, it neither provided information on spatial variations within the geographical boundaries of the Census database, nor about physical characteristics, such as green spaces and the variation in housing density and quality. In this article, we analyze whether different types of sub-standard residential areas can be identified through remote sensing data, combined, where relevant, with ground-truthing and local knowledge. The specific questions address: (1) the extent to which types of residential sub-standard areas can be drawn from remote sensing data, based on patterns of green space, structure of layout, density of built-up areas, size of buildings and other site characteristics; (2) the spatial diversity of these residential types for selected electoral wards; and (3) the correlation between different types of sub-standard residential areas and the results of the index of multiple deprivations utilized at electoral ward level found previously. The results of a limited number of test wards in Delhi showed that it was possible to extract different residential types matching existing settlement categories using the physical indicators structure of layout, built-up density, building size and other site characteristics. However, the indicator 'amount of green spaces' was not useful to identify informal areas. The analysis of heterogeneity showed that wards with higher IMD scores displayed more or less the full range of residential types, implying that visual image interpretation is able to zoom in

  19. New concepts in antimalarial use and mode of action in dermatology.

    Science.gov (United States)

    Kalia, Sunil; Dutz, Jan P

    2007-01-01

    Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed.

  20. Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives

    Directory of Open Access Journals (Sweden)

    Laure-Estelle Cassagnes

    2017-01-01

    Full Text Available Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2, known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.

  1. Synthesis of febrifugine derivatives and development of an effective and safe tetrahydroquinazoline-type antimalarial.

    Science.gov (United States)

    Kikuchi, Haruhisa; Horoiwa, Seiko; Kasahara, Ryota; Hariguchi, Norimitsu; Matsumoto, Makoto; Oshima, Yoshiteru

    2014-04-09

    Febrifugine, a quinazoline alkaloid isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. Although the use of ferifugine as an antimalarial drug has been precluded because of its severe side effects, its potent antimalarial activity has stimulated medicinal chemists to pursue its derivatives instead, which may provide valuable leads for novel antimalarial drugs. In the present study, we synthesized new derivatives of febrifugine and evaluated their in vitro and in vivo antimalarial activities to develop antimalarials that are more effective and safer. As a result, we proposed tetrahydroquinazoline-type derivative as a safe and effective antimalarial candidate. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. Chitosan-based nanocarriers for antimalarials

    Science.gov (United States)

    Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Bende, A.; Borodi, Gh.; Bratu, I.

    2012-02-01

    The objective of this research was to synthesize and characterize chitosan-based liquid and solid materials with unique absorptive and mechanical properties as carriers for quinine - one of the most used antimalarial drug. The use of chitosan (CTS) as base in polyelectrolyte complex systems, to prepare solid release systems as sponges is presented. The preparation by double emulsification of CTS hydrogels carrying quinine as anti-malarial drug is reported. The concentration of quinine in the CTS hydrogel was 0.08 mmol. Chitosan - drug loaded hydrogel was used to generate solid sponges by freeze-drying at -610°C and 0.09 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), spectrofluorimetry, differential scanning calorimetry (DSC) and X-ray diffractometry. The results indicated that the drug molecule is forming temporary chelates in CTS hydrogels and sponges. Electron paramagnetic resonance (EPR) demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan - drug supramolecular cross-linked assemblies.

  3. Antimalarial activity of the terpene nerolidol.

    Science.gov (United States)

    Saito, Alexandre Y; Marin Rodriguez, Adriana A; Menchaca Vega, Danielle S; Sussmann, Rodrigo A C; Kimura, Emília A; Katzin, Alejandro M

    2016-12-01

    Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent. In this study, the antimalarial activity of nerolidol was investigated in a mouse model of malaria. Mice were infected with Plasmodium berghei ANKA and were treated with 1000 mg/kg/dose nerolidol in two doses delivered by the oral or inhalation route. In mice treated with nerolidol, parasitaemia was inhibited by >99% (oral) and >80% (inhalation) until 14 days after infection (P  0.05). The toxicity of nerolidol administered by either route was not significant, whilst genotoxicity was observed only at the highest dose tested. These results indicate that combined use of nerolidol and other drugs targeting different points of the same isoprenoid pathway may be an effective treatment for malaria. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  4. Malaria and antimalarial plants in Roraima, Brazil.

    Science.gov (United States)

    Milliken, W

    1997-01-01

    One of the numerous problems created by the gold rush which took place in northern Brazil (Roraima State) at the end of the 1980s was a severe epidemic of malaria amongst the indigenous peoples of the region. Worst hit were the Yanomami Indians, who had lived in almost total isolation prior to this event. The problem has been exacerbated by the development of chloroquine-resistant strains of Plasmodium falciparum. In an effort to identify viable alternatives to dependence on western medicine for malaria treatment, a survey was carried out on the local plant species (wild and cultivated) used for this purpose in Roraima. Fieldwork was carried out amongst seven indigenous peoples, as well as with the non-indigenous settlers. Over 90 species were collected, many of which have been cited as used for treatment of malaria and fevers elsewhere. Knowledge of antimalarial plants was found to vary greatly between the communities, and in some cases there was evidence of recent experimentation. Initial screening of plant extracts has shown a high incidence of significant antimalarial activity amongst the species collected.

  5. Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin.

    Science.gov (United States)

    Park, Gab-Man; Park, Hyun; Oh, Sangtae; Lee, Seokjoon

    2017-12-01

    We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.

  6. Synthesis and antimalarial evaluation of novel isocryptolepine derivatives.

    Science.gov (United States)

    Whittell, Louise R; Batty, Kevin T; Wong, Rina P M; Bolitho, Erin M; Fox, Simon A; Davis, Timothy M E; Murray, Paul E

    2011-12-15

    A series of mono- and di-substituted analogues of isocryptolepine have been synthesized and evaluated for in vitro antimalarial activity against chloroquine sensitive (3D7) and resistant (W2mef) Plasmodium falciparum and for cytotoxicity (3T3 cells). Di-halogenated compounds were the most potent derivatives and 8-bromo-2-chloroisocryptolepine displayed the highest selectivity index (106; the ratio of cytotoxicity (IC(50)=9005 nM) to antimalarial activity (IC(50)=85 nM)). Our evaluation of novel isocryptolepine compounds has demonstrated that di-halogenated derivatives are promising antimalarial lead compounds. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.

    Science.gov (United States)

    Tanaka, Takeshi Q; Guiguemde, W Armand; Barnett, David S; Maron, Maxim I; Min, Jaeki; Connelly, Michele C; Suryadevara, Praveen Kumar; Guy, R Kiplin; Williamson, Kim C

    2015-03-01

    Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity.

    Science.gov (United States)

    Vanaerschot, Manu; Lucantoni, Leonardo; Li, Tao; Combrinck, Jill M; Ruecker, Andrea; Kumar, T R Santha; Rubiano, Kelly; Ferreira, Pedro E; Siciliano, Giulia; Gulati, Sonia; Henrich, Philipp P; Ng, Caroline L; Murithi, James M; Corey, Victoria C; Duffy, Sandra; Lieberman, Ori J; Veiga, M Isabel; Sinden, Robert E; Alano, Pietro; Delves, Michael J; Lee Sim, Kim; Winzeler, Elizabeth A; Egan, Timothy J; Hoffman, Stephen L; Avery, Vicky M; Fidock, David A

    2017-10-01

    Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

  9. Hexahydroquinolines are Antimalarial Candidates with Potent Blood Stage and Transmission-Blocking Activity

    Science.gov (United States)

    Vanaerschot, Manu; Lucantoni, Leonardo; Li, Tao; Combrinck, Jill M.; Ruecker, Andrea; Kumar, T.R. Santha; Rubiano, Kelly; Ferreira, Pedro E.; Siciliano, Giulia; Gulati, Sonia; Henrich, Philipp P.; Ng, Caroline L.; Murithi, James M.; Corey, Victoria C.; Duffy, Sandra; Lieberman, Ori J.; Veiga, M. Isabel; Sinden, Robert E.; Alano, Pietro; Delves, Michael J.; Sim, Kim Lee; Winzeler, Elizabeth A.; Egan, Timothy J.; Hoffman, Stephen L.; Avery, Vicky M.; Fidock, David A.

    2017-01-01

    Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress P. berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR/Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 as a determinant of parasite resistance to HHQs. Hemoglobin and heme fractionation assays suggest a mode of action that results in reduced hemozoin levels and might involve inhibition of host hemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs including lumefantrine, confirming that HHQs have a different mode of action than other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria. PMID:28808258

  10. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

    Science.gov (United States)

    Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  11. How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Katia Bruxvoort

    Full Text Available BACKGROUND: High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic. OBJECTIVE: We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment. RESULTS: The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90-100% and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained. CONCLUSION: Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report.

  12. How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs.

    Science.gov (United States)

    Bruxvoort, Katia; Goodman, Catherine; Kachur, S Patrick; Schellenberg, David

    2014-01-01

    High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs) in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic. We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment. The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90-100%) and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained. Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report.

  13. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.

    Science.gov (United States)

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa; Gamarro, Francisco; Pérez-Victoria, José M

    2015-10-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. Evolutionary ARMS Race: Antimalarial Resistance Molecular Surveillance.

    Science.gov (United States)

    Prosser, Christiane; Meyer, Wieland; Ellis, John; Lee, Rogan

    2018-04-01

    Molecular surveillance of antimalarial drug resistance markers has become an important part of resistance detection and containment. In the current climate of multidrug resistance, including resistance to the global front-line drug artemisinin, there is a consensus to upscale molecular surveillance. The most salient limitation to current surveillance efforts is that skill and infrastructure requirements preclude many regions. This includes sub-Saharan Africa, where Plasmodium falciparum is responsible for most of the global malaria disease burden. New molecular and data technologies have emerged with an emphasis on accessibility. These may allow surveillance to be conducted in broad settings where it is most needed, including at the primary healthcare level in endemic countries, and extending to the village health worker. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. original article antimalarial use and the associated factors in rural

    African Journals Online (AJOL)

    boaz

    This study was set out to find out the pattern of antimalarial drug use in a Nigerian rural community following the aggressive price subsidy ... facilities in South-East Nigeria also showed that only .... descriptive statistics in the analysis command,.

  16. Synthesis and evaluation of antimalarial activity of curcumin derivatives

    International Nuclear Information System (INIS)

    Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla

    2014-01-01

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC 50 values ranging from 1.7 to 15.2 μg mL -1 ), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  17. Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment.

    Science.gov (United States)

    Andrews, Katherine T; Fisher, Gillian M; Sumanadasa, Subathdrage D M; Skinner-Adams, Tina; Moeker, Janina; Lopez, Marie; Poulsen, Sally-Ann

    2013-11-15

    Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Research Article Antimalarial Drugs for Pediatrics - Prescribing and ...

    African Journals Online (AJOL)

    Erah

    2011-03-23

    Mar 23, 2011 ... is a need to institute measures to ensure rational prescribing, dispensing and use of antimalarial drugs in pediatrics. ... facilities, strategies to control behaviour in the private sector are ..... changes were implemented in 2006 in.

  19. Augmentation of the Differentiation Response to Antitumor Antimalarials

    National Research Council Canada - National Science Library

    Rahim, Rayhana

    2003-01-01

    .... We have shown that the quinoline antimalarials chloroquine (CO) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-10A cells...

  20. Anticancer Effect of AntiMalarial Artemisinin Compounds

    African Journals Online (AJOL)

    Artemisinin is a naturally occurring antimalarial showing anticancer properties. ..... Artemisinins usually promote apoptosis rather than necrosis in most cases ... artemisinin-mediated inhibition of vascular endothelial growth factor C (VEGF-C).

  1. Acridine and Acridinones: Old and New Structures with Antimalarial Activity

    OpenAIRE

    Valdés, Aymé Fernández-Calienes

    2011-01-01

    Since emergence of chloroquine-resistant Plasmodium falciparum and reports of parasite resistance to alternative drugs, there has been renewed interest in the antimalarial activity of acridines and their congeners, the acridinones. This article presents literature compilation of natural acridinone alkaloids and synthetic 9-substituted acridines, acridinediones, haloalcoxyacridinones and 10-N-substituted acridinones with antimalarial activity. The review also provides an outlook to antimalaria...

  2. Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro.

    Science.gov (United States)

    Kedzierska, Ewa; Orzelska, Jolanta; Perković, Ivana; Knežević, Danijel; Fidecka, Sylwia; Kaiser, Marcel; Zorc, Branka

    2016-02-01

    New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  3. Ferroquine and its derivatives: new generation of antimalarial agents.

    Science.gov (United States)

    Wani, Waseem A; Jameel, Ehtesham; Baig, Umair; Mumtazuddin, Syed; Hun, Lee Ting

    2015-08-28

    Malaria has been teasing human populations from a long time. Presently, several classes of antimalarial drugs are available in market, but the issues of toxicity, lower efficacy and the resistance by malarial parasites have decreased their overall therapeutic indices. Thus, the search for new promising antimalarials continues, however, the battle against malaria is far from over. Ferroquine is a derivative of chloroquine with antimalarial properties. It is the most successful of the chloroquine derivatives. Not only ferroquine, but also its derivatives have shown promising potential as antimalarials of clinical interest. Presently, much research is dedicated to the development of ferroquine derivatives as safe alternatives to antimalarial chemotherapy. The present article describes the structural, chemical and biological features of ferroquine. Several classes of ferroquine derivatives including hydroxyferroquines, trioxaferroquines, chloroquine-bridged ferrocenophanes, thiosemicarbazone derivatives, ferrocene dual conjugates, 4-N-substituted derivatives, and others have been discussed. Besides, the mechanism of action of ferroquine has been discussed. A careful observation has been made into pharmacologically significant ferroquine derivatives with better or equal therapeutic effects to that of chloroquine and ferroquine. A brief discussion of the toxicities of ferroquine derivatives has been made. Finally, efforts have been made to discuss the current challenges and future perspectives of ferroquine-based antimalarial drug development. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. Plants as antimalarial agents in Sub-Saharan Africa.

    Science.gov (United States)

    Chinsembu, Kazhila C

    2015-12-01

    Although the burden of malaria is decreasing, parasite resistance to current antimalarial drugs and resistance to insecticides by vector mosquitoes threaten the prospects of malaria elimination in endemic areas. Corollary, there is a scientific departure to discover new antimalarial agents from nature. Because the two antimalarial drugs quinine and artemisinin were discovered through improved understanding of the indigenous knowledge of plants, bioprospecting Sub-Saharan Africa's enormous plant biodiversity may be a source of new and better drugs to treat malaria. This review analyses the medicinal plants used to manage malaria in Sub-Saharan Africa. Chemical compounds with antiplasmodial activity are described. In the Sub-Saharan African countries cited in this review, hundreds of plants are used as antimalarial remedies. While the number of plant species is not exhaustive, plants used in more than one country probably indicate better antimalarial efficacy and safety. The antiplasmodial data suggest an opportunity for inventing new antimalarial drugs from Sub-Saharan-African flora. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Antimalarial activity of plumbagin in vitro and in animal models.

    Science.gov (United States)

    Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

    2014-01-12

    Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.

  6. Analytical sample preparation strategies for the determination of antimalarial drugs in human whole blood, plasma and urine

    DEFF Research Database (Denmark)

    Casas, Mònica Escolà; Hansen, Martin; Krogh, Kristine A

    2014-01-01

    Abstract Antimalarial drugs commonly referred to as antimalarials , include a variety of compounds with different physicochemical properties. There is a lack of information on antimalarial distribution in the body over time after administration, eg the drug ...

  7. World Antimalarial Resistance Network (WARN IV: Clinical pharmacology

    Directory of Open Access Journals (Sweden)

    Gbotosho Grace O

    2007-09-01

    Full Text Available Abstract A World Antimalarial Resistance Network (WARN database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics. By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component

  8. Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs.

    Science.gov (United States)

    Piscianz, Elisa; Cuzzoni, Eva; Sharma, Rajan; Tesser, Alessandra; Sapra, Pooja; Tommasini, Alberto

    2017-09-11

    The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Human serum albumin binding of certain antimalarials

    Science.gov (United States)

    Marković, Olivera S.; Cvijetić, Ilija N.; Zlatović, Mario V.; Opsenica, Igor M.; Konstantinović, Jelena M.; Terzić Jovanović, Nataša V.; Šolaja, Bogdan A.; Verbić, Tatjana Ž.

    2018-03-01

    Interactions between eight in-house synthesized aminoquinolines, along with well-known chloroquine, and human serum albumin (HSA) have been studied by fluorescence spectroscopy. The synthesized aminoquinolines, despite being structurally diverse, were found to be very potent antimalarials. Fluorescence measurements indicate that three compounds having additional thiophene or benzothiophene substructure bind more strongly to HSA than other studied compounds. Competitive binding experiments indicate that these three compounds bind significantly stronger to warfarin compared to diazepam binding site. Fluorescence quenching at three temperatures (20, 25, and 37 °C) was analyzed using classical Stern-Volmer equation, and a static quenching mechanism was proposed. The enthalpy and entropy changes upon sulphur-containing compound-HSA interactions were calculated using Van't Hoff equation. Positive values of enthalpy and entropy changes indicate that non-specific, hydrophobic interactions are the main contributors to HSA-compound interaction. Molecular docking and calculated lipophilicity descriptors indicate the same, pointing out that the increased lipophilicity of sulphur-containing compounds might be a reason for their better binding to HSA. Obtained results might contribute to design of novel derivatives with improved pharmacokinetic properties and drug efficacy.

  10. Benefits of a Pharmacology Antimalarial Reference Standard and Proficiency Testing Program Provided by the Worldwide Antimalarial Resistance Network (WWARN)

    Science.gov (United States)

    Lourens, Chris; Lindegardh, Niklas; Barnes, Karen I.; Guerin, Philippe J.; Sibley, Carol H.; White, Nicholas J.

    2014-01-01

    Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modeling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures is necessary for verification of assay results. Within the Worldwide Antimalarial Resistance Network (WWARN), the goal of the quality assurance/quality control (QA/QC) program is to facilitate and sustain high-quality antimalarial assays. The QA/QC program consists of an international PT program for pharmacology laboratories and a reference material (RM) program for the provision of antimalarial drug standards, metabolites, and internal standards for laboratory use. The RM program currently distributes accurately weighed quantities of antimalarial drug standards, metabolites, and internal standards to 44 pharmacology, in vitro, and drug quality testing laboratories. The pharmacology PT program has sent samples to eight laboratories in four rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC program has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases. PMID:24777099

  11. Antimalarial drug policy in India: past, present & future.

    Science.gov (United States)

    Anvikar, Anupkumar R; Arora, Usha; Sonal, G S; Mishra, Neelima; Shahi, Bharatendu; Savargaonkar, Deepali; Kumar, Navin; Shah, Naman K; Valecha, Neena

    2014-02-01

    The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17 th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions.

  12. Antimalarial drug policy in India: Past, present & future

    Directory of Open Access Journals (Sweden)

    Anupkumar R Anvikar

    2014-01-01

    Full Text Available The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17 th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions.

  13. Quinoline hybrids and their antiplasmodial and antimalarial activities.

    Science.gov (United States)

    Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

    2017-10-20

    Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

    Directory of Open Access Journals (Sweden)

    Bate Roger

    2010-06-01

    Full Text Available Abstract Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug quality have occurred. Since intelligence provided by investigators indicates that some counterfeit producers may be adapting products to pass Minilab tests, the results are compared with those from a Raman spectrometer and discrepancies are discussed. Methods Between mid-2007 and early-2010, samples of anti-malarial drugs were bought covertly from pharmacies in Lagos on three different occasions (October 2007, December 2008, February 2010, and from pharmacies in Accra on two different occasions (October 2007, February 2010. All samples were tested using the Minilab® protocol, which includes disintegration and active ingredient assays as well as visual inspection, and most samples were also tested by Raman spectrometry. Results In Lagos, the failure rate in the 2010 sampling fell to 29% of the 2007 finding using the Minilab® protocol, 53% using Raman spectrometry, and 46% using visual inspection. In Accra, the failure rate in the 2010 sampling fell to 54% of the 2007 finding using the Minilab® protocol, 72% using Raman spectrometry, and 90% using visual inspection. Conclusions The evidence presented shows that drug quality is probably improving in both cities, especially Lagos, since major reductions of failure rates over time occur with all means of assessment. Many more samples failed when examined by Raman spectrometry than by Minilab® protocol. The discrepancy is most likely caused by the two techniques measuring different aspects of the medication

  15. Antimalarial activity of methanolic leaf extract of Piper betle L.

    Science.gov (United States)

    Al-Adhroey, Abdulelah H; Nor, Zurainee M; Al-Mekhlafi, Hesham M; Amran, Adel A; Mahmud, Rohela

    2010-12-28

    The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

  16. Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract

    Directory of Open Access Journals (Sweden)

    E. O. Ajaiyeoba

    2013-01-01

    Full Text Available Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1 in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM and could be a lead for anti-malarial drug discovery.

  17. Quinine conjugates and quinine analogues as potential antimalarial agents.

    Science.gov (United States)

    Jones, Rachel A; Panda, Siva S; Hall, C Dennis

    2015-06-05

    Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. The interaction of x-rays and antimalarials

    International Nuclear Information System (INIS)

    Geoghegan, D.S.; Skinner-Adams, T.; Davis, T.M.E.

    2001-01-01

    Full text: The radiation sensitivity of malaria parasites has three potential clinical applications, namely i) to prevent the transmission of malaria by blood transfusion, ii) as adjunctive therapy when a radioactive isotope is complexed to a conventional antimalarial drug, and iii) to attenuate the pathogenicity of specific parasite stages as part of the development of a vaccine. In the first two applications, detailed information relating to parasite radiosensitivity and the interaction of ionising radiation with antimalarials is of vital importance because dosimetry must allow for the exposure of normal cells. Malaria parasite cultures (Plasmodium falciparum) were exposed to a logarithmic series of concentrations of antimalarial agents and irradiated using a Siemens Stabilipan orthovoltage radiotherapy unit. The irradiation was performed at room temperature and ambient oxygen concentration. Control samples were also irradiated. The DNA synthesis in each culture was measured 48 hours post irradiation by using a 3 H-hypoxanthine incorporation assay. The antimalarials studied are: artesunate, quinine, retinol and chloroquine. The radiosensitivity of Plasmodium falciparum is not dependent on the strain of parasite with the dose required to inhibit 50% of DNA synthesis (ID 50 ) equal to 24.7 ± 3.0 Gy. This applies equally for the drug resistant and drug sensitive strains studied. Because the measured radiosensitivity is dependent on the sera oxygen concentration, the reported value for the ID 50 may not apply in hypoxic situations. The interaction of ionising radiation with the antimalarials shows synergy with retinol and choloquine, additivity with quinine and slight antagonism with artesunate. Radionuclide therapy may emerge as a novel treatment for malaria. If this does occur, then, although all strains appear to be equally radiosensitive, care must be taken when combining ionising radiation with existing antimalarials for the treatment of malaria. Copyright

  19. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  20. The antimalarial drug quinine interferes with serotonin biosynthesis and action

    DEFF Research Database (Denmark)

    Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit......The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor...... tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells....

  1. Quinoline-Based Hybrid Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Xhamla Nqoro

    2017-12-01

    Full Text Available The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies.

  2. Targetting the hemozoin synthesis pathway for antimalarial drug and detected by TEM (Transmission electron microscope)

    Science.gov (United States)

    Abbas, Jamilah; Artanti, Nina; Sundowo, Andini; Dewijanti, Indah Dwiatmi; Hanafi, Muhammad; Lisa, Syafrudin, Din

    2017-11-01

    Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasite species, the alarming spread of drug resistance and limited number of effective drug available now. Therefore it is important to discover new antimalarial drug. Malaria is caused by a singlecelled parasite from the genus Plasmodium. Plasmodium falciparum parasite infect red blood cells, ingesting and degradation hemoglobin in the acidic food vacuola trough a sequential metabolic process involving multiple proteases. During these process, hemoglobin is utilized as the predominant source of nutrition. Proteolysis of hemoglobin yields amino acid for protein synthesis as well as toxic heme. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite has evolved a distinct mechanism for detoxification of heme through conversion into insoluble crystalline pigment, known as hemozoin (β hematoin). Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarial drug. TEM (Transmission Electron Microscope) technology for hemozoin formation in vitro assay was done in this research. Calophyllum aerophyllum Lauterb as medicinal plants was used as a source of antimalarial drug. Acetone extracts of C. lowii showed growth inhibition against parasite P. falciparum with IC50 = 5.2 µg/mL. Whereas from hexane, acetone and methanol fraction of C. aerophyllum showed growth inhibition with IC50 = 0.054, 0.055 and 0.0054 µg/mL respectively. New drug from Calophyllum might have potential compounds that have unique structures and mechanism of action which required to develop new drug for treatment of sensitive and drug resistant strain of malaria.

  3. Bioguided investigation of the antimalarial activities of Trema orientalis

    African Journals Online (AJOL)

    Aghomotsegin

    2015-10-28

    Oct 28, 2015 ... Article Number: 3F00A6755934. ISSN 1684-5315 ... License 4.0 · International License ... extract was analyzed using thin layer chromatography (TLC) plates,. Merck .... makes it a viable candidate in the search for antimalarial.

  4. Antimalarial Activity of Methanolic Leaf Extract of Piper betle L.

    Directory of Open Access Journals (Sweden)

    Adel A. Amran

    2010-12-01

    Full Text Available The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50–400 mg/kg was investigated for its antimalarial activity against Plasmodium berghei (NK65 during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P < 0.05 schizonticidal activity in all three antimalarial evaluation models. Phytochemical screening showed that the leaf extract contains some vital antiplasmodial chemical constituents. The extract also exhibited a potent ability to scavenge the free radicals. The results of acute toxicity showed that the methanol extract of Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

  5. In vivo Antimalarial Activity of Methanol and Water Extracts of ...

    African Journals Online (AJOL)

    review of the plants of the American continent with antimalarial ... dried at room temperature and ground into fine powder using a ball mill .... substance in a liquid is determined by ... In addition, ionic compounds are generally most soluble in ...

  6. QSAR models for anti-malarial activity of 4-aminoquinolines.

    Science.gov (United States)

    Masand, Vijay H; Toropov, Andrey A; Toropova, Alla P; Mahajan, Devidas T

    2014-03-01

    In the present study, predictive quantitative structure - activity relationship (QSAR) models for anti-malarial activity of 4-aminoquinolines have been developed. CORAL, which is freely available on internet (http://www.insilico.eu/coral), has been used as a tool of QSAR analysis to establish statistically robust QSAR model of anti-malarial activity of 4-aminoquinolines. Six random splits into the visible sub-system of the training and invisible subsystem of validation were examined. Statistical qualities for these splits vary, but in all these cases, statistical quality of prediction for anti-malarial activity was quite good. The optimal SMILES-based descriptor was used to derive the single descriptor based QSAR model for a data set of 112 aminoquinolones. All the splits had r(2)> 0.85 and r(2)> 0.78 for subtraining and validation sets, respectively. The three parametric multilinear regression (MLR) QSAR model has Q(2) = 0.83, R(2) = 0.84 and F = 190.39. The anti-malarial activity has strong correlation with presence/absence of nitrogen and oxygen at a topological distance of six.

  7. Natural cocoa as diet-mediated antimalarial prophylaxis.

    Science.gov (United States)

    Addai, F K

    2010-05-01

    The Maya of Central America are credited with the first consumption of cocoa and maintaining its ancient Olmec name kakawa translated in English as "God Food", in recognition of its multiple health benefits. The legend of cocoa is receiving renewed attention in recent years, on account of epidemiological and scientific studies that support its cardiovascular health benefits. Increasing numbers of scientific reports corroborating cocoa's antiquated reputation as health food persuaded this author to promote regular consumption of cocoa in Ghana since 2004. Cocoa is readily available in Ghana; the country is the second largest producer accounting for 14% of the world's output. Numerous anecdotal reports of reduced episodic malaria in people who daily drink natural unsweetened cocoa beverage prompted a search for scientific mechanisms that possibly account for cocoa's antimalarial effects. This paper presents the outcome as a hypothesis. Internet search for literature on effects of cocoa's ingredients on malaria parasites and illness using a variety of search tools. Evidential literature suggests five mechanisms that possibly underpin cocoa's anecdotal antimalarial effects. (i) Increased availability of antioxidants in plasma, (ii) membrane effects in general and erythrocyte membrane in particular, (iii) increased plasma levels of nitric oxide, (iv) antimalarial activity of cocoa flavanoids and their derivatives, and (v) boosted immune system mediated by components of cocoa including cocoa butter, polyphenols, magnesium, and zinc. A hypothesis is formulated that cocoa offers a diet-mediated antimalarial prophylaxis; and an additional novel tool in the fight against the legendary scourge.

  8. Factors contributing to antimalarial drug resistance in Rachuonyo ...

    African Journals Online (AJOL)

    Qualitative and quantitative data were collected among 380 respondents including health care providers, people seeking malaria treatment and Community Own Resource (CORPs), from 47 registered health facilities. The study revealed that all health facilities were using general-purpose trucks to transport antimalarial ...

  9. Antimalarial activity of selected Ethiopian medicinal plants in mice

    Directory of Open Access Journals (Sweden)

    Eshetu M. Bobasa

    2018-02-01

    Full Text Available Context: Parasites are the leading killers in subtropical areas of which malaria took the lion share from protozoan diseases. Measuring the impact of antimalarial drug resistance is difficult, and the impact may not be recognized until it is severe, especially in high transmission areas. Aims: To evaluate the in vivo antimalarial activities of hydroalcoholic extracts of the roots of Piper capense and Adhatoda schimperiana, against Plasmodium berghei in mice. Methods: Four-day suppressive and curative test animal models were used to explore the antimalarial activities of the plants. 200, 400, and 600 mg/kg of each plant extract was administered to check the activities versus vehicle administered mice. Mean survival time and level of parasitemia were the major variables employed to compare the efficacy vs. negative control. Results: In both models the 400 and 600 mg/kg doses of Adhatoda schimperiana and the 600 mg/kg dose Piper capense. showed significant parasitemia suppression and increased in mean survival time at p≤0.05. The middle dose of Piper capense had a border line inhibition where the extracts were considered active when parasitemia was reduced by ≥ 30%. Conclusions: The hydroalcoholic extracts of the roots of Adhatoda schimperiana and Piper capense possess moderate antimalarial activities, which prove its traditional claims. Thus, further studies should be done to isolate the active constituents for future use in the modern drug discovery.

  10. Antimalarial prescribing patterns in state hospitals and selected ...

    African Journals Online (AJOL)

    slowdown of progression to resistance could be achieved by improving prescribing practice, drug quality, and patient compliance. Objective: To determine the antimalarial prescribing pattern and to assess rational prescribing of chloroquine by prescribers in government hospitals and parastatals in Lagos State. Methods: ...

  11. Docking, synthesis and antimalarial activity of novel 4-anilinoquinoline derivatives.

    Science.gov (United States)

    Vijayaraghavan, Shilpa; Mahajan, Supriya

    2017-04-15

    A series of 4-anilinoquinoline triazine derivatives were designed, synthesized and screened for in vivo antimalarial activity against a chloroquine-sensitive strain of Plasmodium berghei. The compounds were further subjected to in vitro antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum and β-haematin inhibition studies. All the compounds exhibited in vivo antimalarial activity better than that shown by the standard drug, chloroquine. Twelve out of fifteen compounds showed better inhibition than that of chloroquine against chloroquine-resistant W2 strain of Plasmodium falciparum. Ten compounds showed β-haematin inhibition, better than that of chloroquine, with IC 50 values in the range of 18-25µM. One compound, 3k, was found to be better than artemisinin against W2 strain of Plasmodium falciparum and also displayed the best β-haematin inhibitory activity, thereby becoming eligible to be explored as a potential lead for antimalarial chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Antimalarial activity of HIV-1 protease inhibitor in chromone series.

    Science.gov (United States)

    Lerdsirisuk, Pradith; Maicheen, Chirattikan; Ungwitayatorn, Jiraporn

    2014-12-01

    Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65μM), was found to be the most potent antimalarial compound with IC50=0.95μM while primaquine and tafenoquine showed IC50=2.41 and 1.95μM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=-13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Safety and Tolerability Profile of Artemisinin-Based Antimalarial ...

    African Journals Online (AJOL)

    The WHO in 2001 advocated artemisinin- based antimalarial combination therapy (ACT), which was adopted by Nigeria in 2005. The objective of this study was to characterize the safety and tolerability profile of the ACTs in adult patients with uncomplicated malaria. A descriptive longitudinal study was conducted in the ...

  14. CNS adverse events associated with antimalarial agents. Fact or fiction?

    NARCIS (Netherlands)

    Phillips-Howard, P. A.; ter Kuile, F. O.

    1995-01-01

    CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

  15. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties

    Directory of Open Access Journals (Sweden)

    Karène Urgin

    2017-01-01

    Full Text Available With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me2 or -N(Et2 in different positions (ortho, meta and para on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

  16. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties.

    Science.gov (United States)

    Urgin, Karène; Jida, Mouhamad; Ehrhardt, Katharina; Müller, Tobias; Lanzer, Michael; Maes, Louis; Elhabiri, Mourad; Davioud-Charvet, Elisabeth

    2017-01-19

    With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N -arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal - N (Me)₂ or - N (Et)₂ in different positions ( ortho , meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N -arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para -position of the substituent remains the most favourable position on the benzyl chain and the carbamate - N HBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei -infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

  17. The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

    Science.gov (United States)

    Marrelli, Mauro Toledo; Brotto, Marco

    2016-11-02

    Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

  18. Deconstructing Quinoline-Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta-Hematin Crystal Growth Inhibitors.

    Science.gov (United States)

    Olafson, Katy N; Nguyen, Tam Q; Vekilov, Peter G; Rimer, Jeffrey D

    2017-10-04

    A versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces and alter their growth rates. Elucidating a modifier's binding specificity to anisotropic crystal surfaces is a ubiquitous challenge that is critical to their design. In this study, we select hematin, a byproduct of malaria parasites, as a model system to examine the complementarity of modifiers (i.e., antimalarial drugs) to β-hematin crystal surfaces. We divide two antimalarials, chloroquine and amodiaquine, into segments consisting of a quinoline base, common to both drugs, and side chains that differentiate their modes of action. Using a combination of scanning probe microscopy, bulk crystallization, and analytical techniques, we show that the base and side chain work synergistically to reduce the rate of hematin crystallization. In contrast to general observations that modifiers retain their function upon segmentation, we show that the constituents do not act as modifiers. A systematic study of quinoline isomers and analogues shows how subtle rearrangement and removal of functional moieties can create effective constituents from previously ineffective modifiers, along with tuning their inhibitory modes of action. These findings highlight the importance of specific functional moieties in drug compounds, leading to an improved understanding of modifier-crystal interactions that could prove to be applicable to the design of new antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay.

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    Joël Lelièvre

    Full Text Available BACKGROUND: Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS: Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV-V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS: The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial

  20. Endoperoxide polyketides from a Chinese Plakortis simplex: further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes.

    Science.gov (United States)

    Chianese, Giuseppina; Persico, Marco; Yang, Fan; Lin, Hou-Wen; Guo, Yue-Wei; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Taglialatela-Scafati, Orazio; Fattorusso, Caterina

    2014-09-01

    Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4-7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure-activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

    Science.gov (United States)

    González, Miguel A; Clark, Julie; Connelly, Michele; Rivas, Fatima

    2014-11-15

    The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.

    Science.gov (United States)

    Faísca Phillips, Ana Maria; Nogueira, Fátima; Murtinheira, Fernanda; Barros, Maria Teresa

    2015-01-01

    The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. In vitro antimalarial activity of Calophyllum bicolor and hemozoin crystals observed by Transmission Electron Microscope (TEM)

    OpenAIRE

    Abbas Jamilah

    2018-01-01

    Objective : In continuation of our antimalarial candidate drug discovery program on Indonesia medicinal plants especially from stem bark of Calophyllum bicolor. Metode : We extracted of bioactive crude extract with hexane, acetone and methanol from stem bark of Calophyllum bicolor and evaluated their antimalarial activity by using parasite Plasmodium falciparum in vitro. Results: Methanol fraction showed most active and potent antimalarial activity dose dependent in in vitro experiments with ...

  4. From crystal to compound: structure-based antimalarial drug discovery.

    Science.gov (United States)

    Drinkwater, Nyssa; McGowan, Sheena

    2014-08-01

    Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

  5. Lead Optimization of Anti-Malarial Propafenone Analogs

    Science.gov (United States)

    Lowes, David; Pradhan, Anupam; Iyer, Lalitha V.; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W. Armand; Sigal, Martina; Clark, Julie A.; Wilson, Emily; Tang, Liang; Connelly, Michele C.; DeRisi, Joseph L.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin

    2015-01-01

    Previously reported studies identified analogs of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are non-toxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID:22708838

  6. Antimicrobial peptides: a new class of antimalarial drugs?

    Directory of Open Access Journals (Sweden)

    Nuno eVale

    2014-12-01

    Full Text Available A range of antimicrobial peptides (AMP exhibit activity on malaria parasites, Plasmodium spp, in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

  7. Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

    OpenAIRE

    Newton, Paul; Suputtamongkol, Yupin; Teja-Isavadharm, Paktiya; Pukrittayakamee, Sasithon; Navaratnam, V; Bates, Imelda; White, Nicholas

    2000-01-01

    The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimal...

  8. In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

    Science.gov (United States)

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  9. Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones.

    Science.gov (United States)

    Sarkar, Souvik; Siddiqui, Asim A; Saha, Shubhra J; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S; Nag, Shiladitya; Adhikari, Susanta; Bandyopadhyay, Uday

    2016-07-01

    We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [(3)H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  10. A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs.

    Science.gov (United States)

    O'Neill, Paul M; Ward, Stephen A; Berry, Neil G; Jeyadevan, J Prince; Biagini, Giancarlo A; Asadollaly, Egbaleh; Park, B Kevin; Bray, Patrick G

    2006-01-01

    A broad overview is presented describing the current knowledge and the ongoing research concerning the 4-aminoquinolines (4AQ) as chemotherapeutic antimalarial agents. Included are discussions of mechanism of action, structure activity relationships (SAR), chemistry, metabolism and toxicity and parasite resistance mechanisms. In discussions of SAR, particular emphasis has been given to activity versus chloroquine resistant strains of Plasmodium falciparum. Promising new lead compounds undergoing development are described and an overview of physicochemical properties of chloroquine and amodiaquine analogues is also included.

  11. POTENCY OF THE INDONESIAN MEDICINAL PLANTS AS ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Subeki Subeki

    2012-12-01

    Full Text Available The Indonesian traditional herbal medicine has been practiced for many centuries in Indonesia to treat malaria diseases. Although modern medicine is becoming increasingly important, herbal medicine is still very popular. In order to select raw material for preparation of safety herbal medicines, forty five medicinal plants have been tested for acute toxicity in mouse at a dose 715 mg/kg body weight. The extracts of Asclepias curassavica leave, Alstonia scholaris leave, Decospermum fruticosum leave, Elaocarpus petiolatus bark, Elaocarpus parvifolius bark, Eurycoma longifolia root, Garcinia rigida bark, Nephelium lappaceum bark, Pentaspodan motleyi leave, Picrasma javanica leave, Phyllanthus niruri whole, Quassia indica leave, Syzygium pycnanthum bark, Tetrasera scandens leave, Cratoxylum glaucum bark, Sandoricum emarginatum bark, Mallotus paniculatus leave, Microcos ovatolanceolata bark, Poikilospermum suaveolens leave, Fibraurea chloroleuea leave, Tetrasera scandens root, and Timonius billitonensis bark showed toxicity with mortality level of 20-100%. The remaining 32 plant extracts were not toxic at dose tested. The toxic plant species should be considered in the preparation of herbal medicines. Of the safety extracts were tested for their antimalarial activity against Plasmodium berghei in vivo at a dose 715 mg/kg body weight. Extract of Carica papaya leave was most active than other plant extracts with parasitemia 1.13%, while control showed 17.21%. More research is needed to scientifically prove efficacy and to identity antimalarial constituents in the plant extracts. Key words: Indonesian medicinal plant, jamu, toxicity, antimalarial activity, Plasmodium berghei.

  12. Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf

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    Helen Bitew

    2017-11-01

    Full Text Available Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl-2-(3,4-dihydroxybut-1-ynyl-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl-2-(3-chloro-4-acetoxy-but-1-yn-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs.

  13. Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies

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    J. O. Adebayo

    2013-01-01

    Full Text Available In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25–500 mg/kg body weight using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P>0.05 function indices of the liver and cardiovascular system at all doses administered but significantly increased (P<0.05 plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles.

  14. SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

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    Mwafongo Winfred

    2010-10-01

    Full Text Available Abstract Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93% was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has

  15. SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

    Science.gov (United States)

    2010-01-01

    Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL) and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93%) was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable) fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has the potential to alleviate

  16. N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials.

    Science.gov (United States)

    Gomes, Ana; Machado, Marta; Lobo, Lis; Nogueira, Fátima; Prudêncio, Miguel; Teixeira, Cátia; Gomes, Paula

    2015-08-01

    In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. In Vivo Antimalarial Activity of Solvent Fractions of the Leaves of ...

    African Journals Online (AJOL)

    Increasing resistance of Plasmodium falciparum to almost all the available antimalarial drugs urges a search for newer antimalarial drugs. Justicia schimperiana Hochst. Ex Nees is traditionally used for the treatment of malaria and a study conducted previously on the crude leaf extract confirmed that the plant is endowed ...

  18. Mechanochemical Synthesis, In vivo Anti-malarial and Safety Evaluation of Amodiaquine-zinc Complex

    Directory of Open Access Journals (Sweden)

    Arise Rotimi Olusanya

    2017-09-01

    Full Text Available So far, some prospective metal-based anti-malarial drugs have been developed. The mechanochemical synthesis and characterization of Zn (II complex with amodiaquine and its anti-malarial efficacy on Plasmodium berghei-infected mice and safety evaluation were described in this study.

  19. Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria

    NARCIS (Netherlands)

    Newton, Paul N.; van Vugt, Michele; Teja-Isavadharm, Paktiya; Siriyanonda, Duangsuda; Rasameesoroj, Maneerat; Teerapong, Pramote; Ruangveerayuth, Ronatrai; Slight, Thra; Nosten, Francois; Suputtamongkol, Yupin; Looareesuwan, Sornchai; White, Nicholas J.

    2002-01-01

    Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ

  20. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

    Science.gov (United States)

    Nondo, Ramadhani S O; Erasto, Paul; Moshi, Mainen J; Zacharia, Abdallah; Masimba, Pax J; Kidukuli, Abdul W

    2016-01-01

    Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 10(7) erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria.

  1. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria

    Directory of Open Access Journals (Sweden)

    Ramadhani SO Nondo

    2016-01-01

    Full Text Available Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L. Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 Χ 10 7 erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day and solvent (5 mL/kg/day were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s. In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria.

  2. Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols.

    Directory of Open Access Journals (Sweden)

    Juliana B R Corrêa Soares

    Full Text Available BACKGROUND: The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN, quinidine (QND and quinacrine (QCR in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day from the 11(th to 17(th day after infection caused significant decreases in worm burden (39%-61% and egg production (42%-98%. Hz formation was significantly inhibited (40%-65% in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms. CONCLUSIONS: The overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a

  3. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

    Science.gov (United States)

    Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

  4. N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.

    Science.gov (United States)

    Pérez, Bianca C; Teixeira, Cátia; Albuquerque, Inês S; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Prudêncio, Miguel; Gomes, Paula

    2013-01-24

    The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

  5. Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents.

    Science.gov (United States)

    Gayam, Venkatareddy; Ravi, Subban

    2017-07-28

    A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9-14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl 2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K 2 CO 3  as base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18-22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25-28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC 50 value of 44.06, 48.04 and 59.37 nM against chloroquine resistant K1 strain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Stevens-Johnson syndrome associated with Malarone antimalarial prophylaxis.

    Science.gov (United States)

    Emberger, Michael; Lechner, Arno Michael; Zelger, Bernhard

    2003-07-01

    To the best of our knowledge, Stevens-Johnson syndrome (SJS) has not been reported previously as an adverse reaction to Malarone, which is a combination of atovaquone and proguanil hydrochloride used for antimalarial prophylaxis and therapy. We describe a 65-year-old patient who had SJS with typical clinical and histopathological findings associated with the use of Malarone prophylaxis for malaria. This report should alert physicians to this severe cutaneous reaction, and Malarone should be added to the list of drugs that can potentially cause SJS.

  7. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

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    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  8. Antimalarials and the fight against malaria in Brazil.

    Science.gov (United States)

    Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

    2009-08-01

    Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.

  9. Plants of the Annonaceae traditionally used as antimalarials: a review

    Directory of Open Access Journals (Sweden)

    Gina Frausin

    2014-01-01

    Full Text Available Species of the Annonaceae family are used all over the tropics in traditional medicine in tropical regions for the treatment of malaria and other illnesses. Phytochemical studies of this family have revealed chemical components which could offer new alternatives for the treatment and control of malaria. Searches in scientific reference sites (SciFinder Scholar, Scielo, PubMed, ScienceDirect and ISI Web of Science and a bibliographic literature search for species of Annonaceae used traditionally to treat malaria and fever were carried out. This family contains 2,100 species in 123 genera. We encountered 113 articles reporting medicinal use of one or more species of this family including 63 species in 27 genera with uses as antimalarials and febrifuges. Even though the same species of Annonaceae are used by diverse ethnic groups, different plant parts are often chosen for applications, and diverse methods of preparation and treatment are used. The ethanol extracts of Polyalthia debilis and Xylopia aromatica proved to be quite active against Plasmodium falciparum in vitro (median inhibition concentration, IC50 < 1.5 µg/mL. Intraperitoneal injection of Annickia chlorantha aqueous extracts (cited as Enantia chlorantha cleared chloroquine-resistant Plasmodium yoelii nigeriensis from the blood of mice in a dose-dependant manner. More phytochemical profiles of Annonaceous species are required; especially information on the more commonly distributed antimalarial compounds in this family.

  10. Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.

    Science.gov (United States)

    Shiraki, Hiroaki; Kozar, Michael P; Melendez, Victor; Hudson, Thomas H; Ohrt, Colin; Magill, Alan J; Lin, Ai J

    2011-01-13

    In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

  11. Effectiveness of involving a nurse specialist for patients with urinary incontinence in primary care: results of a pragmatic multicentre randomised controlled trial.

    NARCIS (Netherlands)

    Albers-Heitner, P.C.; Lagro-Janssen, A.L.M.; Joore, M.M.; Berghmans, B.L.; Nieman, F.F.; Venema, P.P.; Severens, J.J.; Winkens, R.R.

    2011-01-01

    BACKGROUND: Urinary incontinence (UI) primary care management is substandard, offering care rather than cure despite the existence of guidelines that help to improve cure. Involving nurse specialists on incontinence in general practice could be a way to improve care for UI patients. AIMS: We studied

  12. Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets Portfolio.

    Science.gov (United States)

    Chaparro, María Jesús; Calderón, Félix; Castañeda, Pablo; Fernández-Alvaro, Elena; Gabarró, Raquel; Gamo, Francisco Javier; Gómez-Lorenzo, María G; Martín, Julio; Fernández, Esther

    2018-04-13

    Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits. Optimization efforts on several chemical series have been successful, and clinical candidates have been identified. In addition, recent advances in genetics and proteomics have led to the target deconvolution of phenotypic clinical candidates. New mechanisms of action will also be critical to overcome resistance and reduce attrition. Therefore, a complementary strategy focused on identifying well-validated targets to start hit identification programs is essential to reinforce the clinical pipeline. Leveraging published data, we have assessed the status quo of the current antimalarial target portfolio with a focus on the blood stage clinical disease. From an extensive list of reported Plasmodium targets, we have defined triage criteria. These criteria consider genetic, pharmacological, and chemical validation, as well as tractability/doability, and safety implications. These criteria have provided a quantitative score that has led us to prioritize those targets with the highest probability to deliver successful and differentiated new drugs.

  13. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria.

    Science.gov (United States)

    White, Nicholas J; Duong, Tran T; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T; Pertel, Peter; Leong, F Joel

    2016-09-22

    KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and

  14. Impact of introducing subsidized combination treatment with artemether-lumefantrine on sales of anti-malarial monotherapies: a survey of private sector pharmacies in Huambo, Angola.

    Science.gov (United States)

    Lussiana, Cristina; Floridia, Marco; Martinho do Rosário, Joana; Fortes, Filomeno; Allan, Richard

    2016-12-01

    Artemisinin-based combination therapies (ACTs) against malaria are subsidized in many African countries, but the impact of subsidy programs in reducing the sales of concomitantly available antimalarial monotherapies is poorly defined. Data from The MENTOR initiative, that introduced subsidized artemether-lumefantrine (sAL) in the private sector of Huambo province, Angola, were used. The main response variable was represented by sales of sAL and of monotherapies, measured as number of treatment courses. Sales in private pharmacies of sAL and four antimalarial monotherapies between 2009 and 2013 were organized in four time-periods, and analyzed using generalized linear models for repeated measures. A secondary analysis evaluated changes in relative market share. We analyzed data from 34 pharmacies at four time points, taken from a larger survey that involved 165 pharmacies between June 2009 and March 2013. The sAL, following its introduction, became the dominant antimalarial treatment in the private sector, usually exceeding the total sales of all antimalarial monotherapies combined (1480/2800 total treatment courses, 52.8% of all sales in March 2013). Sales of monotherapies decreased significantly, but did not stop, representing 36.7% (1028/2800) of sales at the end of the survey. Subsidized ACTs can attain rapidly a high relative market share. Their introduction reduced, but did not eliminate the demand for less effective monotherapies, that might favor parasite resistance. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.

    Science.gov (United States)

    Oliveira, Rudi; Guedes, Rita C; Meireles, Patrícia; Albuquerque, Inês S; Gonçalves, Lídia M; Pires, Elisabete; Bronze, Maria Rosário; Gut, Jiri; Rosenthal, Philip J; Prudêncio, Miguel; Moreira, Rui; O'Neill, Paul M; Lopes, Francisca

    2014-06-12

    The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.

  16. Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

    Energy Technology Data Exchange (ETDEWEB)

    Cursino, Lorena Mayara de Carvalho; Nunez, Cecilia Veronica [Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, AM (Brazil). Lab. de Bioprospeccao e Biotecnologia; Paula, Renata Cristina de; Nascimento, Maria Fernanda Alves do [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Fac. de Farmacia. Dept. de Produtos Farmaceuticos; Santos, Pierre Alexandre dos, E-mail: cecilia@inpa.gov.br [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil). Fac. de Ciencias Farmaceuticas

    2012-07-01

    Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3{beta}-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts. (author)

  17. Plants of the American continent with antimalarial activity

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    Ingrid R. Mariath

    Full Text Available Malaria is a human parasitic disease caused by protozoa species of the Plasmodium genus. This disease has affected populations of the tropical and subtropical regions. About 500 million new cases occur annually on the world and therefore it is considered an emerging disease of important public health problem. In this context, the natural products as vegetables species have their bioactive molecules as targets for pharmacological, toxicological and phytochemical studies towards the development of more effective medicines for the treatment of many diseases. So this work intends to aid the researchers in the study of natural products to the treatment of malaria. In this review, 476 plants of the American continent were related for the antimalarial activity and of these vegetables species 198 were active and 278 inactive for some type of Plasmodium when they were evaluated through of in vitro or in vivo bioassays models.

  18. 2,3,8-Trisubstituted Quinolines with Antimalarial Activity.

    Science.gov (United States)

    Martinez, Pablo D G; Krake, Susann H; Poggi, Maitia L; Campbell, Simon F; Willis, Paul A; Dias, Luiz C

    2018-01-01

    Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.

  19. 2,3,8-Trisubstituted Quinolines with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    PABLO D.G. MARTINEZ

    2018-05-01

    Full Text Available ABSTRACT Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.

  20. Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

    International Nuclear Information System (INIS)

    Cursino, Lorena Mayara de Carvalho; Nunez, Cecilia Veronica; Paula, Renata Cristina de; Nascimento, Maria Fernanda Alves do; Santos, Pierre Alexandre dos

    2012-01-01

    Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3β-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts. (author)

  1. Perspective for the reproduction of antimalarial drugs in Brazil

    Directory of Open Access Journals (Sweden)

    Benjamin Gilbert

    1992-01-01

    Full Text Available The appears to be no chemical manufacture of antimalarial drugs is Brazil. Technology at laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloquanil, but not perfected nor scaled-up, largely for economic reasons and market uncertainty. Development of primaquine has been contracted but it will run into the same difficulty. Manufacturing capacity for sulfadoxine was registred in the SDI by Roche. A project to produce artemisinine and its derivates is under way at UNICAMP-CPQBA but is hampered by low content in the plant. Proguanil could be produced easily, but apparently no attempt has been made to do so. Quinine is imported on a large scale mostly for softdrink production. Since malarial treatment falls largely within responsability of the Government health authorities, manufacture of drugs in Brazil will depend on an assured medium-term purchase order made to a potential local manufacturer, since competition in the world market is scarcelyviable at the present moment.

  2. Synthesis of chiral chloroquine and its analogues as antimalarial agents.

    Science.gov (United States)

    Sinha, Manish; Dola, Vasanth R; Soni, Awakash; Agarwal, Pooja; Srivastava, Kumkum; Haq, Wahajul; Puri, Sunil K; Katti, Seturam B

    2014-11-01

    In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13 b, S-13c, S-13 d and S-13 i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13 d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Formulation of nanotized curcumin and demonstration of its antimalarial efficacy

    Directory of Open Access Journals (Sweden)

    Ghosh A

    2014-11-01

    Full Text Available Aparajita Ghosh,1 Tanushree Banerjee,2 Suman Bhandary,1 Avadhesha Surolia31Division of Molecular Medicine, Bose Institute, Centenary Campus, Kolkata, West Bengal, India; 2Department of Biotechnology, University of Pune, Pune, India; 3Molecular Biophysics Unit, Indian Institute of Science, Bangalore, IndiaAim: The present study was conducted to overcome the disadvantages associated with the poor water solubility and low bioavailability of curcumin by synthesizing nanotized curcumin and demonstrating its efficacy in treating malaria. Materials and methods: Nanotized curcumin was prepared by a modified emulsion-diffusion-evaporation method and was characterized by means of transmission electron microscopy, atomic force microscopy, dynamic light scattering, Zetasizer, Fourier transform infrared spectroscopy, and differential thermal analysis. The novelty of the prepared nanoformulation lies in the fact that it was devoid of any polymeric matrices used in conventional carriers. The antimalarial efficacy of the prepared nanotized curcumin was then checked both in vitro and in vivo. Results: The nanopreparation was found to be non-toxic and had a particle size distribution of 20–50 nm along with improved aqueous dispersibility and an entrapment efficiency of 45%. Nanotized curcumin (half maximal inhibitory concentration [IC50]: 0.5 µM was also found to be ten-fold more effective for growth inhibition of Plasmodium falciparum in vitro as compared to its native counterpart (IC50: 5 µM. Oral bioavailability of nanotized curcumin was found to be superior to that of its native counterpart. Moreover, when Plasmodium berghei-infected mice were orally treated with nanotized curcumin, it prolonged their survival by more than 2 months with complete clearance of parasites in comparison to the untreated animals, which survived for 8 days only. Conclusion: Nanotized curcumin holds a considerable promise in therapeutics as demonstrated here for treating malaria

  4. Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

    Science.gov (United States)

    Allman, Erik L.; Painter, Heather J.; Samra, Jasmeet; Carrasquilla, Manuela

    2016-01-01

    The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field. PMID:27572391

  5. Epidemiological models for the spread of anti-malarial resistance

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    Antia R

    2003-02-01

    Full Text Available Abstract Background The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. Methods We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. Results In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. Conclusions The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.

  6. Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials.

    Science.gov (United States)

    Zhang, Yiqun; Clark, Julie A; Connelly, Michele C; Zhu, Fangyi; Min, Jaeki; Guiguemde, W Armand; Pradhan, Anupam; Iyer, Lalitha; Furimsky, Anna; Gow, Jason; Parman, Toufan; El Mazouni, Farah; Phillips, Margaret A; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

    2012-05-10

    Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

  7. Synthesis and evaluation of 1-amino-6-halo-β-carbolines as antimalarial and antiprion agents.

    Science.gov (United States)

    Thompson, Mark J; Louth, Jennifer C; Little, Susan M; Jackson, Matthew P; Boursereau, Yohan; Chen, Beining; Coldham, Iain

    2012-04-01

    Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    OpenAIRE

    Huthmacher, Carola; Hoppe, Andreas; Bulik, Sascha; Holzh?tter, Hermann-Georg

    2010-01-01

    Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicte...

  9. Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro.

    Science.gov (United States)

    Tjahjani, Susy

    2017-02-28

    Malaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro. Dry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC 50 ). Analysis of the parasite growth in vitro indicated that IC 50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.

  10. Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

    OpenAIRE

    Iwaniuk, Daniel P.; Whetmore, Eric D.; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C.; Roepe, Paul D.; Wolf, Christian

    2009-01-01

    We report the synthesis and in vitro antimalarial activity of several new 4-amino-and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of P. falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain st...

  11. Comparison of antimalarial activity of Artemisia turanica extract with current drugs in vivo.

    Science.gov (United States)

    Taherkhani, Mahboubeh; Rustaiyan, Abdolhossein; Nahrevanian, Hossein; Naeimi, Sabah; Taherkhani, Tofigh

    2013-03-01

    The purpose of this study was to compare antimalarial activity of Artemisia turanica Krasch as Iranian flora with current antimalarial drugs against Plasmodium berghei in vivo in mice. Air-dried aerial parts of Iranian flora A. turanica were collected from Khorasan, northeastern Iran, extracted with Et2O/MeOH/Petrol and defatted. Toxicity of herbal extracts was assessed on male NMRI mice, and their antimalarial efficacy was compared with antimalarial drugs [artemether, chloroquine and sulfadoxinepyrimethamine (Fansidar)] on infected P. berghei animals. All the groups were investigated for parasitaemia, body weight, hepatomegaly, splenomegaly and anemia. The significance of differences was determined by Analysis of Variances (ANOVA) and Student's t-test using Graph Pad Prism software. The inhibitory effects of A. turanica extract on early decline of P. berghei parasitaemia highlights its antimalarial activity, however, this effect no longer can be observed in the late infection. This may be due to the metabolic process of A. turanica crude extract by mice and reduction of its concentration in the body. Crude extract of A. turanica represented its antisymptomatic effects by stabilization of body, liver and spleen weights. This study confirmed antimalarial effects of A. turanica extracts against murine malaria in vivo during early infection, however, there are more benefits on pathophysiological symptoms by this medication.

  12. Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Mariana Conceição Souza

    2015-06-01

    Full Text Available A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3 inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

  13. 4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents.

    Science.gov (United States)

    de Souza, Nicolli Bellotti; Carmo, Arturene M L; Lagatta, Davi C; Alves, Márcio José Martins; Fontes, Ana Paula Soares; Coimbra, Elaine Soares; da Silva, Adilson David; Abramo, Clarice

    2011-07-01

    The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of β-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  14. Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic

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    Alexandre Manirakiza

    2011-01-01

    Full Text Available Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%, artemisinin-based combinations (26.8% and artemisinin monotherapy (14.4%. Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9% and (13.3%. respectively. Conclusion. This study showed a relatively high rate (>80% of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested.

  15. Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic

    Science.gov (United States)

    Manirakiza, Alexandre; Soula, Georges; Laganier, Remi; Klement, Elise; Djallé, Djibrine; Methode, Moyen; Madji, Nestor; Heredeïbona, Luc Salva; Le Faou, Alain; Delmont, Jean

    2011-01-01

    Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%), artemisinin-based combinations (26.8%) and artemisinin monotherapy (14.4%). Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9%) and (13.3%). respectively. Conclusion. This study showed a relatively high rate (>80%) of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested. PMID:22312567

  16. A qualitative assessment of the challenges of WHO prequalification for anti-malarial drugs in China.

    Science.gov (United States)

    Huang, Yangmu; Pan, Ke; Peng, Danlu; Stergachis, Andy

    2018-04-03

    While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China.

  17. Does anti-malarial drug knowledge predict anti-malarial dispensing practice in drug outlets? A survey of medicine retailers in western Kenya

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    Rusk Andria

    2012-08-01

    Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could

  18. Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

    Science.gov (United States)

    2014-10-01

    OCT 2014 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone...Prescribed by ANSI Std Z39-18 Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone and Arterolane, against Multidrug-Resistant...potent antimalarial activity (2, 3). Despite having a rapid mecha- nism of action, artemisinin resistance eventually emerged and was first detected

  19. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

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    Maria P. Crespo-Ortiz

    2012-01-01

    Full Text Available Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

  20. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement.

    Science.gov (United States)

    Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

    2015-01-01

    Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem-ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic.

  1. Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

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    Rosi Bissinger

    2015-07-01

    Full Text Available Background: The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca2+-activity ([Ca2+]i, and ceramide. Methods: Phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA fluorescence, [Ca2+]i from Fluo3-fluorescence, and ceramide abundance from specific antibody binding. Results: A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 µg/ml, significantly decreased forward scatter (≥5 µg/ml, significantly increased ROS abundance (5 µg/ml, significantly increased [Ca2+]i (7.5 µg/ml and significantly increased ceramide abundance (10 µg/ml. The up-regulation of annexin-V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca2+. Even in the absence of extracellular Ca2+, mefloquine significantly increased annexin-V-binding. Conclusions: Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance.

  2. Antimalarial pyrido[1,2-a]benzimidazoles.

    Science.gov (United States)

    Ndakala, Albert J; Gessner, Richard K; Gitari, Patricia W; October, Natasha; White, Karen L; Hudson, Alan; Fakorede, Foluke; Shackleford, David M; Kaiser, Marcel; Yeates, Clive; Charman, Susan A; Chibale, Kelly

    2011-07-14

    A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.

  3. Considerations on the mechanism of action of artemisinin antimalarials: part 1--the 'carbon radical' and 'heme' hypotheses.

    Science.gov (United States)

    Haynes, Richard K; Cheu, Kwan-Wing; N'Da, David; Coghi, Paolo; Monti, Diego

    2013-08-01

    with concomitant generation of ROS or to inhibit formation of hemozoin. In the last case, just like the aminoquinolines and arylmethanols, the peroxides are not the active agents, but exert their parasiticidal effects through allowing the build-up of free heme-Fe(3+), the ultimate cytotoxic entity. We assess the literature relating to generation of heme by hemoglobin digestion, and the stage at which this process becomes significant in the intraerythrocytic parasite. The claims of production of heme and conversion into hemozoin occurring in a lipid environment may have to be put aside based on recent literature data that indicates crystallization of hemozoin must take place an aqueous interface; association of lipids with the heme/hemozoin is likely to be a reflection of attractive van der Waals interactions involving the hydrophobic surface of the heme or hemozoin aggregates. In addition, the observation leading to the claim that hemozoin manufacture commences at the mid-ring stage cannot be independently verified. That the quinoline and arylmethanol antimalarials have essentially no activities on the ring stage parasites and exert greatest efficacy at the trophozoite stage where heme production is maximal is consistent with this. Conversely, artemisinins, and indeed redox active drugs such as methylene blue and others, are highly active against early ring stage parasites. Thus, there is a prominent disconnect between stage specificities of artemisinins vis-a-vis those of 4-aminoquinolines and arylmethanols suggesting that heme is not the target of the former class of drug. Further, the ability of the Fe(3+) chelate DFO to antagonize antimalarial activities of artemisinins, but not the activities of 4-aminoquinolines, cannot be explained by involvement of heme as a target for artemisinins. We critically examine the basis for formation of products obtained from reaction of heme with artemisinins and synthetic peroxides under conditions ranging from biomimetic

  4. Antimalarial activity of medicinal plants from the Democratic Republic of Congo: A review.

    Science.gov (United States)

    Memvanga, Patrick B; Tona, Gaston L; Mesia, Gauthier K; Lusakibanza, Mariano M; Cimanga, Richard K

    2015-07-01

    Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999-2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines. In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected. Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials

  5. Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

    Science.gov (United States)

    Langer, Christine; Goodman, Christopher D.; McFadden, Geoffrey I.

    2013-01-01

    Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials. PMID:23318799

  6. Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.

    Science.gov (United States)

    Fielding, Alistair J; Lukinović, Valentina; Evans, Philip G; Alizadeh-Shekalgourabi, Said; Bisby, Roger H; Drew, Michael G B; Male, Verity; Del Casino, Alessio; Dunn, James F; Randle, Laura E; Dempster, Nicola M; Nahar, Lutfun; Sarker, Satyajit D; Cantú Reinhard, Fabián G; de Visser, Sam P; Dascombe, Mike J; Ismail, Fyaz M D

    2017-05-17

    Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF 3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF 3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N 1 ,N 2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.

    Science.gov (United States)

    Hou, X; Chen, X; Zhang, M; Yan, A

    2016-01-01

    Plasmodium falciparum, the most fatal parasite that causes malaria, is responsible for over one million deaths per year. P. falciparum dihydroorotate dehydrogenase (PfDHODH) has been validated as a promising drug development target for antimalarial therapy since it catalyzes the rate-limiting step for DNA and RNA biosynthesis. In this study, we investigated the quantitative structure-activity relationships (QSAR) of the antimalarial activity of PfDHODH inhibitors by generating four computational models using a multilinear regression (MLR) and a support vector machine (SVM) based on a dataset of 255 PfDHODH inhibitors. All the models display good prediction quality with a leave-one-out q(2) >0.66, a correlation coefficient (r) >0.85 on both training sets and test sets, and a mean square error (MSE) antimalarial activity. The models are capable of predicting inhibitors' antimalarial activity and the molecular descriptors for building the models could be helpful in the development of new antimalarial drugs.

  8. Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

    Science.gov (United States)

    Meyers, Marvin J; Anderson, Elizabeth J; McNitt, Sarah A; Krenning, Thomas M; Singh, Megh; Xu, Jing; Zeng, Wentian; Qin, Limei; Xu, Wanwan; Zhao, Siting; Qin, Li; Eickhoff, Christopher S; Oliva, Jonathan; Campbell, Mary A; Arnett, Stacy D; Prinsen, Michael J; Griggs, David W; Ruminski, Peter G; Goldberg, Daniel E; Ding, Ke; Liu, Xiaorong; Tu, Zhengchao; Tortorella, Micky D; Sverdrup, Francis M; Chen, Xiaoping

    2015-08-15

    Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Synthesis and evaluation of antimalarial properties of novel 4-aminoquinoline hybrid compounds.

    Science.gov (United States)

    Fisher, Gillian M; Tanpure, Rajendra P; Douchez, Antoine; Andrews, Katherine T; Poulsen, Sally-Ann

    2014-10-01

    Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine. © 2014 John Wiley & Sons A/S.

  10. Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity.

    Science.gov (United States)

    Ke, Hangjun; Morrisey, Joanne M; Qu, Shiwei; Chantarasriwong, Oraphin; Mather, Michael W; Theodorakis, Emmanuel A; Vaidya, Akhil B

    2017-01-01

    Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents. Copyright © 2016 American Society for Microbiology.

  11. A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.

    Science.gov (United States)

    Sadashiva, Maralinganadoddi P; Gowda, Raghavendra; Wu, Xianzhu; Inamdar, Gajanan S; Kuzu, Omer F; Rangappa, Kanchugarakoppal S; Robertson, Gavin P; Gowda, D Channe

    2015-08-01

    Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

    NARCIS (Netherlands)

    Kuhen, K.L.; Chatterjee, A.K.; Rottmann, M.; Gagaring, K.; Borboa, R.; Buenviaje, J.; Chen, Z.; Francek, C.; Wu, T.; Nagle, A.; Barnes, S.W.; Plouffe, D.; Lee, M.C.; Fidock, D.A.; Graumans, W.; Vegte, M.G. van de; Gemert, G.J.A. van; Wirjanata, G.; Sebayang, B.; Marfurt, J.; Russell, B.; Suwanarusk, R.; Price, R.N.; Nosten, F.; Tungtaeng, A.; Gettayacamin, M.; Sattabongkot, J.; Taylor, J.; Walker, J.R.; Tully, D.; Patra, K.P.; Flannery, E.L.; Vinetz, J.M.; Renia, L.; Sauerwein, R.W.; Winzeler, E.A.; Glynne, R.J.; Diagana, T.T.

    2014-01-01

    Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have

  13. Assessing the quality of anti-malarial drugs from Gabonese pharmacies using the MiniLab®: a field study

    NARCIS (Netherlands)

    Visser, Benjamin J.; Meerveld-Gerrits, Janneke; Kroon, Daniëlle; Mougoula, Judith; Vingerling, Rieke; Bache, Emmanuel; Boersma, Jimmy; van Vugt, Michèle; Agnandji, Selidji T.; Kaur, Harparkash; Grobusch, Martin P.

    2015-01-01

    Recent studies alluded to the alarming scale of poor anti-malarial drug quality in malaria-endemic countries, but also illustrated the major geographical gaps in data on anti-malarial drug quality from endemic countries. Data are particularly scarce from Central Africa, although it carries the

  14. Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Garavito G.

    2007-06-01

    Full Text Available Methylene blue (MB is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

  15. Synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants.

    Science.gov (United States)

    Tang, Ling; Bei, Zhuchun; Song, Yabin; Xu, Likun; Wang, Hong; Zhang, Dongna; Dou, Yuanyuan; Lv, Kai; Wang, Hongquan

    2017-07-01

    Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used. We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice. Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED 50 ], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED 50 : 0.48 mg/kg). The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.

  16. The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.

    Science.gov (United States)

    Helgren, Travis R; Sciotti, Richard J; Lee, Patricia; Duffy, Sandra; Avery, Vicky M; Igbinoba, Osayawemwen; Akoto, Matthew; Hagen, Timothy J

    2015-01-15

    A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement. Copyright © 2014 Elqsevier Ltd. All rights reserved.

  17. QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIP OF ANTIMALARIAL COMPOUND OF ARTEMISININ DERIVATIVES USING PRINCIPAL COMPONENT REGRESSION APPROACH

    Directory of Open Access Journals (Sweden)

    Paul Robert Martin Werfette

    2010-06-01

    Full Text Available Analysis of quantitative structure - activity relationship (QSAR for a series of antimalarial compound artemisinin derivatives has been done using principal component regression. The descriptors for QSAR study were representation of electronic structure i.e. atomic net charges of the artemisinin skeleton calculated by AM1 semi-empirical method. The antimalarial activity of the compound was expressed in log 1/IC50 which is an experimental data. The main purpose of the principal component analysis approach is to transform a large data set of atomic net charges to simplify into a data set which known as latent variables. The best QSAR equation to analyze of log 1/IC50 can be obtained from the regression method as a linear function of several latent variables i.e. x1, x2, x3, x4 and x5. The best QSAR model is expressed in the following equation,  (;;   Keywords: QSAR, antimalarial, artemisinin, principal component regression

  18. Synthesis and biological evaluation of febrifugine analogues as potential antimalarial agents.

    Science.gov (United States)

    Zhu, Shuren; Zhang, Quan; Gudise, Chandrashekar; Wei, Lai; Smith, Erika; Zeng, Yuling

    2009-07-01

    Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated for acute toxicity and in vitro and in vivo antimalarial efficacy. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drug chloroquine and are expected to possess wide therapeutic windows. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

  19. Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents.

    Science.gov (United States)

    Kumar, Parvin; Kadyan, Kulbir; Duhan, Meenakshi; Sindhu, Jayant; Singh, Vineeta; Saharan, Baljeet Singh

    2017-11-14

    Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a-g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one yeast i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. In vitro antiplasmodial IC 50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

  20. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.

    Science.gov (United States)

    Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N; Curtis, Joan M; Nguyen, William; Di Rago, Adrian E; Bullen, Hayley E; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M; Cowman, Alan F; Sleebs, Brad E

    2017-02-09

    Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

  1. Formulation of nanotized curcumin and demonstration of its antimalarial efficacy

    Science.gov (United States)

    Ghosh, Aparajita; Banerjee, Tanushree; Bhandary, Suman; Surolia, Avadhesha

    2014-01-01

    Aim The present study was conducted to overcome the disadvantages associated with the poor water solubility and low bioavailability of curcumin by synthesizing nanotized curcumin and demonstrating its efficacy in treating malaria. Materials and methods Nanotized curcumin was prepared by a modified emulsion-diffusion-evaporation method and was characterized by means of transmission electron microscopy, atomic force microscopy, dynamic light scattering, Zetasizer, Fourier transform infrared spectroscopy, and differential thermal analysis. The novelty of the prepared nanoformulation lies in the fact that it was devoid of any polymeric matrices used in conventional carriers. The antimalarial efficacy of the prepared nanotized curcumin was then checked both in vitro and in vivo. Results The nanopreparation was found to be non-toxic and had a particle size distribution of 20–50 nm along with improved aqueous dispersibility and an entrapment efficiency of 45%. Nanotized curcumin (half maximal inhibitory concentration [IC50]: 0.5 μM) was also found to be ten-fold more effective for growth inhibition of Plasmodium falciparum in vitro as compared to its native counterpart (IC50: 5 μM). Oral bioavailability of nanotized curcumin was found to be superior to that of its native counterpart. Moreover, when Plasmodium berghei-infected mice were orally treated with nanotized curcumin, it prolonged their survival by more than 2 months with complete clearance of parasites in comparison to the untreated animals, which survived for 8 days only. Conclusion Nanotized curcumin holds a considerable promise in therapeutics as demonstrated here for treating malaria as a test system. PMID:25484584

  2. Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5*

    Science.gov (United States)

    Liu, Liqiong; Richard, Jessica; Kim, Sunyoung; Wojcik, Edward J.

    2014-01-01

    Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable “next generation” target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are “druggable.” One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease. PMID:24737313

  3. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    DEFF Research Database (Denmark)

    Khalil, Insaf F; Alifrangis, Michael; Recke, Camilla

    2011-01-01

    In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite...

  4. A new in vivo screening paradigm to accelerate antimalarial drug discovery.

    Directory of Open Access Journals (Sweden)

    María Belén Jiménez-Díaz

    Full Text Available The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR, which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0 of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1 or induce parasite clearance (PRR >1 with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a

  5. Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands.

    Science.gov (United States)

    Hubin, Timothy J; Amoyaw, Prince N-A; Roewe, Kimberly D; Simpson, Natalie C; Maples, Randall D; Carder Freeman, TaRynn N; Cain, Amy N; Le, Justin G; Archibald, Stephen J; Khan, Shabana I; Tekwani, Babu L; Khan, M O Faruk

    2014-07-01

    Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development. Published by Elsevier Ltd.

  6. A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

    Science.gov (United States)

    Jiménez-Díaz, María Belén; Viera, Sara; Ibáñez, Javier; Mulet, Teresa; Magán-Marchal, Noemí; Garuti, Helen; Gómez, Vanessa; Cortés-Gil, Lorena; Martínez, Antonio; Ferrer, Santiago; Fraile, María Teresa; Calderón, Félix; Fernández, Esther; Shultz, Leonard D.; Leroy, Didier; Wilson, David M.; García-Bustos, José Francisco; Gamo, Francisco Javier; Angulo-Barturen, Iñigo

    2013-01-01

    The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task

  7. In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

    Directory of Open Access Journals (Sweden)

    Eberlin Marcos N

    2011-05-01

    Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.

  8. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

    Directory of Open Access Journals (Sweden)

    Mpimbaza Arthur

    2008-06-01

    Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

  9. Access to artesunate-amodiaquine, quinine and other anti-malarials: policy and markets in Burundi.

    Science.gov (United States)

    Amuasi, John H; Diap, Graciela; Blay-Nguah, Samuel; Boakye, Isaac; Karikari, Patrick E; Dismas, Baza; Karenzo, Jeanne; Nsabiyumva, Lievin; Louie, Karly S; Kiechel, Jean-René

    2011-02-10

    Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ) as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO) retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials. Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO), a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO) medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment) of AS-AQ, quinine and other anti-malarials were calculated. Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9%) compared to public (4.2%) and NGO (0%) outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu) for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu). Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu), private and NGO sectors (both US$1.61 or 2,000 FBu). Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors, whereas, it was equivalent to 1.5 days worth

  10. The ACTwatch project: methods to describe anti-malarial markets in seven countries.

    Science.gov (United States)

    Shewchuk, Tanya; O'Connell, Kathryn A; Goodman, Catherine; Hanson, Kara; Chapman, Steven; Chavasse, Desmond

    2011-10-31

    Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012.ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate findings widely for decision

  11. Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents.

    Science.gov (United States)

    Comer, Eamon; Beaudoin, Jennifer A; Kato, Nobutaka; Fitzgerald, Mark E; Heidebrecht, Richard W; Lee, Maurice duPont; Masi, Daniela; Mercier, Marion; Mulrooney, Carol; Muncipinto, Giovanni; Rowley, Ann; Crespo-Llado, Keila; Serrano, Adelfa E; Lukens, Amanda K; Wiegand, Roger C; Wirth, Dyann F; Palmer, Michelle A; Foley, Michael A; Munoz, Benito; Scherer, Christina A; Duvall, Jeremy R; Schreiber, Stuart L

    2014-10-23

    Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

  12. Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives.

    Science.gov (United States)

    Bhat, Hans Raj; Singh, Udaya Pratap; Thakur, Anjali; Kumar Ghosh, Surajit; Gogoi, Kabita; Prakash, Anil; Singh, Ramendra K

    2015-10-01

    A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS). Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain.

    Science.gov (United States)

    Iwaniuk, Daniel P; Whetmore, Eric D; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

    2009-09-15

    We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11-15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.

  14. The ACTwatch project: methods to describe anti-malarial markets in seven countries

    Directory of Open Access Journals (Sweden)

    Chapman Steven

    2011-10-01

    Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the

  15. The ACTwatch project: methods to describe anti-malarial markets in seven countries

    Science.gov (United States)

    2011-01-01

    Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate

  16. A call for using natural compounds in the development of new antimalarial treatments – an introduction

    Directory of Open Access Journals (Sweden)

    Deharo Eric

    2011-03-01

    Full Text Available Abstract Natural compounds, mostly from plants, have been the mainstay of traditional medicine for thousands of years. They have also been the source of lead compounds for modern medicine, but the extent of mining of natural compounds for such leads decreased during the second half of the 20th century. The advantage of natural compounds for the development of drugs derives from their innate affinity for biological receptors. Natural compounds have provided the best anti-malarials known to date. Recent surveys have identified many extracts of various organisms (mostly plants as having antiplasmodial activity. Huge libraries of fractionated natural compounds have been screened with impressive hit rates. Importantly, many cases are known where the crude biological extract is more efficient pharmacologically than the most active purified compound from this extract. This could be due to synergism with other compounds present in the extract, that as such have no pharmacological activity. Indeed, such compounds are best screened by cell-based assay where all potential targets in the cell are probed and possible synergies identified. Traditional medicine uses crude extracts. These have often been shown to provide many concoctions that deal better with the overall disease condition than with the causative agent itself. Traditional medicines are used by ~80 % of Africans as a first response to ailment. Many of the traditional medicines have demonstrable anti-plasmodial activities. It is suggested that rigorous evaluation of traditional medicines involving controlled clinical trials in parallel with agronomical development for more reproducible levels of active compounds could improve the availability of drugs at an acceptable cost and a source of income in malaria endemic countries.

  17. Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity.

    Science.gov (United States)

    Vyas, V K; Qureshi, G; Ghate, M; Patel, H; Dalai, S

    2016-06-01

    Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere-Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.

  18. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

    NARCIS (Netherlands)

    Paquet, T.; Manach, C.; Cabrera, D.G.; Younis, Y.; Henrich, P.P.; Abraham, T.S.; Lee, M.C.; Basak, R.; Ghidelli-Disse, S.; Lafuente-Monasterio, M.J.; Bantscheff, M.; Ruecker, A.; Blagborough, A.M.; Zakutansky, S.E.; Zeeman, A.M.; White, K.L.; Shackleford, D.M.; Mannila, J.; Morizzi, J.; Scheurer, C.; Angulo-Barturen, I.; Martinez, M.S.; Ferrer, S.; Sanz, L.M.; Gamo, F.J.; Reader, J.; Botha, M.; Dechering, K.J.; Sauerwein, R.W.; Tungtaeng, A.; Vanachayangkul, P.; Lim, C.S.; Burrows, J.; Witty, M.J.; Marsh, K.C.; Bodenreider, C.; Rochford, R.; Solapure, S.M.; Jimenez-Diaz, M.B.; Wittlin, S.; Charman, S.A.; Donini, C.; Campo, B.; Birkholtz, L.M.; Hanson, K.K.; Drewes, G.; Kocken, C.H.; Delves, M.J.; Leroy, D.; Fidock, D.A.; Waterson, D.; Street, L.J.; Chibale, K

    2017-01-01

    As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with

  19. Trends in pregnancy outcomes in Malawian adolescents receiving antimalarial and hematinic supplements

    NARCIS (Netherlands)

    Msyamboza, Kelias; Savage, Emma; Kalanda, Gertrude; Kazembe, Peter; Gies, Sabine; d'Alessandro, Umberto; Brabin, Bernard J.

    2010-01-01

    Objective. To describe pregnancy outcomes of adolescent and adult primigravidae receiving antimalarials and hematinic supplementation and compare findings with a survey in this area a decade earlier. Design. Cross-sectional surveys in intervention and control sites. Setting. Community, antenatal and

  20. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus

    DEFF Research Database (Denmark)

    Kuhn, A; Sigges, J; Biazar, C

    2014-01-01

    . Smoking behaviour was assessed by the EUSCLE Core Set Questionnaire in 838 patients and statistically analysed using an SPSS database. The results were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the efficacy of antimalarial treatment. RESULTS: A high...

  1. A SAR and QSAR study of new artemisinin compounds with antimalarial activity.

    Science.gov (United States)

    Santos, Cleydson Breno R; Vieira, Josinete B; Lobato, Cleison C; Hage-Melim, Lorane I S; Souto, Raimundo N P; Lima, Clarissa S; Costa, Elizabeth V M; Brasil, Davi S B; Macêdo, Williams Jorge C; Carvalho, José Carlos T

    2013-12-30

    The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs) and molecular docking were used to investigate the interaction between ligands and the receptor (heme). Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE), the charge on the O11 oxygen atom (QO11), the torsion angle O1-O2-Fe-N2 (D2) and the maximum rate of R/Sanderson Electronegativity (RTe+). These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

  2. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    Energy Technology Data Exchange (ETDEWEB)

    Egan, J.A.Judith A.; Laseter, Anne G; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

    2002-09-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

  3. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Cleydson Breno R. Santos

    2013-12-01

    Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

  4. New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica

    DEFF Research Database (Denmark)

    Valsaraj, R; Pushpangadan, P; Smitt, U W

    1997-01-01

    A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....

  5. Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

    Science.gov (United States)

    Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J; Chiu, Francis C K; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L; Urwyler, Heinrich; Charman, William N; Matile, Hugues; Wittlin, Sergio; Charman, Susan A; Vennerstrom, Jonathan L

    2017-04-13

    Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK a and lower log D 7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D 7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

  6. In vivo antimalarial activity of a labdane diterpenoid from the leaves of Otostegia integrifolia Benth.

    Science.gov (United States)

    Endale, Abyot; Bisrat, Daniel; Animut, Abebe; Bucar, Franz; Asres, Kaleab

    2013-12-01

    In Ethiopian traditional medicine, the leaves of Otostegia integrifolia Benth. are used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the 80% methanol leaf extract O. integrifolia was tested for its in vivo antimalarial activity, in a 4-day suppressive assay against Plasmodium berghei. Activity-guided fractionation of this extract which showed potent antiplasmodial activity resulted in the isolation of a labdane diterpenoid identified as otostegindiol. Otostegindiol displayed a significant (P antimalarial activity at doses of 25, 50 and 100 mg/kg with chemosuppression values of 50.13, 65.58 and 73.16%, respectively. Acute toxicity studies revealed that the crude extract possesses no toxicity in mice up to a maximum dose of 5000 mg/kg suggesting the relative safety of the plant when administered orally. The results of the present study indicate that otostegindiol is among the antimalarial principles in this medicinal plant, and further support claims for the traditional medicinal use of the plant for the treatment of malaria. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Potentiation of antimalarial activity of arteether in combination with Vetiver root extract.

    Science.gov (United States)

    Dhawan, Sangeeta; Gunjan, Sarika; Pal, Anirban; Tripathi, Renu

    2016-05-01

    In malaria, development of resistance towards artemisinin derivatives has urged the need for new drugs or new drug combinations to tackle the drug resistant malaria. We studied the fresh root extract of Vetiver zizanioides (Linn.) Nash (VET) with a CDRI-CIMAP antimalarial α/β arteether (ART) together for their antimalarial potential. Our results showed additive to synergistic antimalarial activity of VET and ART with sum fractional inhibitory concentrations Σ FICs 1.02 ± 0.24 and 1.12 ± 0.32 for chloroquine sensitive (CQS) and chloroquine resistant (CQR) strain of Plasmodium falciparum (William H. Welch), respectively. Further, these combinations were explored against multidrug resistant rodent malaria parasite i.e. P. yoelii nigeriensis. Analysis of in vivo interaction of ART and VET showed that 10 mg/kg x 5 days of ART with 1000 mg/kg of VET x 5 days cured 100% mice infected with MDR parasite, while the same dose of ART could produce only up to 30% cure and VET fraction was not curative at all. Synergism/additiveness, found between VET and ART is reported for the first time. The curative dose of ART in the combination was reduced to its one fourth, and thus limits the side effects, if any. Although antimalarial potential of ART was enhanced by VET, action mechanism of later needs to be elucidated in detail.

  8. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    NARCIS (Netherlands)

    Baragana, B.; Hallyburton, I.; Lee, M.C.; Norcross, N.R.; Grimaldi, R.; Otto, T.D.; Proto, W.R.; Blagborough, A.M.; Meister, S.; Wirjanata, G.; Ruecker, A.; Upton, L.M.; Abraham, T.S.; Almeida, M.J.; Pradhan, A.; Porzelle, A.; Martinez, M.S.; Bolscher, J.M.; Woodland, A.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.; Stojanovski, L.; Osuna-Cabello, M.; Brock, P.M.; Churcher, T.S.; Sala, K.A.; Zakutansky, S.E.; Jimenez-Diaz, M.B.; Sanz, L.M.; Riley, J.; Basak, R.; Campbell, M.; Avery, V.M.; Sauerwein, R.W.; Dechering, K.J.; Noviyanti, R.; Campo, B.; Frearson, J.A.; Angulo-Barturen, I.; Ferrer-Bazaga, S.; Gamo, F.J.; Wyatt, P.G.; Leroy, D.; Siegl, P.; Delves, M.J.; Kyle, D.E.; Wittlin, S.; Marfurt, J.; Price, R.N.; Sinden, R.E.; Winzeler, E.A.; Charman, S.A.; Bebrevska, L.; Gray, D.W.; Campbell, S.; Fairlamb, A.H.; Willis, P.A.; Rayner, J.C.; Fidock, D.A.; Read, K.D.; Gilbert, I.H.

    2015-01-01

    There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial

  9. Gracilioethers A-C, Antimalarial Metabolites from the Marine Sponge Agelas gracilis

    NARCIS (Netherlands)

    Ueoka, R.; Nakao, Y.; Kawatsu, S.; Yaegashi, J.; Matsumoto, Y.; Matsunaga, S.; Furihata, K; van Soest, R.W.M.; Fusetani, N.

    2009-01-01

    Three new antiprotozoan compounds, gracilioethers A−C (1−3), have been isolated from the marine sponge Agelas gracilis. Their structures were elucidated on the basis of spectroscopic and chemical methods. Gracilioethers A−C showed antimalarial activity against Plasmodium falciparum with IC50 values

  10. Antimalarial activity of Syzygium guineense during early and established Plasmodium infection in rodent models.

    Science.gov (United States)

    Tadesse, Solomon Asmamaw; Wubneh, Zewdu Birhanu

    2017-01-05

    In Ethiopia, the leaves of Syzygium guineense have been found useful for the prevention and cure of malaria, and demonstrated antiplasmodial activity in vitro. Nevertheless, no scientific study has been conducted to confirm its antimalarial activity in vivo. Therefore, the objective of the study was to evaluate the antimalarial effect of Syzygium guineense leaf extract in mice. Inoculation of the study mice was carried out by using the malaria parasite, Plasmodium berghei. The plant extract was prepared at 200, 400 and 600 mg/kg. Chloroquine and distilled water was administered to the positive and negative control groups respectively. Parameters like parasitaemia, survival time and body weight were determined following standard tests (4-day suppressive, Rane's and repository tests). Syzygium guineense crude leaf extract displayed considerable (p activity in both the repository and curative tests. The extract also prevented body weight loss and prolonged survival date of mice significantly (P antimalarial activity in mice. The test substance was found to be safe with no observable signs of toxicity in the study mice. The results of the present work confirmed the in vitro antiplasmodial finding and traditional claims in vivo in mice. Therefore, Syzygium guineense could be regarded as a potential source to develop safe, effective and affordable antimalarial agent.

  11. Novel series of 1,2,4-trioxane derivatives as antimalarial agents.

    Science.gov (United States)

    Rudrapal, Mithun; Chetia, Dipak; Singh, Vineeta

    2017-12-01

    Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC 50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski's rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

  12. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    International Nuclear Information System (INIS)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N.

    2002-01-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3- 3 H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl- 3 H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [ 3 H] ethyl iodide

  13. Evaluation of In-vivo Antimalarial Activity of Methanol Leaf Extract of ...

    African Journals Online (AJOL)

    Abstract. Purpose: To evaluate the in-vivo antimalarial activity of the methanol extract of the leaves of Glyphaea brevis in ... alternative malarial drugs, with novel modes of action [4]. ... The mean lethal dose of the three fractions. (ethylacetate ...

  14. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Arezoo Rafiee Parhizgar

    2017-03-01

    Full Text Available Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ and amodiaquine (AQ, have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

  15. N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

    Science.gov (United States)

    Gomes, Ana; Pérez, Bianca; Albuquerque, Inês; Machado, Marta; Prudêncio, Miguel; Nogueira, Fátima; Teixeira, Cátia; Gomes, Paula

    2014-02-01

    Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 μM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

    Science.gov (United States)

    Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

    2008-03-15

    Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

  17. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

    Science.gov (United States)

    Parhizgar, Arezoo Rafiee; Tahghighi, Azar

    2017-03-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

  18. Evaluation of in vivo antimalarial activity of the ethanolic leaf extracts ...

    African Journals Online (AJOL)

    Prof. Ogunji

    Plasmodium berghei berghei in mice was evaluated. ... indicated in the consistent increase in weight and slight increase in the PCV ... Key words: Chromolaena odorata, Cymbopogon citratus, anti-malarial .... This was prepared by determining both the percentage parasitaemia and the ..... Malaria vaccine: Multiple targets.

  19. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

    Directory of Open Access Journals (Sweden)

    Leslie Toby

    2008-12-01

    Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

  20. In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra.

    Directory of Open Access Journals (Sweden)

    Komal Kalani

    Full Text Available Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69 µg/ml anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250 mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.

  1. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    Directory of Open Access Journals (Sweden)

    Shen S

    2015-06-01

    Full Text Available Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data

  2. Bioactive compounds fractionated from endophyte Streptomyces SUK 08 with promising ex-vivo antimalarial activity

    Directory of Open Access Journals (Sweden)

    Noraziah Mohamad Zin

    2017-12-01

    Full Text Available Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract. Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry. Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/mL. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/mL. The IC50 of parasitemia at 5% and 30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs. Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations. Keywords: Butyl–propyl–ester, Cyclohexane, 2,3-Heptanedione, Endophyte, Streptomyces, Antimalarial

  3. Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide.

    Science.gov (United States)

    Ugwu, D I; Okoro, U C; Ukoha, P O; Okafor, S; Ibezim, A; Kumar, N M

    2017-07-28

    Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC 50 value of 0.045 mM comparable with 0.34 mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica

    Directory of Open Access Journals (Sweden)

    Misael Chinchilla

    2012-06-01

    Full Text Available Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB, were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae; Xanthosoma undipes (Araceae; Iriartea deltoidea (Arecaceae; Neurolaena lobata (Asteraceae; Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae; Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae; Hampea appendiculata (Malvaceae; Ruagea glabra, Guarea glabra (Meliaceae; Psidium guajava (Myrtaceae; Bocconia frutescens (Papaveraceae; Piper friedrichsthalii (Piperaceae; Clematis dioica (Ranunculaceae; Prunus annularis (Rosaceae; Siparuna thecaphora (Siparunaceae; Solanum arboreum, Witheringia solanácea (Solanaceae; Ticodendrum incognitum (Ticodendraceae; Heliocarpus appendiculatus (Tiliaceae and Myriocarpa longipes (Urticaceae. We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  5. Ameliorative antimalarial effects of the combination of rutin and swertiamarin on malarial parasites

    Directory of Open Access Journals (Sweden)

    Divya Shitlani

    2016-06-01

    Full Text Available Objective: To ameliorate the antimalarial activity via the combination of rutin (flavonoid and swertiamarin (glycoside. Methods: The antimalarial effects were assessed by in vitro and in vivo methodology. In vitro antiplasmodial activity was assessed by using Plasmodium falciparum cultured media and determined the IC 50 value of individual drugs and their combinations. In in vivo methodology, antimalarial effects of rutin, swertiamarin (200–280 mg/kg/day, p.o. and their combination in 1:1, 1:2 and 2:1 ratios were investigated early and established malaria infections using Swiss albino mice infected with Plasmodium berghei. Chloroquine phosphate (5 mg/kg/day, p.o. was used as the standard drug. Results: IC 50 values of the rutin and swertiamarin via in vitro study revealed (9.50 ± 0.29 µg/ mL and (8.17 ± 0.17 µg/mL respectively. Whereas, the combination in 1:1 ratio [IC50 of (5.51 ± 0.18 µg/mL] showed better antiplasmodial activity against Plasmodium falciparum. In vivo results showed that rutin and swertiamarin had chemosuppressant effects in a dose-dependent manner, whereas, combination in 1:1 ratio possessed potential antimalarial activity similar to chloroquine phosphate. The drug interaction between rutin and swertiamarin revealed the synergistic effect on 1:1 ratio and additive effect on 1:2 and 2:1 ratios. Conclusions: The results of the in vitro and in vivo study clearly indicate that the combination (1:1 of rutin and swertiamarin showed potential antimalarial activity rather than an individual of each and their combinations 1:2 and 2:1.

  6. Mass anti-malarial administration in western Cambodia: a qualitative study of factors affecting coverage.

    Science.gov (United States)

    Pell, Christopher; Tripura, Rupam; Nguon, Chea; Cheah, Phaikyeong; Davoeung, Chan; Heng, Chhouen; Dara, Lim; Sareth, Ma; Dondorp, Arjen; von Seidlein, Lorenz; Peto, Thomas J

    2017-05-19

    Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.

  7. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica.

    Science.gov (United States)

    Chinchilla, Misael; Valerio, Idalia; Sánchez, Ronald; Mora, Víctor; Bagnarello, Vanessa; Martínez, Laura; Gonzalez, Antonieta; Vanegas, Juan Carlos; Apestegui, Alvaro

    2012-06-01

    Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biol6gica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9 microg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  8. The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain.

    Science.gov (United States)

    Ehrhardt, Katharina; Davioud-Charvet, Elisabeth; Ke, Hangjun; Vaidya, Akhil B; Lanzer, Michael; Deponte, Marcel

    2013-05-01

    Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are "subversive substrates." These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.

  9. The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

    NARCIS (Netherlands)

    Achan, Jane; Adam, Ishag; Arinaitwe, Emmanuel; Ashley, Elizabeth A.; Awab, Ghulam Rahim; Ba, Mamadou S.; Barnes, Karen I.; Bassat, Quique; Borrmann, Steffen; Bousema, Teun; Dahal, Prabin; D' Alessandro, Umberto; Davis, Timothy M. E.; Dondorp, Arjen M.; Dorsey, Grant; Drakeley, Chris J.; Fanello, Caterina I.; Faye, Babacar; Flegg, Jennifer A.; Gaye, Oumar; Gething, Peter W.; González, Raquel; Guerin, Philippe J.; Hay, Simon I.; Hien, Tran T.; Janssens, Bart; Kamya, Moses R.; Karema, Corine; Karunajeewa, Harin A.; Kone, Moussa; Lell, Bertrand; Marsh, Kevin; Mayxay, Mayfong; Menéndez, Clara; Mens, Petra F.; Meremikwu, Martin; Moreira, Clarissa; Mueller, Ivo; Nabasumba, Carolyn; Nambozi, Michael; Ndiaye, Jean-Louis; Newton, Paul N.; Nguyen, Thuy-Nhien; Nosten, Francois; Nsanzabana, Christian; Omar, Sabah A.; Ouédraogo, Jean-Bosco; Penali, Louis K.; Pene, Mbaye; van Vugt, Michele

    2013-01-01

    Background: Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical

  10. Preparation, characterization and in vitro release kinetics of polyaspartamide-based conjugates containing antimalarial and anticancer agents for combination therapy

    CSIR Research Space (South Africa)

    Aderibigbe, BA

    2016-09-01

    Full Text Available Malaria is treated by combination of two drugs in order to overcome drug resistance. Antimalarials have been found to be more effective by combining them with low doses of anticancer drugs. Polymer-drug conjugates containing aminoquinoline...

  11. Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials▿

    Science.gov (United States)

    Creek, Darren J.; Charman, William N.; Chiu, Francis C. K.; Prankerd, Richard J.; Dong, Yuxiang; Vennerstrom, Jonathan L.; Charman, Susan A.

    2008-01-01

    The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study. PMID:18268087

  12. Synthesis and evaluation of antimalarial activity of curcumin derivatives; Sintese e avaliacao da atividade antimalarica de compostos derivados da curcumina

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa [Universidade Federal de Juiz de Fora (UFSJ), MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla, E-mail: varotti@ufsj.edu.br [Universidade Federal de Sao Joao Del Rei (UFSJ), MG (Brazil). Centro de Ciencias da Saude; others, and

    2014-05-15

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC{sub 50} values ranging from 1.7 to 15.2 μg mL{sup -1}), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  13. Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation.

    Science.gov (United States)

    Maetani, Micah; Zoller, Jochen; Melillo, Bruno; Verho, Oscar; Kato, Nobutaka; Pu, Jun; Comer, Eamon; Schreiber, Stuart L

    2017-08-16

    The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC 50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp 3 )-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

  14. Case management of malaria fever in Cambodia: results from national anti-malarial outlet and household surveys

    Directory of Open Access Journals (Sweden)

    Littrell Megan

    2011-10-01

    Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial

  15. Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN

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    Barnes Karen I

    2010-12-01

    Full Text Available Abstract Background The Worldwide Antimalarial Resistance Network (WWARN is a global collaboration to support the objective that anyone affected by malaria receives effective and safe drug treatment. The Pharmacology module aims to inform optimal anti-malarial drug selection. There is an urgent need to define the drug exposure - effect relationship for most anti-malarial drugs. Few anti-malarials have had their therapeutic blood concentration levels defined. One of the main challenges in assessing safety and efficacy data in relation to drug concentrations is the comparability of data generated from different laboratories. To explain differences in anti-malarial pharmacokinetics in studies with different measurement laboratories it is necessary to confirm the accuracy of the assay methods. This requires the establishment of an external quality assurance process to assure results that can be compared. This paper describes this process. Methods The pharmacology module of WWARN has established a quality assurance/quality control (QA/QC programme consisting of two separate components: 1. A proficiency testing programme where blank human plasma spiked with certified reference material (CRM in different concentrations is sent out to participating bioanalytical laboratories. 2. A certified reference standard programme where accurately weighed amounts of certified anti-malarial reference standards, metabolites, and internal standards are sent to participating bioanalytical and in vitro laboratories. Conclusion The proficiency testing programme is designed as a cooperative effort to help participating laboratories assess their ability to carry out drug analysis, resolve any potential problem areas and to improve their results - and, in so doing, to improve the quality of anti-malarial pharmacokinetic data published and shared with WWARN. By utilizing the same source of standards for all laboratories, it is possible to minimize bias arising from poor

  16. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    OpenAIRE

    Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan

    2010-01-01

    Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...

  17. Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.

    Science.gov (United States)

    Mane, Uttam R; Mohanakrishnan, D; Sahal, Dinkar; Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

    2014-05-22

    Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin-3-yl)carbamate (21, IC50 value 33 μM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 μM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  18. Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake

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    Carmen E Contreras

    2004-03-01

    Full Text Available The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

  19. 4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle.

    Science.gov (United States)

    Roberts, Bracken F; Zheng, Yongsheng; Cleaveleand, Jacob; Lee, Sukjun; Lee, Eunyoung; Ayong, Lawrence; Yuan, Yu; Chakrabarti, Debopam

    2017-04-01

    Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

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    Valter F de Andrade-Neto

    2007-06-01

    Full Text Available In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae, the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae, respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae, all presented significant in vitro inhibition (more active than quinine and chloroquine of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

  1. 4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

    Science.gov (United States)

    Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

    2015-01-07

    A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    Science.gov (United States)

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-06-01

    There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

  3. Screening of the antimalarial activity of plants of the Cucurbitaceae family

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    Cláudia Zuany Amorim

    1991-01-01

    Full Text Available Crude ethanolic extracts (CEEs from two species of Cucurbitaceae, Cucurbita maxima and Momordica charantia (commonly called "abóbora moranga" and melão de São Caetano", respectively were assayed for antimalarial activity by the 4-d suppressive test. The CEE of dry C. maxima seeds showed strong antimalarial activity following oral administration (259 and 500 mg/kg, reducing by 50% the levels of parasistemia in Plasmodium berghey-infected mice. Treatment of normal animals with 500 mg/Kg of the extract three days before intravenous injection of P. berghei caused a significant 30% reduction in parasitemic levels. No effect was observed when the animals were treated with the CEE only on the day of inoculation. Oral administration of the CEE of dry M. charantia leaves adminstered orally was ineffective up to 500 mg/Kg in lowering the parasitemic levels of malarious mice.

  4. Antimalarial activity of 4-(5-trifluoromethyl-1H-pyrazol-1-yl)-chloroquine analogues.

    Science.gov (United States)

    Cunico, Wilson; Cechinel, Cleber A; Bonacorso, Helio G; Martins, Marcos A P; Zanatta, Nilo; de Souza, Marcus V N; Freitas, Isabela O; Soares, Rodrigo P P; Krettli, Antoniana U

    2006-02-01

    The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.

  5. Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas.

    Science.gov (United States)

    Ekoue-Kovi, Kekeli; Yearick, Kimberly; Iwaniuk, Daniel P; Natarajan, Jayakumar K; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

    2009-01-01

    We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC(50)s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

  6. Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

    Energy Technology Data Exchange (ETDEWEB)

    Ei, Shun Lai; Mon, Hla Myat; Myint, Khin Htay

    2008-06-15

    In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively.

  7. Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

    International Nuclear Information System (INIS)

    Shun Lai Ei; Hla Myat Mon; Khin Htay Myint

    2008-06-01

    In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively

  8. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

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    Swain Bijay K

    2009-02-01

    Full Text Available Abstract Background Herbal extracts of Andrographis paniculata (AP and Hedyotis corymbosa (HC are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20 and resistant (MRC-pf-303 strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50 of AP (7.2 μg/ml was found better than HC (10.8 μg/ml. Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC and their individual synergism with curcumin (AP+CUR, HC+CUR were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs.

  9. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    Science.gov (United States)

    Mishra, Kirti; Dash, Aditya P; Swain, Bijay K; Dey, Nrisingha

    2009-01-01

    Background Herbal extracts of Andrographis paniculata (AP) and Hedyotis corymbosa (HC) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20) and resistant (MRC-pf-303) strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50) of AP (7.2 μg/ml) was found better than HC (10.8 μg/ml). Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC) and their individual synergism with curcumin (AP+CUR, HC+CUR) were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs. PMID:19216765

  10. Malaria healthcare policy change in Kenya: implications on sales and marketing of antimalarials.

    Science.gov (United States)

    Ngure, Peter K; Nyaoke, Lorraine; Minja, David

    2012-03-01

    Malaria healthcare policy change in Kenya aimed at improving the control of malaria but faced a number of challenges in implementation related to marketing of the drugs. This research investigated the effect of the change of the national malaria policy on drug sales and strategic marketing responses of antimalarial pharmaceutical companies in Kenya. A descriptive cross-sectional design was employed to describe the existing state of antimalarials market in Kenya after the change of the malaria healthcare policy. Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recorded a 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by all the companies. Further, SPs (which had been replaced as first-line therapy for malaria) registered good sales. In most cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs and generic antimalarial medicines exceeded that of Coartem® for most distributors. The most common change made to marketing strategies by distributors (62.5%) was to increase imports of antimalarials. A total of 40% of the manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the fact that continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence of malaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensure drugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the national guidelines.

  11. Preliminary assessment of medicinal plants used as antimalarials in the southeastern Venezuelan Amazon

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    Caraballo Alejandro

    2004-01-01

    Full Text Available Eighteen species of medicinal plants used in the treatment of malaria in Bolívar State, Venezuela were recorded and they belonged to Compositae, Meliaceae, Anacardiaceae, Bixaceae, Boraginaceae, Caricaceae, Cucurbitaceae, Euphorbiaceae, Leguminosae, Myrtaceae, Phytolaccaceae, Plantaginaceae, Scrophulariaceae, Solanaceae and Verbenaceae families. Antimalarial plant activities have been linked to a range of compounds including anthroquinones, berberine, flavonoids, limonoids, naphthquinones, sesquiterpenes, quassinoids, indol and quinoline alkaloids.

  12. Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals.

    Science.gov (United States)

    Shibi, Indira G; Aswathy, Lilly; Jisha, Radhakrishnan S; Masand, Vijay H; Gajbhiye, Jayant M

    2016-01-01

    Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

  13. Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity.

    Science.gov (United States)

    Levatić, Jurica; Pavić, Kristina; Perković, Ivana; Uzelac, Lidija; Ester, Katja; Kralj, Marijeta; Kaiser, Marcel; Rottmann, Matthias; Supek, Fran; Zorc, Branka

    2018-02-25

    Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R 2  = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  14. Antimalarial and antiplasmodial activity of husk extract and fractions of Zea mays.

    Science.gov (United States)

    Okokon, Jude E; Antia, Bassey S; Mohanakrishnan, Dinesh; Sahal, Dinkar

    2017-12-01

    Zea mays L. (Poacae) husk decoctions are traditionally used in the treatment of malaria by various tribes in Nigeria. To assess the antimalarial and antiplasmodial potentials of the husk extract and fractions on malaria parasites using in vivo and in vitro models. The ethanol husk extract and fractions (187-748 mg/kg, p.o.) of Zea mays were investigated for antimalarial activity against Plasmodium berghei using rodent (mice) malaria models and in vitro activity against chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using the SRBR green assay method. Median lethal dose and cytotoxic activities against HeLa and HEKS cells were also carried out. The GCMS analysis of the most active fraction was carried out. The husk extract (187-748 mg/kg, p.o.) with LD 50 of 1874.83 mg/kg was found to exert significant (p antimalarial activity against P. berghei infection in suppressive, prophylactive and curative tests. The crude extract and fractions also exerted prominent activity against both chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with the ethyl acetate fraction exerting the highest activity with IC 50 values of 9.31 ± 0.46 μg/mL (Pf 3D7) and 3.69 ± 0.66 μg/mL (Pf INDO). The crude extract and fractions were not cytotoxic to the two cell lines tested with IC 50 values of >100 μg/mL against both HeLa and HEKS cell lines. These results suggest that the husk extract/fractions of Zea mays possesses antimalarial and antiplasmodial activities and these justify its use in ethnomedicine to treat malaria infections.

  15. Antimalarial peroxides: the first intramolecular 1,2,4,5-tetraoxane

    Directory of Open Access Journals (Sweden)

    BOGDAN A. SOLAJA

    2002-07-01

    Full Text Available An intramolecular steroidal 1,2,4,5-tetraoxane has been synthesised in six steps starting from methyl 3-oxo-7a,12a-diacetoxy-5b-cholan-24-oate. The synthesised 1,2,4,5-tetraoxane has moderate in vitro antimalarial activity against P. falciparum strains (IC50 (D6 = 0.35 mg/mL; IC50 (W2 = 0.29 mg/mL.

  16. Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues

    OpenAIRE

    Bianca C Perez; Iva Fernandes; Nuno Mateus; Catia Teixeira; Paula Gomes

    2013-01-01

    Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines t...

  17. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    OpenAIRE

    Arezoo Rafiee Parhizgar; Azar Tahghighi

    2017-01-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the othe...

  18. Synthesis of gallinamide A analogues as potent falcipain inhibitors and antimalarials.

    Science.gov (United States)

    Conroy, Trent; Guo, Jin T; Elias, Nabiha; Cergol, Katie M; Gut, Jiri; Legac, Jennifer; Khatoon, Lubna; Liu, Yang; McGowan, Sheena; Rosenthal, Philip J; Hunt, Nicholas H; Payne, Richard J

    2014-12-26

    Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.

  19. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

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    Jason P Wendler

    Full Text Available Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  20. Cutting edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction.

    Science.gov (United States)

    An, Jie; Woodward, Joshua J; Sasaki, Tomikazu; Minie, Mark; Elkon, Keith B

    2015-05-01

    Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi-Goutières syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi-Goutières syndrome. To identify drugs that could potentially inhibit cGAS activity, we performed in silico screening of drug libraries. By computational analysis, we identified several antimalarial drugs (AMDs) that were predicted to interact with the cGAS/dsDNA complex. Our studies validated that several AMDs were effective inhibitors of IFN-β production and that they functioned by inhibiting dsDNA stimulation of cGAS. Because AMDs have been widely used in human diseases and have an excellent safety profile, our findings suggest new therapeutic strategies for the treatment of severe debilitating diseases associated with type I IFNs due to cGAS activation. Copyright © 2015 by The American Association of Immunologists, Inc.

  1. The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock

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    Xiaoli Chen

    2017-01-01

    Full Text Available Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1β and IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1β, IL-18, and Nlrp3 in LPS treated murine bone marrow-derived macrophages (BMDMs, demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1β and IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock.

  2. Chloroquine Interference with Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent

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    Christian A. Schaer

    2013-01-01

    Full Text Available The CD163 scavenger receptor pathway for Hb:Hp complexes is an essential mechanism of protection against the toxicity of extracellular hemoglobin (Hb, which can accumulate in the vasculature and within tissues during hemolysis. Chloroquine is a lysosomotropic agent, which has been extensively used as an antimalarial drug in the past, before parasite resistance started to limit its efficacy in most parts of the world. More recent use of chloroquine is related to its immunomodulatory activity in patients with autoimmune diseases, which may also involve hemolytic disease components. In this study we examined the effects of chloroquine on the human Hb clearance pathway. For this purpose we developed a new mass-spectrometry-based method to specifically quantify intracellular Hb peptides within the endosomal-lysosomal compartment by single reaction monitoring (SRM. We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1 response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.

  3. Antimalarial Activity of Orally Administered Curcumin Incorporated in Eudragit®-Containing Liposomes

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    Elisabet Martí Coma-Cros

    2018-05-01

    Full Text Available Curcumin is an antimalarial compound easy to obtain and inexpensive, having shown little toxicity across a diverse population. However, the clinical use of this interesting polyphenol has been hampered by its poor oral absorption, extremely low aqueous solubility and rapid metabolism. In this study, we have used the anionic copolymer Eudragit® S100 to assemble liposomes incorporating curcumin and containing either hyaluronan (Eudragit-hyaluronan liposomes or the water-soluble dextrin Nutriose® FM06 (Eudragit-nutriosomes. Upon oral administration of the rehydrated freeze-dried nanosystems administered at 25/75 mg curcumin·kg−1·day−1, only Eudragit-nutriosomes improved the in vivo antimalarial activity of curcumin in a dose-dependent manner, by enhancing the survival of all Plasmodium yoelii-infected mice up to 11/11 days, as compared to 6/7 days upon administration of an equal dose of the free compound. On the other hand, animals treated with curcumin incorporated in Eudragit-hyaluronan liposomes did not live longer than the controls, a result consistent with the lower stability of this formulation after reconstitution. Polymer-lipid nanovesicles hold promise for their development into systems for the oral delivery of curcumin-based antimalarial therapies.

  4. Muddled mechanisms: recent progress towards antimalarial target identification [version 1; referees: 2 approved

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    Rachel L. Edwards

    2016-10-01

    Full Text Available In the past decade, malaria rates have plummeted as a result of aggressive infection control measures and the adoption of artemisinin-based combination therapies (ACTs. However, a potential crisis looms ahead. Treatment failures to standard antimalarial regimens have been reported in Southeast Asia, and devastating consequences are expected if resistance spreads to the African continent. To prevent a potential public health emergency, the antimalarial arsenal must contain therapeutics with novel mechanisms of action (MOA. An impressive number of high-throughput screening (HTS campaigns have since been launched, identifying thousands of compounds with activity against one of the causative agents of malaria, Plasmodium falciparum. Now begins the difficult task of target identification, for which studies are often tedious, labor intensive, and difficult to interpret. In this review, we highlight approaches that have been instrumental in tackling the challenges of target assignment and elucidation of the MOA for hit compounds. Studies that apply these innovative techniques to antimalarial target identification are described, as well as the impact of the data in the field.

  5. Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review

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    Shweta Sinha

    2017-10-01

    Full Text Available The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000–2,000,000 compounds per screening campaign, before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug–drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells.

  6. Antimalarial Activity of the Chemical Constituents of the Leaf Latex of Aloe pulcherrima Gilbert and Sebsebe.

    Science.gov (United States)

    Teka, Tekleab; Bisrat, Daniel; Yeshak, Mariamawit Yonathan; Asres, Kaleab

    2016-10-28

    Malaria is one of the three major global public health threats due to a wide spread resistance of the parasites to the standard antimalarial drugs. Considering this growing problem, the ethnomedicinal approach in the search for new antimalarial drugs from plant sources has proven to be more effective and inexpensive. The leaves of Aloe pulcherrima Gilbert and Sebsebe, an endemic Ethiopian plant, are locally used for the treatment of malaria and other infectious diseases. Application of the leaf latex of A. pulcherrima on preparative silica gel TLC led to the isolation of two C -glycosylated anthrones, identified as nataloin ( 1 ) and 7-hydroxyaloin ( 2 ) by spectroscopic techniques (UV, IR, ¹H- and 13 C-NMR, HR-ESIMS). Both the latex and isolated compounds displayed antimalarial activity in a dose-independent manner using a four-day suppressive test, with the highest percent suppression of 56.2% achieved at 200 mg/kg/day for 2 . The results indicate that both the leaf latex of A. pulcherrima and its two major constituents are endowed with antiplasmodial activities, which support the traditional use of the leaves of the plant for the treatment of malaria.

  7. High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death.

    Science.gov (United States)

    Wein, Sharon; Taudon, Nicolas; Maynadier, Marjorie; Tran Van Ba, Christophe; Margout, Delphine; Bordat, Yann; Fraisse, Laurent; Wengelnik, Kai; Cerdan, Rachel; Bressolle-Gomeni, Françoise; Vial, Henri J

    2017-08-01

    Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei -infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei -infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs. Copyright © 2017 American Society for Microbiology.

  8. A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana.

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    Corral, Maxime G; Leroux, Julie; Tresch, Stefan; Newton, Trevor; Stubbs, Keith A; Mylne, Joshua S

    2018-07-01

    To fight herbicide-resistant weeds, new herbicides are needed; particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana. Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained. MMV007978 was active against select monocot and dicot weeds, and physiological profiling indicated that its mode of action is related to germination and cell division. Of interest is the fact that the compound has a profile that is currently not found among known herbicides. We demonstrate that the antimalarial compound MMV007978 is also herbicidal and that exploiting lead compounds that are often understudied could lead to the identification of interesting herbicidal scaffolds. Further structural investigation of MMV007978 could provide improved herbicidal chemistries with a potential new mode of action. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

  9. Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity.

    Science.gov (United States)

    Hwang, Jong Yeon; Kawasuji, Takashi; Lowes, David J; Clark, Julie A; Connelly, Michele C; Zhu, Fangyi; Guiguemde, W Armand; Sigal, Martina S; Wilson, Emily B; Derisi, Joseph L; Guy, R Kiplin

    2011-10-27

    We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.

  10. Microbial burden of some herbal antimalarials marketed at Elele, Rivers State.

    Science.gov (United States)

    Tatfeng, Y M; Olama, E H; Ojo, T O

    2009-12-30

    Herbal antimalarials still remain an alternative to our traditional communities who can not afford orthodox antimalarials. This study was aimed at investigating the microbial quality of six herbal antimalarials using standard microbiological methods. Of the six preparations analyzed, "schnapps", palm wine and water were the media of preparation; the water base preparations recorded higher microbial load. The mean microbial load was 159.5 × 10(5) cfu/ml and 217.4 × 10(2)cfu/ml in water and alcohol base preparations respectively. The microbial profile of the preparations showed that the schnapps base preparations were predominantly contaminated with Bacillus sp (Aerobic spore bearers) and Mucor spp. The palm wine preparation harboured Bacillus sp, yeasts and Mucor spp while the water base preparations had several isolates such as Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli 0157H7, Proteus mirabilis, Enterococcus feacalis, Serratia marcensces, Staph. aureus, Bacillus spp and Mucor spp. Conclusively, this study underlines the public health importance of these preparations given the high burden of such human pathogen as Ecoli O157H7, Ps aeruginosa, Stahp aureus, etc. in the preparations.

  11. Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay.

    Science.gov (United States)

    Linares, María; Viera, Sara; Crespo, Benigno; Franco, Virginia; Gómez-Lorenzo, María G; Jiménez-Díaz, María Belén; Angulo-Barturen, Íñigo; Sanz, Laura María; Gamo, Francisco-Javier

    2015-11-05

    The emergence of Plasmodium falciparum resistance to artemisinins threatens to undermine the effectiveness of artemisinin-based combination anti-malarial therapy. Developing suitable drugs to replace artemisinins requires the identification of new compounds that display rapid parasite killing kinetics. However, no current methods fully meet the requirements to screen large compound libraries for candidates with such properties. This study describes the development and validation of an in vitro parasite viability fast assay for identifying rapidly parasiticidal anti-malarial drugs. Parasite killing kinetics were determined by first culturing unlabelled erythrocytes with P. falciparum in the presence of anti-malarial drugs for 24 or 48 h. After removing the drug, samples were added to erythrocytes pre-labelled with intracellular dye to allow their subsequent identification. The ability of viable parasites to re-establish infection in labelled erythrocytes could then be detected by two-colour flow cytometry after tagging of parasite DNA. Thus, double-stained erythrocytes (with the pre-labelled intracellular dye and the parasite DNA dye) result only after establishment of new infections by surviving parasites. The capacity of the test anti-malarial drugs to eliminate viable parasites within 24 or 48 h could, therefore, be determined. The parasite viability fast assay could be completed within 48 h following drug treatment and distinguished between rapidly parasiticidal anti-malarial drugs versus those acting more slowly. The assay was validated against ten standard anti-malarial agents with known properties and results correlated well with established methods. An abbreviated assay, suitable for adaption to medium-high throughput screening, was validated and applied against a set of 20 compounds retrieved from the publically available Medicines for Malaria Venture 'Malaria Box'. The quantification of new infections to determine parasite viability offers important

  12. Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity.

    Science.gov (United States)

    Wicht, Kathryn J; Combrinck, Jill M; Smith, Peter J; Egan, Timothy J

    2015-08-15

    A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against Plasmodium falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5000 commercially available compounds (Aldrich(CPR)) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

    Science.gov (United States)

    Plouffe, David; Brinker, Achim; McNamara, Case; Henson, Kerstin; Kato, Nobutaka; Kuhen, Kelli; Nagle, Advait; Adrián, Francisco; Matzen, Jason T.; Anderson, Paul; Nam, Tae-gyu; Gray, Nathanael S.; Chatterjee, Arnab; Janes, Jeff; Yan, S. Frank; Trager, Richard; Caldwell, Jeremy S.; Schultz, Peter G.; Zhou, Yingyao; Winzeler, Elizabeth A.

    2008-01-01

    The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈1.7 million compounds, we identified a diverse collection of ≈6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities. PMID:18579783

  14. El citocromo P-450 y la respuesta terapéutica a los antimaláricos Cytochrome P-450 and the response to antimalarial drugs

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    Valentina Guzmán

    2006-01-01

    dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS: Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism, as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS: The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

  15. Antimalarial efficacy of nine medicinal plants traditionally used by the Karens of Andaman and Nicobar Islands, India

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    M. Punnam Chander

    2016-03-01

    Full Text Available The aim of this study was to assess the antimalarial activity of nine medicinal plants used by Karens of Andaman and Nicobar Islands, against Plasmodium falciparum chloroquine-sensitive MRC-2 isolate. The methanol extracts were obtained by cold percolation method and in vitro antimalarial activity was assessed using M-III method. The results indicated that out of nine plant species tested, four plants, viz., Z. spectabilis, S. wallichiana, C. pulcherrima and Amomum sp. demonstrated significant antimalarial activity (50% inhibitory concentration values were 5.5 ± 0.7, 12.0 ± 2.5, 14.6 ± 1.3 and 37.3 ± 2.5 μg/mL respectively with no toxicity effect on erythrocytes.

  16. Characterization of primaquine imidazolidin-4-ones with antimalarial activity by electrospray ionization-ion trap mass spectrometry

    Science.gov (United States)

    Vale, Nuno; Moreira, Rui; Gomes, Paula

    2008-02-01

    The extensive characterization by electrospray ionization-ion trap mass spectrometry (ESI-MSn) of 20 imidazolidin-4-ones derived from the antimalarial primaquine was well obtained. These compounds are being under investigation as potential antimalarials, as they have been previously found to be active against rodent P. berghei malaria and to be highly stable under physiological conditions. Experiments by collision-induced dissociation (CID) in the nozzle-skimmer region or by tandem-MS have shown the title compounds to be remarkably stable. Mechanisms are proposed to explain the major fragmentations observed in ESI-MSn experiments. Overall, this work represents an unprecedented contribution to a deeper insight into imidazolidin-4-one antimalarials based on a classic 8-aminoquinolinic scaffold. Data herein reported and discussed may be an useful guide for future studies on therapeutically relevant molecules possessing either the 8-aminoquinoline or the imidazolidin-4-one motifs.

  17. Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities.

    Science.gov (United States)

    Verlinden, Bianca K; Niemand, Jandeli; Snyman, Janette; Sharma, Shiv K; Beattie, Ross J; Woster, Patrick M; Birkholtz, Lyn-Marie

    2011-10-13

    A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 μM, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.

  18. Sharing individual patient and parasite-level data through the WorldWide Antimalarial Resistance Network platform: A qualitative case study [version 1; referees: 2 approved

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    Elizabeth Pisani

    2017-08-01

    Full Text Available Background: Increasingly, biomedical researchers are encouraged or required by research funders and journals to share their data, but there's very little guidance on how to do that equitably and usefully, especially in resource-constrained settings. We performed an in-depth case study of one data sharing pioneer: the WorldWide Antimalarial Resistance Network (WWARN. Methods: The case study included a records review, a quantitative analysis of WAARN-related publications, in-depth interviews with 47 people familiar with WWARN, and a witness seminar involving a sub-set of 11 interviewees. Results: WWARN originally aimed to collate clinical, in vitro, pharmacological and molecular data into linked, open-access databases intended to serve as a public resource to guide antimalarial drug treatment policies. Our study describes how WWARN navigated challenging institutional and academic incentive structures, alongside funders' reluctance to invest in capacity building in malaria-endemic countries, which impeded data sharing. The network increased data contributions by focusing on providing free, online tools to improve the quality and efficiency of data collection, and by inviting collaborative authorship on papers addressing policy-relevant questions that could only be answered through pooled analyses. By July 1, 2016, the database included standardised data from 103 molecular studies and 186 clinical trials, representing 135,000 individual patients. Developing the database took longer and cost more than anticipated, and efforts to increase equity for data contributors are on-going. However, analyses of the pooled data have generated new methods and influenced malaria treatment recommendations globally. Despite not achieving the initial goal of real-time surveillance, WWARN has developed strong data governance and curation tools, which are now being adapted relatively quickly for other diseases. Conclusions: To be useful, data sharing requires

  19. High content live cell imaging for the discovery of new antimalarial marine natural products

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    Cervantes Serena

    2012-01-01

    Full Text Available Abstract Background The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. Methods A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Results Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Conclusion Collectively, our results show that high-content live cell-imaging (HCLCI can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.

  20. High content live cell imaging for the discovery of new antimalarial marine natural products.

    Science.gov (United States)

    Cervantes, Serena; Stout, Paige E; Prudhomme, Jacques; Engel, Sebastian; Bruton, Matthew; Cervantes, Michael; Carter, David; Tae-Chang, Young; Hay, Mark E; Aalbersberg, William; Kubanek, Julia; Le Roch, Karine G

    2012-01-03

    The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd.

  1. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.

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    Julia Penna-Coutinho

    Full Text Available The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2. The IC(50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.

  2. In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

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    Adeleke Clement Adebajo

    2014-08-01

    Full Text Available Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05 more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

  3. A characterization of the antimalarial activity of the bark of Cylicodiscus gabunensis Harms.

    Science.gov (United States)

    Aldulaimi, Omar; Uche, Fidelia I; Hameed, Hamza; Mbye, Haddijatou; Ullah, Imran; Drijfhout, Falko; Claridge, Timothy D W; Horrocks, Paul; Li, Wen-Wu

    2017-02-23

    A decoction of the bark of Cylicodiscus gabunensis Harms is used as a traditional medicine in the treatment of malaria in Nigeria. This study aims to validate the antimalarial potency of this decoction in vitro against Plasmodium falciparum and define potential bioactive constituents within the C. gabunensis bark. A bioassay-guided separation and fractionation protocol was applied to C. gabunensis extracts, exploiting the use of a Malaria Sybr Green I Fluorescence assay method to monitor antiproliferative effects on parasites as well as define 50% inhibition concentrations. Spectroscopic techniques, including GC-MS, TOF LC-MS and 1 H NMR were used to identify phytochemicals present in bioactive fractions. Analogues of gallic acid were synthesized de novo to support the demonstration of the antimalarial action of phenolic acids identified in C. gabunensis bark. In vitro cytotoxicity of plant extracts, fractions and gallate analogues was evaluated against the HepG2 cell line. The antimalarial activity of ethanolic extracts of C. gabunensis bark was confirmed in vitro, with evidence for phenolic acids, primarily gallic acid and close analogues such as ethyl gallate, likely providing this effect. Further fractionation produced the most potent fraction with a 50% inhibitory concentration of 4.7µg/ml. Spectroscopic analysis, including 1 H NMR, LC-MS and GC-MS analysis of this fraction and its acid hydrolyzed products, indicated the presence of conjugates of gallic acid with oligosaccharides. The extracts/fractions and synthetic alkyl and alkenyl gallates showed moderate selectivity against P. falciparum. These results support the use of the bark of C. gabunensis as a traditional medicine in the treatment of human malaria, with phenolic acid oligosaccharide complexes evident in the most bioactive fractions. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  4. Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies.

    Science.gov (United States)

    Pingaew, Ratchanok; Prachayasittikul, Veda; Worachartcheewan, Apilak; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2015-10-20

    A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Antimalarial efficacy of Albizia lebbeck (Leguminosae against Plasmodium falciparum in vitro & P. berghei in vivo

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    Shagun Kalia

    2015-01-01

    Full Text Available Background & objectives: Albizia lebbeck Benth. (Leguminosae has long been used in Indian traditional medicine. The current study was designed to test antimalarial activity of ethanolic bark extract of A. lebbeck (EBEAL. Methods: EBEAL was prepared by soxhlet extraction and subjected to phytochemical analysis. The extract was evaluated for its in vitro antimalarial activity against Plasmodium falciparum chloroquine (CQ sensitive (MRC2 and CQ resistant (RKL9 strains. Cytotoxicity (CC 50 of extract against HeLa cells was evaluated. Median lethal dose (LD 50 was determined to assess safety of EBEAL in BALB/c mice. Schizonticidal (100-1000 mg/kg and preventive (100-750 mg/kg activities of EBEAL were evaluated against P. berghei. Curative activity (100-750 mg/kg of extract was also evaluated. Results: Phytochemical screening revealed presence of alkaloids, flavonoids, phenols, saponins, terpenes and phytosterols. The extract exhibited IC 50 of 8.2 µg/ml (MRC2 and 5.1 µg/ml (RKL9. CC 50 of extract on HeLa cell line was calculated to be >1000 µg/ml. EBEAL showed selectivity indices (SI of >121.9 and >196.07 against MRC2 and RKL9 strains of P. falciparum, respectively. LD 50 of EBEAL was observed to be >5 g/kg. Dose-dependent chemosuppression was observed with significant ( p100 mg/kg. Significant (P<0.001 curative and repository activities were exhibited by 750 mg/kg concentration of extract on D7. Interpretation & conclusions: The present investigation reports antiplasmodial efficacy of EBEAL in vitro against P. falciparum as evident by high SI values. ED 50 of <100 mg/kg against P. berghei categorizes EBEAL as active antimalarial. Further studies need to be done to exploit its antiplasmodial activity further.

  6. Antimalarial efficacy of Albizia lebbeck (Leguminosae) against Plasmodium falciparum in vitro & P. berghei in vivo.

    Science.gov (United States)

    Kalia, Shagun; Walter, Neha Sylvia; Bagai, Upma

    2015-12-01

    Albizia lebbeck Benth. (Leguminosae) has long been used in Indian traditional medicine. The current study was designed to test antimalarial activity of ethanolic bark extract of A. lebbeck (EBEAL). EBEAL was prepared by soxhlet extraction and subjected to phytochemical analysis. The extract was evaluated for its in vitro antimalarial activity against Plasmodium falciparum chloroquine (CQ) sensitive (MRC2) and CQ resistant (RKL9) strains. Cytotoxicity (CC 50 ) of extract against HeLa cells was evaluated. Median lethal dose (LD 50 ) was determined to assess safety of EBEAL in BALB/c mice. Schizonticidal (100-1000 mg/kg) and preventive (100-750 mg/kg) activities of EBEAL were evaluated against P. berghei. Curative activity (100-750 mg/kg) of extract was also evaluated. Phytochemical screening revealed presence of alkaloids, flavonoids, phenols, saponins, terpenes and phytosterols. The extract exhibited IC 50 of 8.2 µg/ml (MRC2) and 5.1 µg/ml (RKL9). CC 50 of extract on HeLa cell line was calculated to be >1000 µg/ml. EBEAL showed selectivity indices (SI) of >121.9 and >196.07 against MRC2 and RKL9 strains of P. falciparum, respectively. LD 50 of EBEAL was observed to be >5 g/kg. Dose-dependent chemosuppression was observed with significant ( p50 >100 mg/kg. Significant (P50 mg/kg concentration of extract on D7. The present investigation reports antiplasmodial efficacy of EBEAL in vitro against P. falciparum as evident by high SI values. ED 50 of <100 mg/kg against P. berghei categorizes EBEAL as active antimalarial. Further studies need to be done to exploit its antiplasmodial activity further.

  7. Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

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    Benjamin Palafox

    Full Text Available Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia.We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important antimalarial supply sources

  8. Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65.

    Science.gov (United States)

    Awang, Normah; Jumat, Hafizah; Ishak, Shafariatul Akmar; Kamaludin, Nurul Farahana

    2014-06-01

    Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4-n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094±0.011 and 0.892±0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001±0.00009 and 0.0009±0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001±0.00005 and 0.00009±0.00003 μg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents.

  9. Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

    Science.gov (United States)

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Rueda, Sergio Torres; Kiefer, Sabine; O'Connell, Kathryn A; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Chavasse, Desmond

    2014-01-01

    Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia). We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine) dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs) were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important antimalarial supply sources. The structure

  10. In vitro antioxidant and antimalarial activities of leaves, pods and bark extracts of Acacia nilotica (L.) Del.

    Science.gov (United States)

    Sadiq, Muhammad Bilal; Tharaphan, Pattamon; Chotivanich, Kesinee; Tarning, Joel; Anal, Anil Kumar

    2017-07-18

    The emergence of drug resistant malaria is threatening our ability to treat and control malaria in the Southeast Asian region. There is an urgent need to develop novel and chemically diverse antimalarial drugs. This study aimed at evaluating the antimalarial and antioxidant potentials of Acacia nilotica plant extracts. The antioxidant activities of leaves, pods and bark extracts were determined by standard antioxidant assays; reducing power capacity, % lipid peroxidation inhibition and ferric reducing antioxidant power assay. The antimalarial activities of plant extracts against Plasmodium falciparum parasites were determined by the 48 h schizont maturation inhibition assay. Further confirmation of schizonticide activity of extracts was made by extending the incubation period up to 96 h after removing the plant extract residues from parasites culture. Inhibition assays were analyzed by dose-response modelling. In all antioxidant assays, leaves of A. nilotica showed higher antioxidant activity than pods and bark. Antimalarial IC 50 values of leaves, pods and bark extracts were 1.29, 4.16 and 4.28 μg/ml respectively, in the 48 h maturation assay. The IC 50 values determined for leaves, pods and bark extracts were 3.72, 5.41 and 5.32 μg/ml respectively, after 96 h of incubation. All extracts inhibited the development of mature schizont, indicating schizonticide activity against P. falciparum. A. nilotica extracts showed promising antimalarial and antioxidant effects. However, further investigation is needed to isolate and identify the active components responsible for the antimalarial and antioxidant effects.

  11. Elucidating antimalarial drug targets/mode-of-action by application of system biology technologies

    CSIR Research Space (South Africa)

    Becker, J

    2008-11-01

    Full Text Available targets/mode-of-action by application of systems biology technologies J BECKER, L MTWISHA, B CRAMPTON AND D MANCAMA CSIR Biosciences, PO Box 395, Pretoria, 0001, South Africa Email: JBecker@csir.co.za – www.csir.co.za INTRODUCTION Malaria is one... The objective of this study was to use systems biology tools to unravel the drug target/mode-of-action (MoA) of an antimalarial drug (cyclohexylamine) with a known drug target/MoA, by analysing differential expression profiles of drug treated vs untreated...

  12. Effect of Antimalarial Drugs on Plasmodia Cell-Free Protein Synthesis

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    Ana Ferreras

    2002-04-01

    Full Text Available A cell-free system from Plasmodium falciparum able to translate endogenous mRNA was used to determine the effect of artemisinin, chloroquine and primaquine on the protein synthesis mechanism of the parasite. The antimalarial drugs did not inhibit the incorporation of [³H] methionine into parasite proteins even at concentrations higher than the ones found to strongly inhibit the parasite growth. Results clearly indicate that these compounds do not have a direct effect on protein synthesis activity of P. falciparum coded by endogenous mRNA.

  13. Synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine

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    Debanjan Sen

    2010-01-01

    Full Text Available A series of 2-substituted and 2,3-substituted quinazolin -4(3H-one derivatives were designed and synthesized based on the structure of febrifugine. The structures of the new compounds were confirmed by spectral analysis. The in vivo biological activity test results indicated that those compounds exhibited antimalarial activities against Plasmodium berghei in mice, at a dose of 5 mg/kg. Compared to Chloroquine and Artemisinin, these compounds have the advantages of shorter synthetic routes and consequently are highly cost effective in nature.

  14. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    International Nuclear Information System (INIS)

    Rehman, F.U.; Khan, M.F.; Khan, G.M.; Khan, H.; Khan, I.U.

    2010-01-01

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  15. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    Energy Technology Data Exchange (ETDEWEB)

    Rehman, F U; Khan, M F; Khan, G M; Khan, H [Gomal University, D.I. Khan (Pakistan). Dept. of Faculty of Pharmacy; Khan, I U [University of Peshawar (Pakistan). Dept. of Faculty of Pharmacy

    2010-08-15

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  16. Generation of radicals and antimalarial activity of dispiro-1,2,4-trioxolanes

    Science.gov (United States)

    Denisov, E. T.; Denisova, T. G.

    2013-01-01

    The kinetic schemes of the intramolecular oxidation of radicals generated from substituted dispiro-1,2,4-trioxolanes (seven compounds) in the presence of Fe2+ and oxygen were built. Each radical reaction was defined in terms of enthalpy, activation energy, and rate constant. The kinetic characteristics were calculated by the intersecting parabolas method. The competition between the radical reactions was considered. The entry of radicals generated by each compound into the volume was calculated. High antimalarial activity was found for 1,2,4-trioxolanes, which generated hydroxyl radicals. The structural features of trioxolanes responsible for the generation of hydroxyl radicals were determined.

  17. In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

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    Mungthin Mathirut

    2005-08-01

    Full Text Available Abstract Background The Thai-Myanmar and Thai-Cambodia borders have been historically linked with the emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. Indeed, the areas are often described as harbouring multi-drug resistant parasites. These areas of Thailand have experienced significant changes in antimalarial drug exposure patterns over the past decade. This study describes the in vitro antimalarial susceptibility patterns of 95 laboratory-adapted P. falciparum isolates, collected between 1998 and 2003,. Methods Ninety five P. falciparum isolates were collected from five sites in Thailand between 1998 and 2003. After laboratory adaptation to in vitro culture, the susceptibility of these parasites to a range of established antimalarial drugs (chloroquine [CQ], mefloquine [MQ], quinine [QN] and dihydroartemisinin [DHA] was determined by the isotopic microtest. Results Mefloquine (MQ sensitivity remained poorest in areas previously described as MQ-resistant areas. Sensitivity to MQ of parasites from this area was significantly lower than those from areas reported to harbour moderate (p = 0.002 of low level MQ resistance (p = 000001. Importantly for all drugs tested, there was a considerable range in absolute parasite sensitivities. There was a weak, but statistically positive correlation between parasite sensitivity to CQ and sensitivity to both QN and MQ and a positive correlation between MQ and QN. In terms of geographical distribution, parasites from the Thai-Cambodia were tended to be less sensitive to all drugs tested compared to the Thai-Myanmar border. Parasite sensitivity to all drugs was stable over the 6-year collection period with the exception of QN. Conclusion This study highlights the high degree of variability in parasite drug sensitivity in Thailand. There were geographical differences in the pattern of resistance which might reflect differences in drug usage in each area. In contrast to many

  18. Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname

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    Evans Lawrence

    2012-06-01

    Full Text Available Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector and unlicensed facilities (informal sector is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58% anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30 and 11% (5/47 respectively. A higher proportion of medicines sampled from the private sector 34% (11/32 failed quality control tests versus 16% (7/45 in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86% were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to

  19. Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues.

    Science.gov (United States)

    Pérez, Bianca C; Fernandes, Iva; Mateus, Nuno; Teixeira, Cátia; Gomes, Paula

    2013-12-15

    Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname.

    Science.gov (United States)

    Evans, Lawrence; Coignez, Veerle; Barojas, Adrian; Bempong, Daniel; Bradby, Sanford; Dijiba, Yanga; James, Makeida; Bretas, Gustavo; Adhin, Malti; Ceron, Nicolas; Hinds-Semple, Alison; Chibwe, Kennedy; Lukulay, Patrick; Pribluda, Victor

    2012-06-15

    Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines

  1. Saleability of anti-malarials in private drug shops in Muheza, Tanzania

    DEFF Research Database (Denmark)

    Ringsted, Frank M; Massawe, Isolide S; Lemnge, Martha M

    2011-01-01

    women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform...... practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug...

  2. Photoreactivity of biologically active compounds. VII. Interaction of antimalarial drugs with melanin in vitro as part of phototoxicity screening.

    Science.gov (United States)

    Kristensen, S; Orsteen, A L; Sande, S A; Tønnesen, H H

    1994-10-01

    The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds accumulate in melanin-rich tissues and cause toxic reactions which may be light induced. As part of the screening of the photochemical properties and phototoxic capabilities of antimalarials, the in vitro interaction of eight antimalarials with melanin was studied. The dissociation constant for the drug-melanin complex and the relative number of binding sites on melanin were estimated for six of the drugs using a curve-fitting program. The reaction rate for the formation of the melanin-drug complex was determined, and the complexes were further characterized by zeta potential measurements.

  3. Access to artemisinin-combination therapy (ACT) and other anti-malarials: national policy and markets in Sierra Leone.

    Science.gov (United States)

    Amuasi, John H; Diap, Graciela; Nguah, Samuel Blay; Karikari, Patrick; Boakye, Isaac; Jambai, Amara; Lahai, Wani Kumba; Louie, Karly S; Kiechel, Jean-Rene

    2012-01-01

    Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$1.56), quinine tablets (US$0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$0.31 in the public sector and US$0.47 in the private sector, while SP had a median cost of US$0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days' worth of wages in both the public and private sectors.

  4. Synthesis and antimalarial activity evaluation of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one derivatives

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    Mukesh Kumar Kumawat

    2016-09-01

    Full Text Available Some novel derivatives of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro antimalarial activity against chloroquine sensitive strain of Plasmodium falciparum (RKL-2 employing chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities towards the parasite in comparison to the standard. It was found that antimalarial activity of 3-(3-(7-chloroquinolin-4-ylaminopropyl-2-(4-bromophenyl-1,3-thiazinan-4-one was marginally superior than all the compounds evaluated.

  5. Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance.

    Science.gov (United States)

    Carey, Maureen A; Papin, Jason A; Guler, Jennifer L

    2017-07-19

    Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.

  6. The Effectiveness of Local Plants from Lom and Sawang Ethnics as Antimalarial Medicine

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    Henny Helmi

    2016-09-01

    Full Text Available Native people or ethnic societies that live in endemic malaria islands such as in Bangka Island and Belitung Island have used many medicinal plants to cure malaria. Leaves of kesembung (Scaevola taccada (Gaertn Roxb, roots of kebentak (Wikstroemia androsaemofolia Decne, and roots of medang mencena (Dapniphyllum laurinum (Benth are the examples. This research was aimed to investigate the present of some biochemical compound and evaluate the antimalarial activity of ethanol extract of the plants against Plasmodium falciparum 3D7 in vitro. The IC50 level was determined through visual observation under microscope over 5000 of giemsa-stained erythrocytes then analyzed by probit analysis. Results showed that kebentak root ethanol extract was effective to inhibit P. falciparum 3D7 with level 0.485 µg/mL. Furthermore, the IC50 level of kesembung leaves and medang root were 44.352 µg/mL and 1486.678 µg/mL respectively. Phytochemical test result showed that kebentak leaf ethanol crude extract contained triterpenoid, kesembung root contained phenol and tannins; moreover, medang root contained alkaloid, saponin, and triterpenoid.How to CiteHelmi, H., Afriyansyah, B. & Ekasari, W. (2016. The Effectiveness of Local Plants from Lom and Sawang Ethnics as Antimalarial Medicine. Biosaintifika: Journal of Biology & Biology Education, 8(2, 193-200. 

  7. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

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    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  8. PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists.

    Science.gov (United States)

    Canfield, C J; Milhous, W K; Ager, A L; Rossan, R N; Sweeney, T R; Lewis, N J; Jacobus, D P

    1993-07-01

    A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.

  9. Antimalarial and cytotoxic activities of roots and fruits fractions of Astrodaucus persicus extract

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    Saied Goodarzi

    2017-12-01

    Full Text Available Objective(s:Astrodaucus persicus (Apiaceae is one of the two species of this genus which grows in different parts of Iran. Roots of this plant were rich in benzodioxoles and used as food additive or salad in Iran and near countries. The aim of present study was evaluation of antimalarial and cytotoxic effects of different fractions of A. persicus fruits and roots extracts. Materials and Methods: Ripe fruits and roots of A. persicuswere extracted and fractionated by hexane, chloroform, ethyl acetate and methanol, separately. Antimalarial activities of fractions were performed based on Plasmodium berghei suppressive test in mice model and percentage of parasitemia and suppression were determined for each sample. Cytotoxicity of fruits and roots fractions were investigated against human breast adenocarcinoma (MCF-7, colorectal carcinoma (SW480 and normal (L929 cell lines by MTT assay and IC50 of them were measured. Results: Hexane fraction of roots extract (RHE and ethyl acetate fraction of fruits extract (FEA of A. persicus demonstrated highest parasite inhibition (73.3 and 72.3%, respectively at 500 mg/kg/day which were significantly different from negative control group (P

  10. Safety of antimalarial medications for use while scuba diving in malaria Endemic Regions.

    Science.gov (United States)

    Petersen, Kyle; Regis, David P

    2016-01-01

    Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is unknown. Of particular concern would be medications with adverse effects that could either mimic diving related illnesses such as barotrauma, decompression sickness (DCS) and gas toxicities, or increase the risk for such illnesses. We conducted a review of PubMed and Cochrane databases to determine rates of neurologic adverse effects or other effects from antimalarials that may be a problem in the diving environment. One case report was found on diving and mefloquine. Multiple case reports and clinical trials were found describing neurologic adverse effects of the major chemoprophylactic medications atovaquone/proguanil, chloroquine, doxycycline, mefloquine, and primaquine. Of the available literature, atovaquone/proguanil and doxycycline are most likely the safest agents and should be preferred; atovaquone/proguanil is superior due to reduced rates of sunburn in the marine environment. Primaquine also appears to be safe, but has reduced efficacy against P. falciparum ; mefloquine possesses the highest rate of neurologic side effects and therefore these agents should be limited to extreme cases of patients intolerant to other agents. Chloroquine appears unsafe in the hyperbaric environment and should be avoided. More studies are required to include database reviews of returned divers traveling to malaria endemic areas and randomized controlled trials in the hyperbaric environments.

  11. Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.

    Science.gov (United States)

    Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stephane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie-Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gael; Le Bihan, Amelie; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio

    2016-09-20

    More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Heme polymerization inhibition activity (HPIA) assay of synthesized xanthone derivative as antimalarial compound

    Science.gov (United States)

    Fitriastuti, Dhina; Jumina, Priatmoko

    2017-03-01

    Xanthone is a phenolic secondary metabolite of Garcinia and Calophyllum herbs which has been clinically proven to display anti malaria activity. In the present paper, 2,3,4-trihydroxy-5-methyl xanthone which has been synthesized from gallic acid and o-cresol in Eaton's reagent was tested for its activity as antimalarial. Thus, HPIA assay of the synthesized xanthones was successfully conducted. The HPIA assay was carried out towards the xanthone, chloroquine diphosphate as positive control and distilled water as negative control in various concentration. The samples were reacted with hematin (ferriprotoporphyrin IX hydroxide) and the absorbance of the precipitate was observed by using Elisa reader. The results of HPIA assay showed that 2,3,4-trihydroxy-5-methyl xanthone and chloroquine have IC50 values of 0.755 and 1.462 mg/mL or 2.92 and 4.57 mM, respectively. 2,3,4-Trihydroxy-5-methyl xanthone displayed better antimalarial activity than chloroquine.

  13. Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo

    Directory of Open Access Journals (Sweden)

    Dorcas Osei-Safo

    2014-01-01

    Full Text Available This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs, semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3% and imported medicines (77.5% were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7% than registered medicines (70.8%. Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.

  14. Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues.

    Science.gov (United States)

    Bharate, Sandip B; Bhutani, Kamlesh K; Khan, Shabana I; Tekwani, Babu L; Jacob, Melissa R; Khan, Ikhlas A; Singh, Inder Pal

    2006-03-15

    In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.

  15. QSAR studies of some side chain modified 7-chloro-4-aminoquinolines as antimalarial agents

    Directory of Open Access Journals (Sweden)

    Nitendra K. Sahu

    2014-11-01

    Full Text Available The quantitative structure–activity relationship (QSAR analyses were carried out for a series of new side chain modified 4-amino-7-chloroquinolines to find out the structural requirements of their antimalarial activities against both chloroquine sensitive (HB3 and resistant (Dd2 Plasmodium falciparum strain. The statistically significant best 2D QSAR models for Dd2, having correlation coefficient (r2 = 0.9188 and cross validated squared correlation coefficient (q2 = 0.8349 with external predictive ability (pred_r2 = 0.7258 and for HB3, having r2 = 0.9024, q2 = 0.8089 and pred_r2 = 0.7463 were developed by multiple linear regression coupled with genetic algorithm (GA–MLR and stepwise (SW–MLR forward algorithm, respectively. The results of the present study may be useful on the designing of more potent analogues as antimalarial agents.

  16. A survey of synthetic and natural phytotoxic compounds and phytoalexins as potential antimalarial compounds.

    Science.gov (United States)

    Bajsa, Joanna; Singh, Kshipra; Nanayakkara, Dhammika; Duke, Stephen Oscar; Rimando, Agnes Mamaril; Evidente, Antonio; Tekwani, Babu Lal

    2007-09-01

    The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

  17. Phytochemical Analysis and Antimalarial Activity Aqueous Extract of Lecaniodiscus cupanioides Root

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    Mikhail Olugbemiro Nafiu

    2013-01-01

    Full Text Available Root aqueous extract of Lecaniodiscus cupanioides was evaluated for antimalarial activity and analyzed for its phytochemical constituents. Twenty-four (24 albino mice were infected by intraperitoneal injection of standard inoculum of chloroquine sensitive Plasmodium berghei (NK 65. The animals were randomly divided into 6 groups of 3 mice each. Group 1 served as the control while groups II–IV were orally administered 50, 150, and 250 mg/kg body weights of extract. Groups 5 and 6 received 1.75 and 5 mg/kg of artesunate and chloroquine, respectively. The results of the phytochemical analysis showed the presence of alkaloids (2.37%, saponin (0.336, tannin (0.012 per cent, phenol (0.008 per cent, and anthraquinone (0.002 per cent. There was 100 per cent parasite inhibition in the chloroquine group and 70 per cent in the 50 mg/kg body weight on day 12, respectively. The mean survival time (MST, for the control group was 14 days, artesunate 16 days, and chloroquine 30 days, while the groups that received 50 and 250 mg/kg body weight recorded similar MST of 17 days and the 150 mg/kg body weight group recorded 19 days. The results obtained indicated that the aqueous extract of Lecaniodiscus cupanioides may provide an alternative antimalarial.

  18. Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: Implications for embryotoxicity

    International Nuclear Information System (INIS)

    D'Alessandro, Sarah; Gelati, Maurizio; Basilico, Nicoletta; Parati, Eugenio Agostino; Haynes, Richard K.; Taramelli, Donatella

    2007-01-01

    Artemisinin derivatives are highly effective and well-tolerated antimalarial drugs that now form the basis of antimalarial combination therapies recommended by the World Health Organization. Although not yet reported to be a problem in clinical use, neurotoxicity and embryotoxicity are displayed by the compound class in in vitro and in vivo experimental models, in particular by dihydroartemisinin, the main metabolite of all current clinical artemisinins. Embryotoxicity appears to be connected with defective angiogenesis and vasculogenesis in certain stages of embryo development. This may prevent the use of artemisinin derivatives in malaria during pregnancy, when both mother and fetus are at high risk of death. Artemisone is a novel 10-alkylamino derivative which is not metabolised to dihydroartemisinin. It was selected as a clinical drug candidate on the basis of its high efficacy against Plasmodium falciparum in vitro and its lack of detectable neurotoxicity in both in vitro and in vivo screens. Here we describe the results of a comparative study of the anti-angiogenic properties of both artemisone and dihydroartemisinin in different model systems. We evaluated the proliferation of human endothelial cells and their migration on a fibronectin matrix, the sprouting of new vessels from rat aorta sections grown in collagen and the production of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and interleukin-8 (CXCL-8). The data show that artemisone is significantly less anti-angiogenic than dihydroartemisinin in all the experimental models, suggesting that it will be safer to use than the current clinical artemisinins during pregnancy

  19. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

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    Khodakarim Nastaran

    2010-05-01

    Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.

  20. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    Science.gov (United States)

    2010-01-01

    Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain) and CY27 (chloroquine-sensitive strain), using the parasite lactate dehydrogenase (pLDH) assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain). Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy), Solanum surattense (Burm.f.) and Prosopis juliflora (Sw.) showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml) and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time. PMID:20462416

  1. Phytochemical screening and antimalarial activity of some plants traditionally used in Indonesia

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    Syamsudin Abdillah

    2015-06-01

    Full Text Available Objective: To evaluate ethanolic extracts of phytochemical screening, in vitro and in vivo antiplasmodial activities of 15 plants used as antimalarial in Sei Kepayang, North Sumatra. Methods: Extraction was done through maceration with 70% ethanol and screened against chemical content, in vitro test anti-plasmodium against Plasmodium falciparum 3D7 strain and in vivo test in mice infected Plasmodium berghei. Results: The results showed that the plant extract contained a group of saponins, flavonoids, alkaloids, quinone, sterols, triterpene, tannins and cumarine. However, extract of Momordica charantia, Carica papaya, Garcinia atroviridis, Alstonia scholaris, Smallanthus sonchifolia and Cassia siamea had strong anti-plasmodium activity both in vitro and in vivo. Conclusions: In vitro and in vivo antiplasmodial activities of 15 plants are used as antimalarial in Sei Kepayang, North Sumatra. All the plants have in vitro and in vivo anti-plasmodium activity except Orthosiphon stamineus and Luffa cylindrica (ED50 > 1 000 mg/kg body weight and IC50 > 100 μg/mL, respectively.

  2. Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials.

    Science.gov (United States)

    Love, Melissa S; Millholland, Melanie G; Mishra, Satish; Kulkarni, Swapnil; Freeman, Katie B; Pan, Wenxi; Kavash, Robert W; Costanzo, Michael J; Jo, Hyunil; Daly, Thomas M; Williams, Dewight R; Kowalska, M Anna; Bergman, Lawrence W; Poncz, Mortimer; DeGrado, William F; Sinnis, Photini; Scott, Richard W; Greenbaum, Doron C

    2012-12-13

    Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Natural products as starting points for future anti-malarial therapies: going back to our roots?

    Directory of Open Access Journals (Sweden)

    Wells Timothy NC

    2011-03-01

    Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal

  4. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica

    Directory of Open Access Journals (Sweden)

    Misael Chinchilla

    2012-06-01

    Full Text Available Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB, were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae; Xanthosoma undipes (Araceae; Iriartea deltoidea (Arecaceae; Neurolaena lobata (Asteraceae; Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae; Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae; Hampea appendiculata (Malvaceae; Ruagea glabra, Guarea glabra (Meliaceae; Psidium guajava (Myrtaceae; Bocconia frutescens (Papaveraceae; Piper friedrichsthalii (Piperaceae; Clematis dioica (Ranunculaceae; Prunus annularis (Rosaceae; Siparuna thecaphora (Siparunaceae; Solanum arboreum, Witheringia solanácea (Solanaceae; Ticodendrum incognitum (Ticodendraceae; Heliocarpus appendiculatus (Tiliaceae and Myriocarpa longipes (Urticaceae. We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  5. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.

    Science.gov (United States)

    Phyo, Aung Pyae; Jittamala, Podjanee; Nosten, François H; Pukrittayakamee, Sasithon; Imwong, Mallika; White, Nicholas J; Duparc, Stephan; Macintyre, Fiona; Baker, Mark; Möhrle, Jörg J

    2016-01-01

    Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were

  6. Donor support for quality assurance and pharmacovigilance of anti-malarials in malaria-endemic countries.

    Science.gov (United States)

    Kovacs, Stephanie D; Mills, Brianna M; Stergachis, Andy

    2017-07-11

    Malaria control efforts have been strengthened by funding from donor groups and government agencies. The Global Fund to Fight AIDS, Tuberculosis and the Malaria (Global Fund), the US President's Malaria Initiative (PMI) account for the majority of donor support for malaria control and prevention efforts. Pharmacovigilance (PV), which encompasses all activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem, is a necessary part of efforts to reduce drug resistance and improve treatment outcomes. This paper reports on an analysis of PV plans in the Global Fund and PMI and World Bank's grants for malaria prevention and control. All active malaria grants as of September 2015 funded by the Global Fund and World Bank, and fiscal year 2015 and 2016 PMI Malaria Operational Plans (MOP) were identified. The total amount awarded for PV-related activities and drug quality assurance was abstracted. A Key-Word-in-Context (KWIC) analysis was conducted for the content of each grant. Specific search terms consisted of pharmacovigilance, pregn*, registry, safety, adverse drug, mass drug administration, primaquine, counterfeit, sub-standard, and falsified. Grants that mentioned PV activities identified in the KWIC search, listed PV in their budgets, or included the keywords: counterfeit, sub-standard, falsified, mass drug administration, or adverse event were thematically coded using Dedoose software version 7.0. The search identified 159 active malaria grants including 107 Global Fund grants, 39 fiscal year 2015 and 2016 PMI grants and 13 World Bank grants. These grants were primarily awarded to low-income countries (57.2%) and in sub-Saharan Africa (SSA) (70.4%). Thirty-seven (23.3%) grants included a budget line for PV- or drug quality assurance-related activities, including 21 PMI grants and 16 Global Fund grants. Only 23 (14.5%) grants directly mentioned PV. The primary focus area was improving drug

  7. QSAR, docking and ADMET studies of artemisinin derivatives for antimalarial activity targeting plasmepsin II, a hemoglobin-degrading enzyme from P. falciparum.

    Science.gov (United States)

    Qidwai, Tabish; Yadav, Dharmendra K; Khan, Feroz; Dhawan, Sangeeta; Bhakuni, R S

    2012-01-01

    This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r(2)) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV(2)) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

  8. The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.

    Science.gov (United States)

    Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael; Davioud-Charvet, Elisabeth

    2016-09-01

    Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  9. Possible artefacts in the in vitro determination of antimalarial activity of natural products that incorporate into lipid bilayer

    DEFF Research Database (Denmark)

    Ziegler, Hanne Lindvig; Jensen, Thomas Høgh; Christensen, Jette

    2002-01-01

    Dehydroabietinol isolated from Hyptis suaveolens (L.) Poit. was found to inhibit growth of chloroquine-sensitive as well as chloroquine-resistant strains of Plasmodium falciparum cultivated in erythrocytes in vitro (IC 50 26-27 microM). However, erythrocytes exposed to dehydroabietinol were trans...... be generally used to support claims of antimalarial effects of apolar natural products....

  10. Antimalarial activity of 80 % methanolic extract of Brassica nigra (L.) Koch. (Brassicaceae) seeds against Plasmodium berghei infection in mice.

    Science.gov (United States)

    Muluye, Abrham Belachew; Melese, Eshetie; Adinew, Getnet Mequanint

    2015-10-15

    Resistances to currently available drugs and insecticides, significant drug toxicities and costs and lack of vaccines currently complicated the treatment of malaria. A continued search for safe, effective and affordable plant-based antimalarial agents thus becomes crucial and vital in the face of these difficulties. The aim of the study was to evaluate the antimalarial activity of 80 % methanolic extract of the seeds of Brassica nigra against Plasmodium berghei infection in mice. Chloroquine sensitive Plasmodium berghei (ANKA strain) was used to test the antimalarial activity of the extract. In suppressive and prophylactic models, Swiss albino male mice were randomly grouped into five groups of five mice each. Group I mice were treated with the vehicle, group II, III and IV were treated with 100, 200, and 400 mg/kg of the extract, respectively and the last group (V) mice were treated with chloroquine (10 mg/kg). The level of parasitemia, survival time and variation in weight of mice were used to determine the antimalarial activity of the extract. Chemosuppressive activities produced by the extract of the seeds of Brassica nigra were 21.88, 50.00 (P activities were 17.42, 21.21 and 53.79 % (P activities and the plant may contain biologically active principles which are relevant in the treatment and prophylaxis of malaria, thus supporting further studies of the plant for its active components.

  11. Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

    Directory of Open Access Journals (Sweden)

    Alaíde Braga de Oliveira

    2009-08-01

    Full Text Available Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

  12. Effects of the anti-malarial compound cryptolepine and its analogues in human lymphocytes and sperm in the Comet assay.

    Science.gov (United States)

    Gopalan, Rajendran C; Emerce, Esra; Wright, Colin W; Karahalil, Bensu; Karakaya, Ali E; Anderson, Diana

    2011-12-15

    Malaria is a mosquito-borne infectious disease caused by the genus Plasmodium. It causes one million deaths per year in African children under the age of 5 years. There is an increasing development of resistance of malarial parasites to chloroquine and other currently used anti-malarial drugs. Some plant products such as the indoloquinoline alkaloid cryptolepine have been shown to have potent activity against P. falciparum in vitro. On account of its toxicity, cryptolepine is not suitable for use as an antimalarial drug but a number of analogues of cryptolepine have been synthesised in an attempt to find compounds that have reduced cytotoxicity and these have been investigated in the present study in human sperm and lymphocytes using the Comet assay. The results suggest that cryptolepine and the analogues cause DNA damage in lymphocytes, but appear to have no effect on human sperm at the assessed doses. In the context of antimalarial drug development, the data suggest that all cryptolepine compounds and in particular 2,7-dibromocryptolepine cause DNA damage and therefore may not be suitable for pre clinical development as antimalarial agents. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Analytical sample preparation strategies for the determination of antimalarial drugs in human whole blood, plasma and urine

    DEFF Research Database (Denmark)

    Casas, Monica Escolà; Hansen, Martin; Krogh, Kristine A

    2014-01-01

    the available sample preparation strategies combined with liquid chromatographic (LC) analysis to determine antimalarials in whole blood, plasma and urine published over the last decade. Sample preparation can be done by protein precipitation, solid-phase extraction, liquid-liquid extraction or dilution. After...

  14. Antimycobacterial and antimalarial activities of endophytic fungi associated with the ancient and narrowly endemic neotropical plant Vellozia gigantea from Brazil.

    Science.gov (United States)

    Ferreira, Mariana C; Cantrell, Charles L; Wedge, David E; Gonçalves, Vívian N; Jacob, Melissa R; Khan, Shabana; Rosa, Carlos A; Rosa, Luiz H

    2017-10-01

    Endophytic fungi, present mainly in the Ascomycota and Basidiomycota phyla, are associated with different plants and represent important producers of bioactive natural products. Brazil has a rich biodiversity of plant species, including those reported as being endemic. Among the endemic Brazilian plant species, Vellozia gigantea (Velloziaceae) is threatened by extinction and is a promising target to recover endophytic fungi. The present study focused on bioprospecting of bioactive compounds of the endophytic fungi associated with V. gigantea, an endemic, ancient, and endangered plant species that occurs only in the rupestrian grasslands of Brazil. The capability of 285 fungal isolates to produce antimicrobial and antimalarial activities was examined. Fungi were grown at solid-state fermentation to recover their crude extracts in dichloromethane. Bioactive extracts were analysed by chromatographic fractionation and NMR and displayed compounds with antimicrobial, antimycobacterial, and antimalarial activities. Five fungi produced antimicrobial and antimalarial compounds. Extracts of Diaporthe miriciae showed antifungal, antibacterial, and antimalarial activities; Trichoderma effusum displayed selective antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare; and three Penicillium species showed antibacterial activity. D. miriciae extract contained highly functionalised secondary metabolites, yielding the compound epoxycytochalasin H with high antimalarial activity against the chloroquine-resistant strain of Plasmodium falciparum, with an IC50 approximately 3.5-fold lower than that with chloroquine. Our results indicate that V. gigantea may represent a microhabitat repository hotspot of potential fungi producers of bioactive compounds and suggest that endophytic fungal communities might be an important biological component contributing to the fitness of the plants living in the rupestrian grassland.

  15. Parental involvement

    Directory of Open Access Journals (Sweden)

    Ezra S Simon

    2005-01-01

    Full Text Available Parent-Teacher Associations and other community groups can play a significant role in helping to establish and run refugee schools; their involvement can also help refugee adults adjust to their changed circumstances.

  16. Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

    Science.gov (United States)

    Maiteki-Sebuguzi, Catherine; Jagannathan, Prasanna; Yau, Vincent M; Clark, Tamara D; Njama-Meya, Denise; Nzarubara, Bridget; Talisuna, Ambrose O; Kamya, Moses R; Rosenthal, Philip J; Dorsey, Grant; Staedke, Sarah G

    2008-01-01

    Background Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. Methods A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. Results Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1

  17. Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

    Directory of Open Access Journals (Sweden)

    Kamya Moses R

    2008-06-01

    Full Text Available Abstract Background Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. Methods A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP, artesunate + amodiaquine (AS+AQ, or artemether-lumefantrine (AL. Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. Results Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years. At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7, or AS

  18. Quinolinemethanol Antimalarials.

    Science.gov (United States)

    1974-12-01

    Yield of pure iaterinl froto a mi’xt of 5c and Se. *Yield froin the acid 7d. ,Yield front life ester 8d. r Anal, were wit hin ± t. fojr C, 11, N Ilr...DA-49-193-MD-2955 F 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT. PROJECT, TASK Uiversity of Virginia, Chemistry Dept. AREA & WORK

  19. Photoreactivity of biologically active compounds. VIII. Photosensitized polymerization of lens proteins by antimalarial drugs in vitro.

    Science.gov (United States)

    Kristensen, S; Wang, R H; Tønnesen, H H; Dillon, J; Roberts, J E

    1995-02-01

    The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds cause dermal and ocular toxic reactions that may be light induced. The in vitro photopolymerization of calf lens proteins in the presence of antimalarial drugs was studied as part of a screening of the photochemical properties and phototoxic capabilities of these compounds. The pseudo-first-order rate constant for the reaction was calculated, and related to the amount of light absorbed by the compounds in order to determine the relative photosensitizing effect of each drug. The reaction mechanisms were evaluated by adding a variety of quenchers to the reaction medium during irradiation. Based on the results obtained in this study and previous knowledge about the pharmacokinetic behavior of these compounds, several of the drugs investigated have to be considered as potential photosensitizers in the human lens, the retina and the skin.

  20. Antimalarial activity of novel 4-aminoquinolines active against drug resistant strains.

    Science.gov (United States)

    Kondaparla, Srinivasarao; Soni, Awakash; Manhas, Ashan; Srivastava, Kumkum; Puri, Sunil K; Katti, S B

    2017-02-01

    In the present study we have synthesized a new class of 4-aminoquinolines and evaluated against Plasmodium falciparum in vitro (3D7-sensitive strain & K1-resistant strain) and Plasmodium yoelii in vivo (N-67 strain). Among the series, eleven compounds (5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 21) showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogues showed 100% suppression of parasitemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that this series of compounds act on heme polymerization target. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

    Science.gov (United States)

    Howard, Brittany L.; Thompson, Philip E.; Manallack, David T.

    2011-08-01

    The similarity between Plasmodium falciparum phosphodiesterase enzymes ( PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

  2. Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

    Science.gov (United States)

    Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

    2015-09-01

    A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil.

    Science.gov (United States)

    Zheljazkov, Valtcho D; Gawde, Archana; Cantrell, Charles L; Astatkie, Tess; Schlegel, Vicki

    2015-01-01

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given duration of the steam distillation time (DT). Ten DT durations were tested in this study: 5, 7.5, 15, 30, 60, 120, 240, 360, 480, and 600 min. Oil yields increased with an increase in the DT. Maximum oil yield (content, 2.3 g/100 seed), was achieved at 480 min; longer DT did not increase oil yields. The concentrations of the major oil constituents α-pinene (0.14-0.5% concentration range), β-pinene (3.7-10.3% range), γ-cymene (5-7.3% range), γ-terpinene (1.8-7.2% range), cumin aldehyde (50-66% range), α-terpinen-7-al (3.8-16% range), and β-terpinen-7-al (12-20% range) varied as a function of the DT. The concentrations of α-pinene, β-pinene, γ-cymene, γ-terpinene in the oil increased with the increase of the duration of the DT; α-pinene was highest in the oil obtained at 600 min DT, β-pinene and γ-terpinene reached maximum concentrations in the oil at 360 min DT; γ-cymene reached a maximum in the oil at 60 min DT, cumin aldehyde was high in the oils obtained at 5-60 min DT, and low in the oils obtained at 240-600 min DT, α-terpinen-7-al reached maximum in the oils obtained at 480 or 600 min DT, whereas β-terpinen-7-al reached a maximum concentration in the oil at 60 min DT. The yield of individual oil constituents (calculated from the oil yields and the concentration of a given compound at a particular DT) increased and reached a maximum at 480 or 600 min DT. The antimalarial activity of the cumin seed oil obtained during the 0-5 and at 5-7.5 min DT timeframes was twice higher than the antimalarial activity of the oils obtained at the other DT. This study opens the possibility for distinct marketing and utilization for these improved oils. The antioxidant

  4. Antimalarial, antimicrobial, cytotoxic, DNA interaction and SOD like activities of tetrahedral copper(II) complexes

    Science.gov (United States)

    Mehta, Jugal V.; Gajera, Sanjay B.; Patel, Mohan N.

    2015-02-01

    The mononuclear copper(II) complexes with P, O-donor ligand and different fluoroquinolones have been synthesized and characterized by elemental analysis, electronic spectra, TGA, EPR, FT-IR and LC-MS spectroscopy. An antimicrobial efficiency of the complexes has been tested against five different microorganisms in terms of minimum inhibitory concentration (MIC) and displays very good antimicrobial activity. The binding strength and binding mode of the complexes with Herring Sperm DNA (HS DNA) have been investigated by absorption titration and viscosity measurement studies. The studies suggest the classical intercalative mode of DNA binding. Gel electrophoresis assay determines the ability of the complexes to cleave the supercoiled form of pUC19 DNA. Synthesized complexes have been tested for their SOD mimic activity using nonenzymatic NBT/NADH/PMS system and found to have good antioxidant activity. All the complexes show good cytotoxic and in vitro antimalarial activities.

  5. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    Science.gov (United States)

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  6. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

    Science.gov (United States)

    Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

    2016-10-01

    Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under

  7. Phenylpropanoids and furanocoumarins as antibacterial and antimalarial constituents of the Bhutanese medicinal plant Pleurospermum amabile.

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    Wangchuk, Phurpa; Pyne, Stephen G; Keller, Paul A; Taweechotipatr, Malai; Kamchonwongpaisane, Sumalee

    2014-07-01

    With the objective of determining safety and verifying the traditional uses of the Bhutanese medicinal plant, Pleurospermum amabile Craib & W. W. Smith, we investigated its crude extracts and the isolated phytochemicals for their biological activities. Four phenylpropanoids [(E)-isomyristicin (1), (E)-isoapiol (2), methyl eugenol (3) and (E)-isoelemicin (4)] and six furanocoumarins [psoralen (5), bergapten (6), isoimperatorin (7), isopimpinellin (8), oxypeucedanin hydrate (9) and oxypeucedanin methanolate (10)] were isolated from this plant. Among the test samples, compound 10 showed weak antibacterial activity against Bacillus subtilis and best antimalarial activity against the Plasmodium falciparum strains, TM4/8.2 (chloroquine and antifolate sensitive) and K1CB1 (multidrug resistant). None of the test samples showed cytotoxicity. This study generated scientific data that support the traditional medical uses of the plant.

  8. Antimalarial β-carbolines from the New Zealand ascidian Pseudodistoma opacum.

    Science.gov (United States)

    Chan, Susanna T S; Pearce, A Norrie; Page, Michael J; Kaiser, Marcel; Copp, Brent R

    2011-09-23

    One tetrahydro-β-carboline, (-)-7-bromohomotrypargine (1), and three alkylguanidine-substituted β-carbolines, opacalines A, B, and C (2-4), have been isolated from the New Zealand ascidian Pseudodistoma opacum. The structures of the metabolites were determined by analysis of mass spectrometric and 2D NMR spectroscopic data. Natural products 2 and 3, synthetic debromo analogues 8 and 9, and intermediate 16 exhibited moderate antimalarial activity toward a chloroquine-resistant strain of Plasmodium falciparum, with an IC50 range of 2.5-14 μM. The biosynthesis of 1-4 is proposed to proceed via a Pictet-Spengler condensation of 6-bromotryptamine and the α-keto acid transamination product of either arginine or homoarginine. Cell separation and 1H NMR analysis of P. opacum identified tetrahydro-β-carboline 1 to be principally located in the zooids, while fully aromatized analogues 2-4 were localized to the test.

  9. Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies.

    Science.gov (United States)

    Lavrado, João; Cabal, Ghislain G; Prudêncio, Miguel; Mota, Maria M; Gut, Jiri; Rosenthal, Philip J; Díaz, Cecília; Guedes, Rita C; dos Santos, Daniel J V A; Bichenkova, Elena; Douglas, Kenneth T; Moreira, Rui; Paulo, Alexandra

    2011-02-10

    The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.

  10. In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

    Science.gov (United States)

    Rocha e Silva, Luiz Francisco; Nogueira, Karla Lagos; Pinto, Ana Cristina da Silva; Katzin, Alejandro Miguel; Sussmann, Rodrigo A. C.; Muniz, Magno Perêa; Neto, Valter Ferreira de Andrade; Chaves, Francisco Célio Maia; Coutinho, Julia Penna; Lima, Emerson Silva; Krettli, Antoniana Ursine; Tadei, Wanderli Pedro

    2015-01-01

    4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from Piper peltatum roots. O-Acylation or O-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. The aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in Plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibited in vitro hemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester 2 significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone 8, menaquinone 4, and dolichol 12 in cultures of P. falciparum 3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol 12. P. falciparum in vitro protein synthesis was not affected by compounds 2 or 3. At oral doses of 50 mg per kg of body weight per day, compound 2 suppressed Plasmodium berghei NK65 in infected BALB/c mice by 44%. This in vivo result for derivative 2 represents marked improvement over that obtained previously for natural product 1. Compound 2 was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasma in vitro. However, it was detected after in vitro contact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential. PMID:25801563

  11. QUANTITAVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR OF ANTIMALARIAL 1,10-PHENANTHROLINE DERIVATIVES COMPOUNDS

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    Ruslin Hadanu

    2010-06-01

    Full Text Available Quantitative Electronic Structure-Activity Relationship (QSAR analysis of a series of 1,10-phenanthroline derivatives as antiplasmodial compounds have been conducted using atomic net charges (q, dipole moment (μ ELUMO, EHOMO, polarizability (α and log P as the descriptors. The descriptors were obtained from computational chemistry method using semi-empirical PM3. Antiplasmodial activities were taken as the activity of the drugs  against  chloroquine-resistant Plasmodium falciparum FCR3 strain and are presented as the value of ln (1/IC50 where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best model of QSAR model was determine by multiple linear regression method and giving equation of QSAR: ln 1/IC50  =  3.732 + (5.098 qC5 + (7.051 qC7 + (36.696 qC9 + (41.467 qC11 -(135.497 qC12 + (0.332 μ -                    (0.170 α + (0.757 log P. The equation was significant on the 95% level with statistical parameters: n=16; r=0.987; r2= 0.975; SE=0.317;  Fcalc/Ftable = 15.337 and gave the PRESS=0.707. Its means that there were only a relatively few deviations between the experimental and theoretical data of antimalarial activity.   Keywords: QSAR, antimalarial, semi-empirical method, 1,10-phenanthroline.

  12. Chemical composition and anticancer, antiinflammatory, antioxidant and antimalarial activities of leaves essential oil of Cedrelopsis grevei.

    Science.gov (United States)

    Afoulous, Samia; Ferhout, Hicham; Raoelison, Emmanuel Guy; Valentin, Alexis; Moukarzel, Béatrice; Couderc, François; Bouajila, Jalloul

    2013-06-01

    The essential oil from Cedrelopsis grevei leaves, an aromatic and medicinal plant from Madagascar, is widely used in folk medicine. Essential oil was characterized by GC-MS and quantified by GC-FID. Sixty-four components were identified. The major constituents were: (E)-β-farnesene (27.61%), δ-cadinene (14.48%), α-copaene (7.65%) and β-elemene (6.96%). The essential oil contained a complex mixture consisting mainly sesquiterpene hydrocarbons (83.42%) and generally sesquiterpenes (98.91%). The essential oil was tested cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum), antiinflammatory and antioxidant (ABTS and DPPH assays) activities. C. grevei essential oil was active against MCF-7 cell lines (IC50=21.5 mg/L), against P. falciparum, (IC50=17.5mg/L) and antiinflammatory (IC50=21.33 mg/L). The essential oil exhibited poor antioxidant activity against DPPH (IC50>1000 mg/L) and ABTS (IC50=110 mg/L) assays. A bibliographical review was carried out of all essential oils identified and tested with respect to antiplasmodial, anticancer and antiinflammatory activities. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial, anticancer and antiinflammatory). According to the obtained correlations, 1,4-cadinadiene (R(2)=0.61) presented a higher relationship with antimalarial activity. However, only (Z)-β-farnesene (R(2)=0.73) showed a significant correlation for anticancer activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. New molecular settings to support in vivo anti-malarial assays.

    Science.gov (United States)

    Bahamontes-Rosa, Noemí; Alejandre, Ane Rodriguez; Gomez, Vanesa; Viera, Sara; Gomez-Lorenzo, María G; Sanz-Alonso, Laura María; Mendoza-Losana, Alfonso

    2016-03-08

    Quantitative real-time PCR (qPCR) is now commonly used as a method to confirm diagnosis of malaria and to differentiate recrudescence from re-infection, especially in clinical trials and in reference laboratories where precise quantification is critical. Although anti-malarial drug discovery is based on in vivo murine efficacy models, use of molecular analysis has been limited. The aim of this study was to develop qPCR as a valid methodology to support pre-clinical anti-malarial models by using filter papers to maintain material for qPCR and to compare this with traditional methods. FTA technology (Whatman) is a rapid and safe method for extracting nucleic acids from blood. Peripheral blood samples from mice infected with Plasmodium berghei, P. yoelii, or P. falciparum were kept as frozen samples or as spots on FTA cards. The extracted genetic material from both types of samples was assessed for quantification by qPCR using sets of specific primers specifically designed for Plasmodium 18S rRNA, LDH, and CytB genes. The optimal conditions for nucleic acid extraction from FTA cards and qPCR amplification were set up, and were confirmed to be suitable for parasite quantification using DNA as template after storage at room temperature for as long as 26 months in the case of P. berghei samples and 52 months for P. falciparum and P. yoelii. The quality of DNA extracted from the FTA cards for gene sequencing and microsatellite amplification was also assessed. This is the first study to report the suitability of FTA cards and qPCR assay to quantify parasite load in samples from in vivo efficacy models to support the drug discovery process.

  14. Antileishmanial, antimalarial and antimicrobial activities of the extract and isolated compounds from Austroplenckia populnea (Celastraceae).

    Science.gov (United States)

    Andrade, Sérgio F; da Silva Filho, Ademar A; de O Resende, Dimas; Silva, Márcio L A; Cunha, Wilson R; Nanayakkara, N P Dhammika; Bastos, Jairo Kenupp

    2008-01-01

    Austroplenckia populnea (Celastraceae), known as "marmelinho do campo", is used in Brazilian folk medicine as antimicrobial, anti-inflammatory, and antitumoural agent. The aim of the present work was to evaluate the antimicrobial, antileishmanial and antimalarial activities of the crude hydroalcoholic extract of A. populnea (CHE) and some of its isolated compounds. The phytochemical study of the CHE was carried out affording the isolation of methyl populnoate (1), populnoic acid (2), and stigmast-5-en-3-O-beta-(D-glucopyranoside) (3). This is the first time that the presence of compound 3 in A. populnea is reported. The results showed that the CHE presents antifungal and antibacterial activities, especially against Candida glabrata and Candida albicans, for which the CHE showed IC50 values of 0.7 microg mL(-1) and 5.5 microg mL(-1), respectively, while amphotericin B showed an IC50 value of 0.1 microg mL(-1) against both microorganisms. Compounds 1-3 were inactive against all tested microorganisms. In the antileishmanial activity test against Leishmania donovani, the CHE showed an IC50 value of 52 microg mL(-1), while compounds 2 and 3 displayed an IC50 value of 18 microg mL(-1) In the antimalarial assay against Plasmodium falciparum (D6 and W2 clones), it was observed that all evaluated samples were inactive. In order to compare the effect on the parasites with the toxicity to mammalian cells, the cytotoxicity activity of the isolated compounds was evaluated against Vero cells, showing that all evaluated samples exhibited no cytotoxicity at the maximum dose tested.

  15. Inhibition test of heme detoxification (ITHD as an approach for detecting antimalarial agents in medicinal plants

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    M. Mosaddegh

    2018-01-01

    Full Text Available Background and objectives: There are several methods to assess the in vitro capability of heme inhibitory activity of antimalarial compounds; most of them require some specific equipment or toxic substances and sometimes the needed materials are not accessible. Regarding the necessity and importance of optimizing and standardizing experimental conditions, the present study has intended to improve the in vitro assessment conditions of the β-hematin formation inhibitory activity for screening herbal samples. Methods: Hemin, tween 20, and samples (9:9:2 were incubated in different conditions including: hemin concentration (30, 60, and 120 µg/mL, duration (4, 24, 48, and 72 h, pH of buffer (3.6, 4, 4.4, 4.8, and 5, and temperature (37 and 60 °C in 96-well plates. Also, a total of 165 plant extracts and fractions were tested in the most suitable conditions. Results: The reaction time and the incubation temperature were determined as the critical factors. The effective conditions for β-hematin formation were found to be 60 °C after 24 h incubation. In this method, proper correlations with respect to negative (69% and positive (67% predictive values were obtained in comparison with the anti-plasmodial assay. Antimalarial activities of Pistacia atlantica, Myrtus communis, Pterocarya fraxinifolia, and Satureja mutica were found to correlate significantly with inhibition of the heme detoxification assay. Conclusion: These results support a rapid, simple and reliable approach for selecting and identifying a number of herbs for further related antimalaria investigations.

  16. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Science.gov (United States)

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications.

  17. High-level semi-synthetic production of the potent antimalarial artemisinin.

    Science.gov (United States)

    Paddon, C J; Westfall, P J; Pitera, D J; Benjamin, K; Fisher, K; McPhee, D; Leavell, M D; Tai, A; Main, A; Eng, D; Polichuk, D R; Teoh, K H; Reed, D W; Treynor, T; Lenihan, J; Fleck, M; Bajad, S; Dang, G; Dengrove, D; Diola, D; Dorin, G; Ellens, K W; Fickes, S; Galazzo, J; Gaucher, S P; Geistlinger, T; Henry, R; Hepp, M; Horning, T; Iqbal, T; Jiang, H; Kizer, L; Lieu, B; Melis, D; Moss, N; Regentin, R; Secrest, S; Tsuruta, H; Vazquez, R; Westblade, L F; Xu, L; Yu, M; Zhang, Y; Zhao, L; Lievense, J; Covello, P S; Keasling, J D; Reiling, K K; Renninger, N S; Newman, J D

    2013-04-25

    In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

  18. Antimalarial evaluation of selected medicinal plant extracts used in Iranian traditional medicine

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    Mohammad Hossein Feiz Haddad

    2017-04-01

    Full Text Available Objective(s: In an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on Iranian traditional medicine. Materials and Methods: Ten plant species found in Iran were selected and collected based on the available literature about the Iranian traditional medicine. The methanolic extracts of these plants were investigated for in vitro antimalarial properties against chloroquine-sensitive (3D7 and multi-drug resistant (K1 strains of Plasmodium falciparum. Their in vivo activity against Plasmodium berghei infection in mice was also determined. Cytotoxicity tests were carried out using the Raji cells line using the MTT assay. The extracts were phytochemically screened for their active constituents. Results: According to the IC50 and selectivity index (SI values, of the 10 selected plant species, Citrullus colocynthis, Physalis alkekengi, and Solanum nigrum displayed potent in vitro antimalarial activity against both 3D7 and K1 strains with no toxicity (IC50= 2.01-18.67 µg/ml and SI=3.55 to 19.25.  Comparisons between treated and untreated control mice showed that the mentioned plant species reduced parasitemia by 65.08%, 57.97%, and 60.68%, respectively.  The existence of antiplasmodial compounds was detected in these plant extracts. Conclusion: This was the first study to highlight the in vitro and in vivo antiplasmodial effects of             C. colocynthis, P. alkekengi, and S. nigrum in Iran. Future studies can use these findings to design further biological tests to identify the active constituents of the mentioned plant species and clarify their mechanism of action.

  19. Development of a TaqMan Allelic Discrimination Assay for detection of Single Nucleotides Polymorphisms associated with anti-malarial drug resistance

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    Kamau Edwin

    2012-01-01

    Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in

  20. Antimalarial efficacy of Pongamia pinnata (L) Pierre against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA).

    Science.gov (United States)

    Satish, P V V; Sunita, K

    2017-09-11

    The objective of the current study was to assess the in vitro antiplasmodial activities of leaf, bark, flower, and the root of Pongamia pinnata against chloroquine-sensitive Plasmodium falciparum (3D7 strain), cytotoxicity against Brine shrimp larvae and THP-1 cell line. For in vivo study, the plant extract which has shown potent in vitro antimalarial activity was tested against Plasmodium berghei (ANKA strain). The plant Pongamia pinnata was collected from the herbal garden of Acharya Nagarjuna University of Guntur district, Andhra Pradesh, India. Sequentially crude extracts of methanol (polar), chloroform (non-polar), hexane (non-polar), ethyl acetate (non-polar) and aqueous (polar) of dried leaves, bark, flowers and roots of Pongamia pinnata were prepared using Soxhlet apparatus. The extracts were screened for in vitro antimalarial activity against P. falciparum 3D7 strain. The cytotoxicity studies of crude extracts were conducted against Brine shrimp larvae and THP-1 cell line. Phytochemical analysis of the plant extracts was carried out by following the standard methods. The chemical injury to erythrocytes due to the plant extracts was checked. The in vivo study was conducted on P. berghei (ANKA) infected BALB/c albino mice by following 4-Day Suppressive, Repository, and Curative tests. Out of all the tested extracts, the methanol extract of the bark of Pongamia pinnata had shown an IC 50 value of 11.67 μg/mL with potent in vitro antimalarial activity and cytotoxicity evaluation revealed that this extract was not toxic against Brine shrimp and THP-1 cells. The injury to erythrocytes analysis had not shown any morphological alterations and damage to the erythrocytes after 48 h of incubation. Because methanolic bark extract of Pongamia pinnata has shown good antimalarial activity in vitro, it was also tested in vivo. So the extract had exhibited an excellent activity against P. berghei malaria parasite while decrement of parasite counts was moderately low and

  1. Differential speciation of ferriprotoporphyrin IX in the presence of free base and diprotic 4-aminoquinoline antimalarial drugs

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    Gildenhuys, Johandie; Müller, Ronel; le Roex, Tanya; de Villiers, Katherine A.

    2017-03-01

    The crystal structures of the μ-propionato dimer and π-π dimer of ferriprotoporphyrin IX (Fe(III)PPIX) have been determined by single crystal X-ray diffraction (SCD). Both species were obtained in the presence of the synthetic 4-aminoquinoline antimalarial drug, amodiaquine (AQ). The solution that afforded the μ-propionato dimer contained AQ as a free base (i.e. with both quinoline and terminal amine nitrogen atoms neutral). On the other hand, when the diprotic salt of AQ was included in the crystallization medium, the Fe(III)PPIX π-π dimer was obtained. The structure of the μ-propionato dimer, which is the discrete structural unit that constitutes haemozoin (malaria pigment), is identical to that obtained previously in presence of chloroquine free base. We suspect that the drug, via its two available basic sites, facilitates dissociation of one of the two Fe(III)PPIX propionic acid groups to yield a propionate group that is required for reciprocal coordination of the metal centre to form the centrosymmetric dimer. On the other hand, this proton transfer is not possible when the drug is present as a diprotic salt. In this case, the π-π dimer of Fe(III)PPIX is obtained. In the current study, the π-π dimer of haemin (chloro-Fe(III)PPIX) was obtained as a DMF solvate from non-aqueous aprotic solution (dimethyl formamide and chloroform), however the π-π dimer is also known to exist in aqueous solution (as aqua- or hydroxo-Fe(III)PPIX), where it is purportedly involved in the nucleation of haemozoin. We have been able to unambiguously determine the positions of all non-hydrogen atoms, as well as locate or assign all hydrogen atoms in the structure of the π-π dimer, which was not possible in the SCD structure of haemin reported by Koenig in 1965 owing to disorder in the vinyl and methyl substituents. Interestingly, no disorder in the methyl and vinyl groups is observed in the current structure. Both the π-π and μ-propionato dimers of Fe(III)PPIX are

  2. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate

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    Kirti Mishra

    2011-01-01

    Full Text Available Andrographolide (AND, the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plant Andrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages of Plasmodium falciparum in vitro and Plasmodium berghei ANKA in vivo. IC50s for artesunate (AS, andrographolide (AND, and curcumin (CUR were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND was found synergistic with curcumin (CUR and addictively interactive with artesunate (AS. In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%, compared to the control (81%, but also by extending the life span by 2-3 folds. Being nontoxic to the in vivo system this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

  3. Vector incrimination and effects of antimalarial drugs on malaria transmission and control in the Amazon Basin of Brazil

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    T. A. Klein

    1992-01-01

    Full Text Available World ecosystems differ significantly and a multidisciplinary malaria control approach must be adjusted to meet these requirements. These include a comprehensive understanding of the malaria vectors, their behavior, seasonal distribution and abundance, susceptibility to insecticides (physiological and behavioral, methods to reduce the numbers of human gametocyte carriers through effective health care systems and antimalarial drug treatment, urban malaria transmission versus rural or forest malaria transmission, and the impact of vaccine development. Many malaria vectors are members of species complexes and individual relationship to malaria transmission, seasonal distribution, bitting behavior, etc. is poorly understood. Additionaly, malaria patients are not examined for circulating gametocytes and both falciparum and vivax malaria patients may be highly infective to mosquitoes after treatment with currently used antimalarial drugs. Studies on the physiological and behavioral effects of DDT and other insecticides are inconclusive and need to be evalusted.

  4. Evaluation of antimalarial, free-radical-scavenging and insecticidal activities of Artemisia scoparia and A. Spicigera, Asteraceae

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    Fariba H. Afshar

    2011-12-01

    Full Text Available Artemisia species (Asteraceae, widespread throughout the world, are a group of important medicinal plants. The extracts of two medicinal plants of this genus, Artemisia scoparia Waldst. & Kit. and A. spicigera C. Koch, were evaluated for potential antimalarial, free-radical-scavenging and insecticidal properties, using the heme biocrystallisation and inhibition assay, the DPPH assay and the contact toxicity bioassay using the pest Tribolium castaneum, respectively. The methanol extracts of both species showed strong free-radical-scavenging activity and the RC50 values were 0.0317 and 0.0458 mg/mL, respectively, for A. scoparia and A. spicigera. The dichloromethane extracts of both species displayed a moderate level of potential antimalarial activity providing IC50 at 0.778 and 0.999 mg/mL for A. scoparia and A. spicigera, respectively. Both species of Artemisia showed insecticidal properties. However, A. spicigera was more effective than A. scoparia.

  5. 7-Chloroquinolinotriazoles: synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies.

    Science.gov (United States)

    Pereira, Guilherme R; Brandão, Geraldo Célio; Arantes, Lucas M; de Oliveira, Háliton A; de Paula, Renata Cristina; do Nascimento, Maria Fernanda A; dos Santos, Fábio M; da Rocha, Ramon K; Lopes, Júlio César D; de Oliveira, Alaíde Braga

    2014-02-12

    Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  6. Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

    Science.gov (United States)

    Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

    2017-03-31

    A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.

    Science.gov (United States)

    Pacorel, Bénédicte; Leung, Suet C; Stachulski, Andrew V; Davies, Jill; Vivas, Livia; Lander, Hollie; Ward, Stephen A; Kaiser, Marcel; Brun, Reto; O'Neill, Paul M

    2010-01-28

    In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.

  8. In vitro and in vivo antimalarial potential of oleoresin obtained from Copaifera reticulata Ducke (Fabaceae) in the Brazilian Amazon rainforest.

    Science.gov (United States)

    de Souza, Giovana A G; da Silva, Nazaré C; de Souza, Juarez; de Oliveira, Karen R M; da Fonseca, Amanda L; Baratto, Leopoldo C; de Oliveira, Elaine C P; Varotti, Fernando de Pilla; Moraes, Waldiney P

    2017-01-15

    In view of the wide variety of the flora of the Amazon region, many plants have been studied in the search for new antimalarial agents. Copaifera reticulata is a tree distributed throughout the Amazon region which contains an oleoresin rich in sesquiterpenes and diterpenes with β-caryophyllene as the major compound. The oleoresin has demonstrated antiparasitic activity against Leishmania amazonensis. Because of this previously reported activity, this oleoresin would be expected to also have antimalarial activity. In this study we evaluated the in vitro and in vivo antimalarial potential of C. reticulata oleoresin. In vitro assays were done using P. falciparum W2 and 3D7 strains and the human fibroblast cell line 26VA Wi-4. For in vivo analysis, BALB/c mice were infected with approximately 10 6 erythrocytes parasitized by P. berghei and their parasitemia levels were observed over 7 days of treatment with C. reticulata; hematological and biochemical parameters were analyzed at the end of experiment. The oleoresin of C. reticulata containing the sesquiterpenes β-caryophyllene (41.7%) and β-bisabolene (18.6%) was active against the P. falciparum W2 and 3D7 strains (IC 50  = 1.66 and 2.54 µg/ml, respectively) and showed low cytotoxicity against the 26VA Wi-4 cell line (IC 50  > 100 µg/ml). The C. reticulata oleoresin reduced the parasitemia levels of infected animals and doses of 200 and 100 mg/kg/day reached a rate of parasitemia elimination resembling that obtained with artemisinin 100 mg/kg/day. In addition, treatment with oleoresin improved the hypoglycemic, hematologic, hepatic and renal parameters of the infected animals. The oleoresin of C. reticulata has antimalarial properties and future investigations are necessary to elucidate its mechanism of action. Copyright © 2016 Elsevier GmbH. All rights reserved.

  9. New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

    Science.gov (United States)

    Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

    2015-06-01

    Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Cyquant cell proliferation assay as a fluorescence-based method for in vitro screening of antimalarial activity.

    Science.gov (United States)

    Sriwilaijaroen, Nongluk; Kelly, Jane Xu; Riscoe, Michael; Wilairat, Prapon

    2004-12-01

    The appearance of drug resistant parasites and the absence of an effective vaccine have resulted in the need for new effective antimalarial drugs. Consequently, a convenient method for in vitro screening of large numbers of antimalarial drug candidates has become apparent. The CyQUANT cell proliferation assay is a highly sensitive fluorescence-based method for quantitation of cell number by measuring the strong fluorescence produced when green GR dye binds to nucleic acids. We have applied the CyQUANT assay method to evaluate the growth of Plasmodium falciparum D6 strain in culture. The GR-nucleic acid fluorescence linearly correlated with percent parasitemia at both 0.75 or 1 percent hematocrit with the same correlation coefficient of r2 = 0.99. The sensitivity of P. falciparum D6 strain to chloroquine and to 3,6-bis-omega-diethylaminoamyloxyxanthone, a novel antimalarial, determined by the CyQUANT assay were comparable to those obtained by the traditional [3H]-ethanolamine assay: IC50 value of chloroquine was 54 nM and 51 nM by the CyQUANT and [3H]-ethanolamine assay, respectively; IC50 value for 3,6-bis-omega-diethylaminoamyloxyxanthone was 254 nM and 223 nM by the CyQUANT and [3H]-ethanolamine assay, respectively. This procedure requires no radioisotope, uses simple equipment, and is an easy and convenient procedure, with no washing and harvesting steps. Moreover, all procedures can be set up continuously and thus, the CyQUANT assay is suitable in automatic high through-put drug screening of antimalarial drugs.

  11. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

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    Mullié Catherine

    2012-03-01

    Full Text Available Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ (+- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R -enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S and (R-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

  12. Early home treatment of childhood fevers with ineffective antimalarials is deleterious in the outcome of severe malaria

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    Olumese Peter E

    2008-07-01

    Full Text Available Abstract Background Early diagnosis and prompt treatment including appropriate home-based treatment of malaria is a major strategy for malaria control. A major determinant of clinical outcome in case management is compliance and adherence to effective antimalarial regimen. Home-based malaria treatment with inappropriate medicines is ineffective and there is insufficient evidence on how this contributes to the outcome of severe malaria. This study evaluated the effects of pre-hospital antimalarial drugs use on the presentation and outcome of severe malaria in children in Ibadan, Nigeria. Methods Two hundred and sixty-eight children with a median age of 30 months comprising 114 children with cerebral malaria and 154 with severe malarial anaemia (as defined by WHO were prospectively enrolled. Data on socio-demographic data, treatments given at home, clinical course and outcome of admission were collected and analysed. Results A total of 168 children had treatment with an antimalarial treatment at home before presenting at the hospital when there was no improvement. There were no significant differences in the haematocrit levels, parasite counts and nutritional status of the pre-hospital treated and untreated groups. The most commonly used antimalarial medicine was chloroquine. Treatment policy was revised to Artemesinin-based Combination Therapy (ACT in 2005 as a response to unacceptable levels of therapeutic failures with chloroquine, however chloroquine use remains high. The risk of presenting as cerebral malaria was 1.63 times higher with pre-hospital use of chloroquine for treatment of malaria, with a four-fold increase in the risk of mortality. Controlling for other confounding factors including age and clinical severity, pre-hospital treatment with chloroquine was an independent predictor of mortality. Conclusion This study showed that, home treatment with chloroquine significantly impacts on the outcome of severe malaria. This finding

  13. Identification and reconstitution of the polyketide synthases responsible for biosynthesis of the anti-malarial agent, cladosporin

    OpenAIRE

    Cochrane, Rachel V. K.; Sanichar, Randy; Lambkin, Gareth R.; Reiz, Béla; Xu, Wei; Tang, Yi; Vederas, John C.

    2015-01-01

    The anti-malarial agent cladosporin is a nanomolar inhibitor of Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood and liver stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it was believed to be biosynthesized by a highly reducing (HR) and non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism, and subsequent heterologous expression of these enzymes in Sacchar...

  14. In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

    Science.gov (United States)

    Olasehinde, Grace I; Ojurongbe, Olusola; Adeyeba, Adegboyega O; Fagade, Obasola E; Valecha, Neena; Ayanda, Isaac O; Ajayi, Adesola A; Egwari, Louis O

    2014-02-20

    The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia ('Ejirin') Diospyros monbuttensis ('Egun eja') and Morinda lucida ('Oruwo') was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2 nM) while the lowest was obtained from M. lucida (IC50 = 25 nM). Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.

  15. Isolation and Purification of C-phycocyanin from Nostoc muscorum (Cyanophyceae and Cyanobacteria Exhibits Antimalarial Activity In vitro

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    Sukla Biswas

    2010-10-01

    Full Text Available The Phycobilin pigments are intensively fluorescent and water soluble. They are categorized into three types, such as pigments containing high, intermediate and low energies are Phycoerythrins (Phycoerythrocyanins, Phycocyanins and Allophycocyanins, respectively. Besides light harvesting, the Phycobiliproteins have shown industrial and biomedical importance. Among them, C-phycocyanin (C-PC has been considered to be the most preferred one. The present study was undertaken to evaluate the antimalarial activity of C-PC isolated from a Nitrogen-fixing Cyanobacterium and Nostoc muscorum. C- PC was extracted and purified by acetone extraction and ammonium sulfate precipitation and dialysis followed by amicon filtration. It was isolated as a~124 kDa water soluble protein molecule. It showed antimalarial activity in vitro against Chloroquine sensitive and resistant Plasmodium falciparum strains. Inhibitory concentrations at 50%, 90% and 95% were determined as 10.27±2.79, 53.53±6.26 and 73.78±6.92 µg/ml against the Chloroquine-sensitive strains; 10.37±1.43, 56.99±11.07 and 72.79±8.59 µg/ml against Chloroquine resistant of Plasmodium falciparum strains. C-PC was found to have antimalarial activity even at a concentration of 3.0 µg/ml. The possible mechanism might be relied on the destruction of polymerization of Haemozoin by binding of C-PC with Ferriprotoporphyrin-IX at the water surface of the plasma membrane.

  16. Synthesis, in vitro and in silico antimalarial activity of 7-chloroquinoline and 4H-chromene conjugates.

    Science.gov (United States)

    Parthiban, A; Muthukumaran, J; Manhas, Ashan; Srivastava, Kumkum; Krishna, R; Rao, H Surya Prakash

    2015-10-15

    A new series of chloroquinoline-4H-chromene conjugates incorporating piperizine or azipane tethers were synthesized and their anti-malarial activity were evaluated against two Plasmodium falciparum strains namely 3D7 chloroquine sensitive (CQS) and K1 chloroquine resistant (CQR). Chloroquine was used as the standard and also reference for comparison. The conjugates exhibit intense UV absorption with λmax located at 342 nm (log ε=4.0), 254 nm (log ε=4.2), 223 nm (log ε=4.4) which can be used to spectrometrically track the molecules even in trace amounts. Among all the synthetic compounds, two molecules namely 6-nitro and N-piperazine groups incorporated 7d and 6-chloro and N-azapane incorporated 15b chloroquinoline-4H-chromene conjugates showed significant anti-malarial activity against two strains (3D7 and K1) of P. falciparum. These values are lesser than the values of standard antimalarial compound. Molecular docking results suggested that these two compounds showing strong binding affinity with P. falciparum lactate dehydrogenase (PfLDH) and also they occupy the co-factor position which indicated that they could be the potent inhibitors for dreadful disease malaria and specifically attack the glycolytic pathway in parasite for energy production. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

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    Cervantes Serena

    2009-06-01

    Full Text Available Abstract Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency.

  18. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

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    Daria Van Tyne

    2011-04-01

    Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

  19. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

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    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  20. New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication.

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    Youki Ueda

    Full Text Available BACKGROUND: Persistent hepatitis C virus (HCV infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed. METHODOLOGY/PRINCIPAL FINDINGS: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8 were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251 showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect. CONCLUSIONS/SIGNIFICANCE: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

  1. Formation of the diuretic chlorazanil from the antimalarial drug proguanil--implications for sports drug testing.

    Science.gov (United States)

    Thevis, Mario; Geyer, Hans; Thomas, Andreas; Tretzel, Laura; Bailloux, Isabelle; Buisson, Corinne; Lasne, Francoise; Schaefer, Maximilian S; Kienbaum, Peter; Mueller-Stoever, Irmela; Schänzer, Wilhelm

    2015-11-10

    Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chlorophenyl)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chlorophenyl)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic

  2. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

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    Chance Michael L

    2011-08-01

    Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum

  3. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications.

    Science.gov (United States)

    Mubjer, Reem A; Adeel, Ahmed A; Chance, Michael L; Hassan, Amir A

    2011-08-21

    This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP). Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt)-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr)-C59R and dihydropteroate synthase (dhps)-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it

  4. A retrospective analysis of the change in anti-malarial treatment policy: Peru

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    Vincent-Mark Arlene

    2009-04-01

    Full Text Available Abstract Background National malaria control programmes must deal with the complex process of changing national malaria treatment guidelines, often without guidance on the process of change. Selecting a replacement drug is only one issue in this process. There is a paucity of literature describing successful malaria treatment policy changes to help guide control programs through this process. Objectives To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru. Methods Using qualitative methods (individual and focus group interviews, stakeholder analysis and a review of documents, a retrospective analysis of the process of change in Peru's anti-malarial treatment policy from the early 1990's to 2003 was completed. Results The decision to change Peru's policies resulted from increasing levels of anti-malarial drug resistance, as well as complaints from providers that the drugs were no longer working. The context of the change occurred in a time in which Peru was changing national governments, which created extreme challenges in moving the change process forward. Peru utilized a number of key strategies successfully to ensure that policy change would occur. This included a having the process directed by a group who shared a common interest in malaria and who had long-established social and professional networks among themselves, b engaging in collaborative teamwork among nationals and between nationals and international collaborators, c respect for and inclusion of district-level staff in all phases of the process, d reliance on high levels of technical and scientific knowledge, e use of standardized protocols to collect data, and f transparency. Conclusion Although not perfectly or fully implemented by 2003, the change in malaria treatment policy in Peru occurred very quickly, as compared to other countries. They identified a problem, collected the data necessary to justify the

  5. G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study.

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    Benedikt Ley

    Full Text Available The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0-2 plus single dose primaquine (0.75mg/kg on day2 for P. falciparum infections, or with chloroquine (days 0-2 plus 14 days primaquine (3.5mg/kg total over 14 days for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374.Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections. Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2-27.3 hours for P. falciparum, 20.0 (IQR: 9.5-22.7 hours for P. vivax and 16.6 (IQR: 10.0-46.0 hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174 had severe G6PD deficiency (<10% activity, five participants (5/174 had mild G6PD deficiency (10-60% activity. The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0% and -7.4% (95%CI: -4.5 to -10.4% respectively.The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather

  6. Malaria overdiagnosis and subsequent overconsumption of antimalarial drugs in Angola: Consequences and effects on human health.

    Science.gov (United States)

    Manguin, Sylvie; Foumane, Vincent; Besnard, Patrick; Fortes, Filomeno; Carnevale, Pierre

    2017-07-01

    Microscopic blood smear examinations done in health centers of Angola demonstrated a large overdiagnosis of malaria cases with an average rate of errors as high as 85%. Overall 83% of patients who received Coartem ® had an inappropriate treatment. Overestimated malaria diagnosis was noticed even when specific symptoms were part of the clinical observation, antimalarial treatments being subsequently given. Then, malaria overdiagnosis has three main consequences, (i) the lack of data reliability is of great concern, impeding epidemiological records and evaluation of the actual influence of operations as scheduled by the National Malaria Control Programme; (ii) the large misuse of antimalarial drug can increase the selective pressure for resistant strain and can make a false consideration of drug resistant P. falciparum crisis; and (iii) the need of strengthening national health centers in term of human, with training in microscopy, and equipment resources to improve malaria diagnosis with a large scale use of rapid diagnostic tests associated with thick blood smears, backed up by a "quality control" developed by the national health authorities. Monitoring of malaria cases was done in three Angolan health centers of Alto Liro (Lobito town) and neighbor villages of Cambambi and Asseque (Benguéla Province) to evaluate the real burden of malaria. Carriers of Plasmodium among patients of newly-borne to 14 years old, with or without fever, were analyzed and compared to presumptive malaria cases diagnosed in these health centers. Presumptive malaria cases were diagnosed six times more than the positive thick blood smears done on the same children. In Alto Liro health center, the percentage of diagnosis error reached 98%, while in Cambambi and Asseque it was of 79% and 78% respectively. The percentage of confirmed malaria cases was significantly higher during the dry (20.2%) than the rainy (13.2%) season. These observations in three peripheral health centers confirmed what

  7. Brine shrimp toxicity and antimalarial activity of some plants traditionally used in treatment of malaria in Msambweni district of Kenya.

    Science.gov (United States)

    Nguta, J M; Mbaria, J M

    2013-07-30

    In Kenya, most people especially in rural areas use traditional medicine and medicinal plants to treat many diseases including malaria. Malaria is of national concern in Kenya, in view of development of resistant strains of Plasmodium falciparum to drugs especially chloroquine, which had been effective and affordable. There is need for alternative and affordable therapy. Many antimalarial drugs have been derived from medicinal plants and this is evident from the reported antiplasmodial activity. The present study reports on the in vivo antimalarial activity and brine shrimp lethality of five medicinal plants traditionally used to treat malaria in Msambweni district, Kenya. A total of five aqueous crude extracts from different plant parts used in traditional medicine for the treatment of malaria were evaluated for their in vivo antimalarial activity using Plasmodium berghei infected Swiss mice and for their acute toxicity using Brine shrimp lethality test. The screened crude plant extracts suppressed parasitaemia as follows: Azadirachta indica (L) Burm. (Meliaceae), 3.1%; Dichrostachys cinerea (L) Wight et Arn (Mimosaceae), 6.3%; Tamarindus indica L. (Caesalpiniaceae), 25.1%; Acacia seyal Del. (Mimosaceae) 27.8% and Grewia trichocarpa Hochst ex A.Rich (Tiliaceae) 35.8%. In terms of toxicity, A.indica root bark extract had an LC50 of 285.8 µg/ml and was considered moderately toxic. T.indica stem bark extract and G.trichocarpa root extract had an LC50 of 516.4 and 545.8 µg/ml respectively and were considered to be weakly toxic while A.seyal and D.cinerea root extracts had a LC50>1000 µg/ml and were therefore considered to be non toxic. The results indicate that the aqueous extracts of the tested plants when used alone as monotherapy had antimalarial activity which was significantly different from that of chloroquine (P≤0.05). The results also suggest that the anecdotal efficacy of the above plants reported by the study community is related to synergism of

  8. avoidable factors, missed opportunities and substandard care

    African Journals Online (AJOL)

    representing metropolitan areas, cities and towns, and rural areas. Method. Users of the ... three categories has the obvious advantage that information gained can be fed ..... Ho JJ, Subramaiam P, Hendersen-:-Smart D}, Davis PG. Continuous ...

  9. Substandard Journal Management: Wastage of Authors’ Motivation

    Directory of Open Access Journals (Sweden)

    Shahryar Sorooshian

    2018-03-01

    Full Text Available Authors who offer papers for publication to professional journals are under the impression that their work is publication-worthy. The editors as well as reviewers adjudge whether the manuscripts should be taken up for publication. This paper presents certain cases of unreliable journals’ management processes with an aim to show how a journal reviewer or editor could squander authors’ time and negatively impact the motivation of scholars to publish.

  10. Involving women.

    Science.gov (United States)

    Agbo, J

    1994-01-01

    I am a primary health care (PHC) coordinator working with the May Day Rural project, a local NGO involved in integrated approaches and programs with rural communities in the Ga District of the Greater-Accra region in Ghana. When we talk about the community development approach we must first and foremost recognize that we are talking about women, because in the developing world frequent childbirths mean that her burden of mortality is higher than a man's; her workload is extremely heavy--whether in gardening, farming, other household duties, caring for the sick, or the rearing of children; she has a key role in PHC and community development, because men are always looking for greener pastures elsewhere, leaving the women behind. Women's concerns are critical in most health care projects and women and children are their main beneficiaries. Why not include women in the management team, project design, implementation and evaluation processes? That is what the May Day Rural project is practicing, encouraging women's participation and creating a relationship of trust. full text

  11. The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin

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    Barik Sailen

    2003-09-01

    Full Text Available Abstract Background The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA, is a specific inhibitor of heat shock protein 90 (Hsp90 and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. Results We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively and on all erythrocytic stages of the parasite. Conclusions Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

  12. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

    Science.gov (United States)

    Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

    2007-01-04

    The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

  13. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

    Science.gov (United States)

    Paquet, Tanya; Le Manach, Claire; Cabrera, Diego González; Younis, Yassir; Henrich, Philipp P; Abraham, Tara S; Lee, Marcus C S; Basak, Rajshekhar; Ghidelli-Disse, Sonja; Lafuente-Monasterio, María José; Bantscheff, Marcus; Ruecker, Andrea; Blagborough, Andrew M; Zakutansky, Sara E; Zeeman, Anne-Marie; White, Karen L; Shackleford, David M; Mannila, Janne; Morizzi, Julia; Scheurer, Christian; Angulo-Barturen, Iñigo; Martínez, María Santos; Ferrer, Santiago; Sanz, Laura María; Gamo, Francisco Javier; Reader, Janette; Botha, Mariette; Dechering, Koen J; Sauerwein, Robert W; Tungtaeng, Anchalee; Vanachayangkul, Pattaraporn; Lim, Chek Shik; Burrows, Jeremy; Witty, Michael J; Marsh, Kennan C; Bodenreider, Christophe; Rochford, Rosemary; Solapure, Suresh M; Jiménez-Díaz, María Belén; Wittlin, Sergio; Charman, Susan A; Donini, Cristina; Campo, Brice; Birkholtz, Lyn-Marie; Hanson, Kirsten K; Drewes, Gerard; Kocken, Clemens H M; Delves, Michael J; Leroy, Didier; Fidock, David A; Waterson, David; Street, Leslie J; Chibale, Kelly

    2017-04-26

    As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment. Copyright © 2017, American Association for the Advancement of Science.

  14. Efficacy of Eosin B as a New Antimalarial Drug in a Murine Model

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    Zahra Zamani

    2012-01-01

    Full Text Available The initial success of any adopted anti-infective strategy to malaria is followed by a descent due to the emergence of resistance to it. The search for new drugs and drug targets is a consistent demand in this disease. Eosin B, a common laboratory dye, is reported to have good antiparasitic properties in vitro. It was studied for its antiparasitic effect in vivo on chloroquine-sensitive Plasmodium berghei murine malaria. Eosin B was administered in 2 different doses by either the oral or parenteral route, once or twice daily to mice infected with Plasmodium berghei. Both the doses of eosin B 400 mg/kg and 800 mg/kg gave better results than the controls which were 40 mg/kg chloroquine and 100 mg/kg of arteether with P<0.005 significance. Percentage suppressive activity by Peter’s test of eosin B was better, though at a higher dose than both the controls. Survival rate of mice receiving the higher dose of eosin B was longer than that of the controls. When administered twice daily, the mice were fully cured after 4 days. Eosin B seems to be a promising drug exhibiting good antimalarial effects in the murine model of the disease.

  15. Cytotoxic and Antimalarial Amaryllidaceae Alkaloids from the Bulbs of Lycoris radiata

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    Bin Hao

    2013-02-01

    Full Text Available Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+-5,6-dehydrolycorine (1, (+-3α,6β-diacetyl-bulbispermine (2, (+-3α-hydroxy-6β-acetyl- bulbispermine (3, (+-8,9-methylenedioxylhomolycorine-N-oxide (5, and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7, together with two known compounds, (+-3α-methoxy- 6β-acetylbulbispermine (4 and (+-homolycorine- N-oxide (6. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251, as well as HL-60, SMMC-7721, and W480 cell lines with IC50 values of 9.4–11.6 μM. Additonally, compound 1 exhibited antimalarial activity with IC50 values of 2.3 μM for D-6 strain and 1.9 μM for W-2 strain of Plasmodium falciparum.

  16. Antimalarial activity of selected Sudanese medicinal plants with emphasis to Maytenus senegalensis

    Energy Technology Data Exchange (ETDEWEB)

    Idris, Ahmed El Tahir Mohamed [Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum (Sudan)

    1998-03-01

    The aim of the present study is to identify and characterize the antimalrial agents from traitional Sudanese medicinal plants. 49 plants parts representing 26 species from 15 families were extracted and screened for their in vitro antimalrial activity using P. falciparum strain 3D7 which is chloroquine sensitive and Dd2 strain which is chloroquine resistant and pyrimethamine sensitive.The plant species investigated exhibited diverse botanical families. They includes Annonaceae, Aristolochiaceae, Asteraceae, Balantiaceae, Caesalpiniceae, Celasteraceae, Cucurbitaceae, Fabaceae, Graminae, Meliaceae, Myrtaceae, Polygonaceae, Rubiaceae, Rutaceae, and simaroubaceae. The evaluation of these plants for their antimalarial activity and their effect on lymphocyte proliferation was carried out. 57 extracts were tested on the chloroquine sensitive strain (3D7). Where 34 extracts (59%) exhibited significant activity against 3D7 with IC{sub 50} values {<=} 50 {mu} g/ml. While 21 extracts (57%) showed antimalrial activities with IC{sub 50} values {<=} 50 {mu} g/ml on Dd2. 13 extracts (22%) and ten extracts (18%) only showed an activity with IC{sub 50} values {<=} 5 {mu} g/ml on 3 D7 and Dd2, respectively. The activities of some plant extracts, which affected 3D7 strain, were measured using the radiolabelled ({sup 3}H) hypoxanthine method and microscopical count. 15 plant extracts (48%) from 32 showed IC{sub 50} values {<=} 50 {mu} g/ml against 3D7 strain using the radiolabelled hypoxanthine methods and only 5 extracts (16%) showed IC{sub 50} values {<=} 5 {mu} g/ml against 3D7. Most of the extracts screened had a low effect on lymphocyte proliferation (IC{sub 50} values >100 {mu} g/ml), where as Sonochous cornatus, Balanites aegyptiaca, Tamarindus indica, Acacia nilotica, Annona squamosa, Eucalyptus globulus and Cassia tora enhanced lymphocyte proliferation. liquid-liquid partition of methanolic preparation of Acacia nilotica seeds and husk showed that the ethylacetate phase

  17. Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives.

    Science.gov (United States)

    Pereira, Glaécia A N; Souza, Gisele C; Santos, Lourivaldo S; Barata, Lauro E S; Meneses, Carla C F; Krettli, Antoniana U; Daniel-Ribeiro, Cláudio Tadeu; Alves, Cláudio Nahum

    2017-09-01

    The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs. © 2017 John Wiley & Sons A/S.

  18. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

    International Nuclear Information System (INIS)

    Paeshuyse, Jan; Coelmont, Lotte; Vliegen, Inge; Hemel, Johan van; Vandenkerckhove, Jan; Peys, Eric; Sas, Benedikt; Clercq, Erik De; Neyts, Johan

    2006-01-01

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC 5 ) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 ± 21 μM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 μM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin

  19. Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design

    Science.gov (United States)

    Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

    Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

  20. Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

    Directory of Open Access Journals (Sweden)

    Bo Zhai

    2014-01-01

    Full Text Available Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

  1. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

    Energy Technology Data Exchange (ETDEWEB)

    Paeshuyse, Jan [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Coelmont, Lotte [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Vliegen, Inge [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Hemel, Johan van [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Vandenkerckhove, Jan [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Peys, Eric [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Sas, Benedikt [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Clercq, Erik De [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Neyts, Johan [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium)

    2006-09-15

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC{sub 5}) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 {+-} 21 {mu}M. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 {mu}M) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.

  2. Antimalarial activity of selected Sudanese medicinal plants with emphasis to Maytenus senegalensis

    International Nuclear Information System (INIS)

    Idris, Ahmed El Tahir Mohamed

    1998-03-01

    The aim of the present study is to identify and characterize the antimalrial agents from traitional Sudanese medicinal plants. 49 plants parts representing 26 species from 15 families were extracted and screened for their in vitro antimalrial activity using P. falciparum strain 3D7 which is chloroquine sensitive and Dd2 strain which is chloroquine resistant and pyrimethamine sensitive.The plant species investigated exhibited diverse botanical families. They includes Annonaceae, Aristolochiaceae, Asteraceae, Balantiaceae, Caesalpiniceae, Celasteraceae, Cucurbitaceae, Fabaceae, Graminae, Meliaceae, Myrtaceae, Polygonaceae, Rubiaceae, Rutaceae, and simaroubaceae. The evaluation of these plants for their antimalarial activity and their effect on lymphocyte proliferation was carried out. 57 extracts were tested on the chloroquine sensitive strain (3D7). Where 34 extracts (59%) exhibited significant activity against 3D7 with IC 50 values ≤ 50 μ g/ml. While 21 extracts (57%) showed antimalrial activities with IC 50 values ≤ 50 μ g/ml on Dd2. 13 extracts (22%) and ten extracts (18%) only showed an activity with IC 50 values ≤ 5 μ g/ml on 3 D7 and Dd2, respectively. The activities of some plant extracts, which affected 3D7 strain, were measured using the radiolabelled ( 3 H) hypoxanthine method and microscopical count. 15 plant extracts (48%) from 32 showed IC 50 values ≤ 50 μ g/ml against 3D7 strain using the radiolabelled hypoxanthine methods and only 5 extracts (16%) showed IC 50 values ≤ 5 μ g/ml against 3D7. Most of the extracts screened had a low effect on lymphocyte proliferation (IC 50 values >100 μ g/ml), where as Sonochous cornatus, Balanites aegyptiaca, Tamarindus indica, Acacia nilotica, Annona squamosa, Eucalyptus globulus and Cassia tora enhanced lymphocyte proliferation. liquid-liquid partition of methanolic preparation of Acacia nilotica seeds and husk showed that the ethylacetate phase possessed the highest activity against both 3D7 and Dd2

  3. Quinones: reactions with hemoglobin, effects within erythrocytes and potential for antimalarial development

    International Nuclear Information System (INIS)

    Denny, B.J.

    1986-01-01

    The focus of this research was to characterize the interactions of some simple quinone like compounds with purified hemoglobin and to study the effects of these compounds within erythrocytes. It is proposed that these sorts of agents can have an antimalarial effect. The simplest compounds chosen for study were benzoquinone, methylquinone (toluquinone) and hydroquinone. When 14 C-quinone was reacted with purified hemoglobin (Hb) there was rapid binding of the first two moles of substrate per Hb molecule. An unusual property of the modified Hb's is that in the presence of a redox sensitive agent such as cytochrome c they are capable of generating superoxide anions. Within erythrocytes, quinone and toluquinone which differ only by a single methyl group have completely different effects. Toluquinone causes the cells to hemolyse and the effect was enhanced when the erythrocyte superoxide dismutase was inhibited; the effect was diminished when scavengers of activated oxygen such as histidine, mannitol and vital E were present. Benzoquinone on the other hand did not cause the cells to hemolyse and instead appeared to protect the cells from certain hemolytic stresses. Growth of malaria parasites in erythrocytes has been shown to be inhibited by activated forms of oxygen, also some quinone like agents in the past have been shown to inhibit the parasite's metabolism. An initial experiment with erythrocytes infected with malaria parasites showed that quinone and toluquinone could both inhibit the growth rate of parasites

  4. Resistance of Plamodium falciparum to Antimalarial Drugs in Zaragoza (Antioquia, Colombia, 1998

    Directory of Open Access Journals (Sweden)

    Silvia Blair-Trujillo

    2002-04-01

    Full Text Available Plasmodium falciparum sensitivity to chloroquine (CHL, amodiaquine (AMO and sulfadoxine/pyrimethamine (SDX/PYR was assessed in vivo and in vitro in a representative sample from the population of Zaragoza in El Bajo Cauca region (Antioquia-Colombia. There were 94 patients with P. falciparum evaluated. For the in vivo test the patients were followed by clinical examination and microscopy, during 7 days. The in vitro test was performed following the recommendations of the World Health Organization. The in vivo prevalence of resistance to CHL was 67%, to AMO 3% and to SDX/PYR 9%. The in vitro test showed sensitivity to all antimalarials evaluated. Concordance for CHL between the in vivo and in vitro tests was 33%. For AMO and SDX/PYR, the concordance was 100%. We conclude that a high percentage of patients are resistant to CHL (in vivo. A high rate of intestinal parasitism might explain in part, the differences observed between the in vivo and the in vitro results. Therefore, new policies and treatment regimens should be proposed for the treatment of the infection in the region. Nationwide studies assessing the degree of resistance are needed.

  5. A microtitre-based method for measuring the haem polymerization inhibitory activity (HPIA) of antimalarial drugs.

    Science.gov (United States)

    Basilico, N; Pagani, E; Monti, D; Olliaro, P; Taramelli, D

    1998-07-01

    The malaria parasite metabolizes haemoglobin and detoxifies the resulting haem by polymerizing it to form haemozoin (malaria pigment). A polymer identical to haemozoin, beta-haematin, can be obtained in vitro from haematin at acidic pH. Quinoline-containing anti-malarials (e.g. chloroquine) inhibit the formation of either polymer. Haem polymerization is an essential and unique pharmacological target. To identify molecules with haem polymerization inhibitory activity (HPIA) and quantify their potency, we developed a simple, inexpensive, quantitative in-vitro spectrophotometric microassay of haem polymerization. The assay uses 96-well U-bottomed polystyrene microplates and requires 24 h and a microplate reader. The relative amounts of polymerized and unpolymerized haematin are determined, based on solubility in DMSO, by measuring absorbance at 405 nm in the presence of test compounds as compared with untreated controls. The final product (a solid precipitate of polymerized haematin) was validated using infrared spectroscopy and the assay proved reproducible; in this assay, activity could be partly predicted based on the compound's chemical structure. Both water-soluble and water-insoluble compounds can be quantified by this method. Although the throughput of this assay is lower than that of radiometric methods, the assay is easier to set up and cheaper, and avoids the problems related to radioactive waste disposal.

  6. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

    Directory of Open Access Journals (Sweden)

    Anna Caroline Campos Aguiar

    Full Text Available Chloroquine (CQ is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index. However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ and compared with a previously synthesized bisquinoline (BAQ, both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

  7. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

    Science.gov (United States)

    Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

    2012-01-01

    Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

  8. Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action.

    Science.gov (United States)

    Singh, Shiv Vardan; Manhas, Ashan; Kumar, Yogesh; Mishra, Sonali; Shanker, Karuna; Khan, Feroz; Srivastava, Kumkum; Pal, Anirban

    2017-05-01

    A clinical emergency stands due to the appearance of drug resistant Plasmodium strains necessitate novel and effective antimalarial chemotypes, where plants seem as the prime option, especially after the discovery of quinine and artemisinin. The present study was aimed towards bioprospecting leaves of Flueggea virosa for its antimalarial efficacy and active principles. Crude hydro-ethanolic extract along with solvent derived fractions were tested in vitro against Plasmodium falciparum CQ sensitive (3D7) and resistant (K1) strains, where all the fractions exhibited potential activity (IC 50 values active constituent (IC 50, 8.07±2.05μM) of ethyl acetate fraction with the inhibition of heme polymerization pathway of malaria parasite being one of the possible chemotherapeutic target. Furthermore, bergenin exhibited a moderate antimalarial activity against P. berghei and also ameliorated parasite induced systemic inflammation in host (mice). Safe toxicity profile elucidated through in vitro cytotoxicity and in silico ADME/T predications evidently suggest that bergenin possess drug like properties. Hence, the present study validates the traditional usage of F. indica as an antimalarial remedy and also insists for further chemical modifications of bergenin to obtain more effective antimalarial chemotypes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Peculiarities in cases of spina bifida cystica managed recently in south-east Nigeria: could antimalarial drugs be a major but unrecognized etiologic factor?

    Science.gov (United States)

    Emejulu, Jude-Kennedy C; Okwaraoha, Blaise Ogedi

    2011-01-01

    Spina bifida is a long-known disease arising from the incomplete fusion of the caudal neuropore in the first month of intrauterine life. It is thought to have a multifactorial etiology, the most important of which is folic acid deficiency. In evaluating its etiology, the role of antifolate agents like antimalarial drugs is rarely given a strong mention. This is a 44-month prospective study of consecutive cases of spina bifida cystica presenting to the Neurosurgery Unit of Nnamdi Azikiwe University Teaching Hospital, Nnewi, South-East Nigeria. Data collection was with a structured proforma from presentation, and collation done with Microsoft Excel broadsheet and data analysis with SPSS and χ2 test. A total of 41 cases of spina bifida were attended to within the period, with 92.7% cases of spina bifida cystica. Most presented by >12-24 months, with a consistent history of maternal ingestion of antimalarial drugs during the first trimester of pregnancy. Spina bifida cystica was diagnosed mostly in children whose mothers ingested antimalarial drugs during the first trimester of gestation. There may be a need to critically evaluate the contribution of antimalarial drugs to the etiopathogenesis of this malformation and develop safer antimalarial treatment in pregnancy. Copyright © 2012 S. Karger AG, Basel.

  10. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    Energy Technology Data Exchange (ETDEWEB)

    Ofulla, A V.O.

    1995-01-01

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro {sup 3}H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC{sub 50}s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC{sub 50} of 5.98 {+-} 2.9 SD, n=6), followed by A. mossambicensis (mean IC{sub 50} 73.36 {+-} 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 ({+-} 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs.

  11. Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

    Science.gov (United States)

    Devender, Nalmala; Gunjan, Sarika; Chhabra, Stuti; Singh, Kartikey; Pasam, Venkata Reddy; Shukla, Sanjeev K; Sharma, Abhisheak; Jaiswal, Swati; Singh, Sunil Kumar; Kumar, Yogesh; Lal, Jawahar; Trivedi, Arun Kumar; Tripathi, Renu; Tripathi, Rama Pati

    2016-02-15

    In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  12. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    International Nuclear Information System (INIS)

    Ofulla, A.V.O.

    1995-01-01

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3 H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC 50 s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC 50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC 50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

  13. Imported malaria in Finland 1995 to 2008: an overview of surveillance, travel trends, and antimalarial drug sales.

    Science.gov (United States)

    Guedes, Sandra; Siikamäki, Heli; Kantele, Anu; Lyytikäinen, Outi

    2010-01-01

    To improve pre-travel advice, we analyzed nationwide population-based surveillance data on malaria cases reported to the National Infectious Disease Register of Finland (population 5.3 million) during 1995 to 2008 and related it to data on traveling and antimalarial drug sales. Surveillance data comprised information on malaria cases reported to the National Infectious Disease Register during 1995 to 2008. Traveling data were obtained from Statistics Finland (SF) and the Association of Finnish Travel Agents (AFTA). SF data included information on overnight leisure trips to malaria-endemic countries during 2000 to 2008. AFTA data included annual number of organized trips during 1999 to 2007. Quarterly numbers of antimalarial drug sales were obtained from the Finnish Medicines Agency. Descriptive and time series analyses were performed. A total of 484 malaria cases (average annual incidence 0.7/100,000 population) were reported; 283 patients were Finnish- and 201 foreign-born. In all, 15% of all cases were children; 72% foreign- and 28% Finnish-born. Malaria infections were mostly acquired in Africa (76%). Among foreign-born cases, 89% of the infections were acquired in the region of birth. The most common species were Plasmodium falciparum (61%) and Plasmodium vivax (22%). Although traveling to malaria-endemic areas increased, no increase occurred in malaria cases, and a decreasing trend was present in antimalarial drug sales. Traveling to malaria-endemic countries and drug sales followed the same seasonal pattern, with peaks in the first and last quarter of the year. More efforts should be focused on disseminating pre-travel advice to immigrants planning to visit friends and relatives and travelers on self-organized trips. © 2010 International Society of Travel Medicine.

  14. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    Directory of Open Access Journals (Sweden)

    Hubbard Alan E

    2010-01-01

    Full Text Available Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL vs. dihydroartemisinin-piperaquine (DP performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66 and poor agreement in Apac (kappa = 0.24. Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5. However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03. Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission

  15. Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity†

    Science.gov (United States)

    Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen; Martínez, Alberto; Estrada, Jesús; Smith, Peter J.; Haukka, Matti; Sánchez-Delgado, Roberto A.; Nordlander, Ebbe

    2012-01-01

    Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID:22249579

  16. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda.

    Science.gov (United States)

    Gupta, Vinay; Dorsey, Grant; Hubbard, Alan E; Rosenthal, Philip J; Greenhouse, Bryan

    2010-01-15

    Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL) vs. dihydroartemisinin-piperaquine (DP) performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66) and poor agreement in Apac (kappa = 0.24). Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5). However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03). Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission, gel electrophoresis appears adequate to estimate comparative

  17. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure.

    Science.gov (United States)

    Mishra, Neelima; Srivastava, Bina; Bharti, Ram Suresh; Rana, Roma; Kaitholia, Kamlesh; Anvikar, Anupkumar R; Das, Manoj Kumar; Ghosh, Susanta K; Bhatt, Rajendra M; Tyagi, Prajesh K; Dev, Vas; Phookan, Sobhan; Wattal, Suman Lata; Sonal, Gagan Singh; Dhariwal, Akshay Chand; Valecha, Neena

    2016-01-01

    To combat the problem of antimalarial drug resistance, monitoring the changes in drug efficacy over time through periodic surveillance is essential. Since 2009, systematic and continuous monitoring is being done through nationwide sentinel site system. Potential early warning signs like partner drug resistance markers were also monitored in the clinical samples from the study areas. A total of 1864 patients with acute uncomplicated malaria were enrolled in therapeutic efficacy studies of artesunate plus sulphadoxine-pyrimethamine (AS+SP) for Plasmodium falciparum; those infected with P. vivax were given chloroquine (CQ). Polymerase chain reaction (PCR) was used to distinguish post-treatment reinfection from treatment failures. Isolates of P. falciparum were also analysed for dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) gene mutations. Overall, 1687 (91.7%) patients completed the follow-up. In most of the falciparum patients the parasitaemia was cleared within 24 h of treatment, except 12 patients who remained parasite positive after 72 h. Presence of dhfr and dhps quintuple mutation was observed predominantly in treatment failure samples. A daily dose of artesunate of 95% cases in all the sentinel sites except in Northeastern region (NE). Chloroquine remained 100% efficacious in case of P. vivax infections. Till 2012, India's national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region.

  18. In Vivo Antimalarial Effects of Iranian Flora Artemisia khorassanica against Plasmodium berghei and Pharmacochemistry of its Natural Components

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    M Amini

    2010-02-01

    Full Text Available "nBackground: The aim of this study was to evaluate the antimalarial effects of Iranian flora Artemisia khorassanica against Plasmodium berghei in vivo and pharmacochemistry of its natural components."nMethods: The aerial parts of Iranian flora A. khorasanica were collected at flowering stage from Khorassan Province, northeastern Iran in 2008. They were air-dried at room temperature; powder was macerated in methanol and the extract defatted in refrigerator, filtered, diluted with water, then eluted with n-hexane and finally non-polar components were identified through Gas Chromatography and Mass Spectroscopy (GC-MS. Toxicity of herbal extracts was assessed on naïve NMRI mice, and its anti-malarial efficacy was investigated on infected Plasmodium berghei animals. This is the first ap­plication on A. khorssanica extract for treatment of murine malaria. The significance of differences was determined by Analysis of Variances (ANOVA and Student's t-test using Graph Pad Prism Software."nResults: The herbal extract was successfully tested in vivo for its anti-plasmodial activity through ar­temisin composition, which is widely used as a standard malaria treatment."nConclusion: Although, this study confirmed less anti-malarial effects of A. khorssanica against mur­ine malaria in vivo, how­ever there are some evidences on reducing pathophysiology by this medica­tion. In complementary assay, major components were detected by GC-MS analysis in herbal extract including chrysanthe­none (7.8%, palmitic acid (7.4% and cis-thujone (5.8%.  The most retention indices of the compo­nent are given as n-eicosane, palmitic acid and n-octadecane.

  19. Use of Antimalarial in the Management of Fever during a Community Survey in the Kintampo Districts of Ghana.

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    Livesy Naafoe Abokyi

    Full Text Available Epidemiology of malaria and related fevers in most parts of Africa is changing due to scale up of interventions such as appropriate use of ACTs in the effort towards sustained control and eventual elimination of malaria. The use of ACTs in the management of malaria-associated fever was evaluated in the Kintampo districts of Ghana.Household survey was conducted between October 2009 and February, 2011. A random selection of 370 households was generated from 25,000 households existing within the Health and Demographic Surveillance Systems in Kintampo, Ghana at the time. All household members present at the time of survey in the eligible households were interviewed based on a two weeks reported fever recall and the use of antimalarial for the management of fever. A finger-prick blood sample was also obtained from each member of the household present and later examined for malaria parasites using microscopy. Descriptive analysis was performed, with univariate and multivariate analysis used to identify predictors of fever and malaria parasitemia.A total of 1436 individuals were interviewed from 370 households. Overall, fever prevalence was 23.8% (341/1436 and was 38.8% (77/198 in children < 5 years, 21.3% (264/1238 in older children plus adults. Participants who sought treatment for fever were 84% (285/341 with 47.7% (136/285 using any anti-malarial. Artemisinin-based Combination Therapy use was in 69.1% (94/136 of cases while 30.9% used mono-therapies. Malaria parasitaemia rate was 28.2% (397/1407.The study reports high community fever prevalence, frequent use of antimalarials for fever treatment and relatively high use of mono-therapies especially in children < 5 years in an area with high malaria parasite prevalence in Ghana.

  20. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

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    Renata Rachide Nunes

    Full Text Available The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001 against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol. The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2 and a human cell line (WI-26VA4. Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM and inactive against WI-26VA4 (IC50 > 200 µM. Further ligand optimisation cycles generated new prospects for docking and biological assays.

  1. Selection of Parasites with Diminished Drug Sensitivity by Amodiaquine-Containing Antimalarial Regimens in Uganda

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    Nawaz, Fatima; Nsobya, Samuel L.; Kiggundu, Moses; Joloba, Moses; Rosenthal, Philip J.

    2009-01-01

    Background Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. Methods We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized to treatment with AQ/SP, AS/AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro sensitivity to monodesethylamodiaquine (MDAQ) was measured with a histidine rich protein-2-based ELISA, and potential resistance-mediating polymorphisms pfmdr-1were evaluated. Results Parasites from subjects previously treated with AQ/SP or AS/AQ within 12 weeks were less sensitive to MDAQ (n=18; mean IC50 62.9 nM; range 12.7–158.3 nM) than parasites from those not treated within 12 weeks (n=43; mean IC50 37.5 nM; range 6.3–184.7 nM; p=0.0085) or only those in the treatment arm that did not contain AQ (n=20; mean IC50 28.8 nM; range 6.3–121.8 nM; p=0.0042). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr-1 86Y and 1246Y) increased after prior AQ therapy, although differences were not significant. Conclusions Prior therapy selected for diminished response to MDAQ, suggesting that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr-1. PMID:19905933

  2. New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: synthesis, and in vitro antimalarial activity.

    Science.gov (United States)

    Guillon, Jean; Moreau, Stéphane; Mouray, Elisabeth; Sinou, Véronique; Forfar, Isabelle; Fabre, Solene Belisle; Desplat, Vanessa; Millet, Pascal; Parzy, Daniel; Jarry, Christian; Grellier, Philippe

    2008-10-15

    Following our search for antimalarial compounds, novel series of ferrocenic pyrrolo[1,2-a]quinoxaline derivatives 1-2 were synthesized from various substituted nitroanilines and tested for in vitro activity upon the erythrocytic development of Plasmodiumfalciparum strains with different chloroquine-resistance status. The pyrrolo[1,2-a]quinoxalines 1 were prepared in 6-8 steps through a regioselective palladium-catalyzed monoamination by coupling 4-chloropyrrolo[1,2-a]quinoxalines with 1,3-bis(aminopropyl)piperazine or -methylamine using Xantphos as the ligand. The ferrocenic bispyrrolo[1,2-a]quinoxalines 2 were prepared by reductive amination of previously described bispyrrolo[1,2-a]quinoxalines 9 with ferrocene-carboxaldehyde, by treatment with NaHB(OAc)(3). The best results were observed with ferrocenic pyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus and no substitution on the terminal N-ferrocenylmethylamine function enhanced the pharmacological activity. Selected compounds 1b, 1f-h, 1l and 2a were tested for their ability to inhibit beta-haematin formation, the synthetic equivalent of hemozoin, by using the HPIA (heme polymerization inhibitory activity) assay. Of the tested compounds, only 2a showed a beta-haematin formation inhibition, but no inhibition of haem polymerization was observed with the other selected ferrocenic monopyrrolo[1,2-a]quinoxaline derivatives 1b, 1f-h and 1l, as the IC(50) values were superior to 10 equivalents.

  3. A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.

    Science.gov (United States)

    Okour, Malek; Derimanov, Geo; Barnett, Rodger; Fernandez, Esther; Ferrer, Santiago; Gresham, Stephanie; Hossain, Mohammad; Gamo, Francisco-Javier; Koh, Gavin; Pereira, Adrian; Rolfe, Katie; Wong, Deborah; Young, Graeme; Rami, Harshad; Haselden, John

    2018-03-01

    GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 μg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607. A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans. The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure. The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound. © 2017 The British Pharmacological Society.

  4. Disturbance in hemoglobin metabolism and in vivo antimalarial activity of azole antimycotics

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    Juan Ricardo Rodrigues

    2011-02-01

    Full Text Available Plasmodium parasites degrade host hemoglobin to obtain free amino acids, essential for protein synthesis. During this event, free toxic heme moieties crystallize spontaneously to produce a non-toxic pigment called hemozoin or ß-hematin. In this context, a group of azole antimycotics, clotrimazole (CTZ, ketoconazole (KTZ and fluconazole (FCZ, were investigated for their abilities to inhibit ß-hematin synthesis (IßHS and hemoglobin proteolysis (IHbP in vitro. The ß-hematin synthesis was recorded by spectrophotometry at 405 nm and the hemoglobin proteolysis was determined by SDS-PAGE 12.5%, followed by densitometric analysis. Compounds were also assayed in vivo in a malaria murine model. CTZ and KTZ exhibited the maximal effects inhibiting both biochemical events, showing inhibition of β-hematin synthesis (IC50 values of 12.4 ± 0.9 µM and 14.4 ± 1.4 µM respectively and inhibition of hemoglobin proteolysis (80.1 ± 2.0% and 55.3 ± 3.6%, respectively. There is a broad correlation to the in vivo results, especially CTZ, which reduced the parasitemia (%P of infected-mice at 4th day post-infection significantly compared to non-treated controls (12.4 ± 3.0% compared to 26.6 ± 3.7%, p = 0.014 and prolonged the survival days post-infection. The results indicated that the inhibition of the hemoglobin metabolism by the azole antimycotics could be responsible for their antimalarial effect.

  5. Antimalarials as a risk factor for elevated muscle enzymes in systemic lupus erythematosus.

    Science.gov (United States)

    Tselios, K; Gladman, D D; Su, Jiandong; Urowitz, M B

    2016-04-01

    To investigate the relationship between antimalarials (AM) and elevated muscle enzymes in systemic lupus erythematosus (SLE). 325 lupus patients with abnormal creatine phosphokinase (CPK) for at least two consecutive clinic visits were enrolled; 54 patients on statins/fibrates (n = 43) and/or active myositis (n = 14) were excluded. The control group consisted of 1453 lupus patients with no CPK elevation during follow-up. Descriptive statistics and Cox regression analyses were performed, p < 0.05 was considered significant. Cases and controls did not differ regarding age at SLE diagnosis, gender ratio, or disease duration. AM use was more frequent in cases, which had more prolonged AM use. Total frequency of elevated CPK in AM users was 216/1322 (16.3%). Chloroquine was associated with a 3.3-fold, and hydroxychloroquine with a 3.1-fold, increased risk for CPK elevation. Black race was associated with higher CPK (HR = 2.941), whereas female gender was protective (HR = 0.697). 203 patients were followed for 7.3 ± 5.6 years; 49.8% had persistent and 14.8% intermittent CPK elevation, while in 35.4% CPK was normalized. Clinical proximal muscle weakness developed in 5/203 patients. Chronic AM use is a potential risk factor for muscle enzyme elevation in SLE patients. CPK abnormalities persist in almost two thirds of the patients, but this remains mainly a biochemical finding, evolving to clinical myopathy in about 2.5%. © The Author(s) 2015.

  6. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

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    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  7. Antimalarial activity of synthetic 1,2,4-trioxanes and cyclic peroxy ketals, a quantum similarity study

    Science.gov (United States)

    Gironés, X.; Gallegos, A.; Carbó-Dorca, R.

    2001-12-01

    In this work, the antimalarial activity of two series of 20 and 7 synthetic 1,2,4-trioxanes and a set of 20 cyclic peroxy ketals are tested for correlation search by means of Molecular Quantum Similarity Measures (MQSM). QSAR models, dealing with different biological responses (IC90, IC50 and ED90) of the parasite Plasmodium Falciparum, are constructed using MQSM as molecular descriptors and are satisfactorily correlated. The statistical results of the 20 1,2,4-trioxanes are deeply analyzed to elucidate the relevant structural features in the biological activity, revealing the importance of phenyl substitutions.

  8. Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria

    OpenAIRE

    Nguetse, Christian N.; Adegnika, Ayola Akim; Agbenyega, Tsiri; Ogutu, Bernhards R.; Krishna, Sanjeev; Kremsner, Peter G.; Velavan, Thirumalaisamy P.

    2017-01-01

    BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped fo...

  9. Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

    Science.gov (United States)

    Hindley, Stephen; Ward, Stephen A; Storr, Richard C; Searle, Natalie L; Bray, Patrick G; Park, B Kevin; Davies, Jill; O'Neill, Paul M

    2002-02-28

    The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot

  10. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study

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    Swai Ndeniria

    2011-04-01

    Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic

  11. Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

    Science.gov (United States)

    Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

    2018-05-25

    Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  12. Analysis of the electrochemical reactivity of natural hemozoin and β-hemozoin in the presence of antimalarial drugs

    International Nuclear Information System (INIS)

    Esteban Reyes-Cruz, Victor; Urbano Reyes, Gustavo; Veloz Rodriguez, Maria Aurora; Imbert Palafox, Jose Luis

    2011-01-01

    We report an evaluation of the reactivity of hemozoin (HZ) and β-hemozoin (β-HZ) obtained from the Triatoma Meccus longipennis, alone and in combination with quinine and amodiaquine. Using cyclic voltammetry and carbon paste electrodes, the redox processes that these compounds undergo were analysed. The results indicated that the atom Fe presence, the substance concentration, the drugs existence and the nature of the electrolytic medium are important in the redox processes. The strongest reactivity was for β-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of β-HZ and indicates that like HZ, β-HZ could be associate with phospholipid bilayers and interfere with their physical and chemical integrity, contributing to membrane breakdown and hyper-oxidation of molecules. It was further observed that when measuring the reactivity of HZ and β-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the β-HZ, which could explain the effectiveness of amodiaquine as a better antimalarial drug. Finally, it was concluded that electrochemical evaluation may be a convenient tool in determining the efficiency of antimalarial drugs and the identification of their redox processes.

  13. De Novo Transcriptome Assembly (NGS) of Curcuma longa L. Rhizome Reveals Novel Transcripts Related to Anticancer and Antimalarial Terpenoids

    Science.gov (United States)

    Jayakumar, Vasanthan; Damodaran, Anand C.; Rao, Sudha Narayana; Katta, Mohan A. V. S. K.; Gopinathan, Sreeja; Sarma, Santosh Prasad; Senthilkumar, Vanitha; Niranjan, Vidya; Gopinath, Ashok; Mugasimangalam, Raja C.

    2013-01-01

    Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa. PMID:23468859

  14. Phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in Nigeria.

    Science.gov (United States)

    Bankole, A E; Adekunle, A A; Sowemimo, A A; Umebese, C E; Abiodun, O; Gbotosho, G O

    2016-01-01

    The use of plant to meet health-care needs has greatly increased worldwide in the recent times. The search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. Thus, we evaluated the antimalarial activity of three medicinal plants used in Nigerian folklore for the treatment of malaria infection. A modified Peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse model of chloroquine-resistant Plasmodium berghei ANKA strain. Animals were treated with 250, 500, or 800 mg/kg of aqueous extract. It was observed that of all the three plants studied, Markhamia tomentosa showed the highest chemosuppression of parasites of 73 % followed by Polyalthia longifolia (53 %) at day 4. All the doses tested were well tolerated. Percentage suppression of parasite growth on day 4 post-infection ranged from 1 to 73 % in mice infected with P. berghei and treated with extracts when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 90 %. The percentage survival of mice that received extract ranged from 0 to 60 % (increased as the dose increases to 800 mg/kg). Phytochemical analysis revealed the presence of tannins, saponins, and phenolic compounds in all the three plants tested.

  15. In vivo antimalarial activity of crude extracts and solvent fractions of leaves of Strychnos mitis in Plasmodium berghei infected mice.

    Science.gov (United States)

    Fentahun, Selamawit; Makonnen, Eyasu; Awas, Tesfaye; Giday, Mirutse

    2017-01-05

    Malaria is a major public health problem in the world which is responsible for death of millions particularly in sub-Saharan Africa. Today, the control of malaria has become gradually more complex due to the spread of drug-resistant parasites. Medicinal plants are the unquestionable source of effective antimalarials. The present study aimed to evaluate antiplasmodial activity and acute toxicity of the plant Strychnos mitis in Plasmodium berghei infected mice. Standard procedures were employed to investigate acute toxicity and 4-day suppressive effect of crude aqueous and hydro-methanolic extracts of the leaves of Strychnos mitis against P. berghei in Swiss albino mice. Water, n-hexane and chloroform fractions, obtained from crude hydro-methanolic extract, were also tested for their suppressive effect against P. berghei. All crude extracts revealed no obvious acute toxicity in mice up to the highest dose administered (2000 mg/kg). All crude and solvent fractions of the leaves of Strychnos mitis inhibited parasitaemia significantly (p antimalarial agent.

  16. Potential antimalarial activity of Methyl Jasmonate and its effect on lipid profiles in Plasmodium Berghei infected mice.

    Science.gov (United States)

    Oyinloye, Oladapo E; Kosoko, Ayokulehin M; Emikpe, Benjamin; Falade, Catherine O; Ademowo, Olusegun G

    2015-09-01

    The antimalarial activity and lipid profiles of Methyl Jasmonate (MJ) were investigated against established malaria infection in vivo using BALB/c mice. Arteether (AE) and chloroquine (CQ) were used as reference drugs while ethanol was used as the vehicle for drug delivery for MJ. Mice treated with 10 and 25 mg/kg MJ showed a remarkable reduction in percentage parasitemia by 68.3% and 78.2% on day 10(post treatment) respectively while 45.4% and 87.2% reduction in percentage parasitemia were observed in the group treated with 50 mg/kg on day 3 and 10 (post treatment) respectively. The highest mean survival time was observed in CQ followed by AE and MJ in dose-dependent manner. A progressive decrease in packed cell volume (PCV) was observed in infected untreated mice which led to the death of all the mice by day 9 (post treatment). Infected mice treated with MJ showed reduced level of HDL and LDL compared with infected untreated group. As the dose of MJ increased in infected mice cholesterol levels increased while there was reduction in triglyceride. Overall there was marked decrease in parasitemia in Plasmodium berghei infected mice treated with graded doses of MJ but appears to have reduced antimalarial activity compared with CQ and AE.

  17. The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

    Directory of Open Access Journals (Sweden)

    Krettli Antoniana U

    2001-01-01

    Full Text Available In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae. Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

  18. De Novo transcriptome assembly (NGS of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

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    Ramasamy S Annadurai

    Full Text Available Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  19. De Novo transcriptome assembly (NGS) of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

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    Annadurai, Ramasamy S; Neethiraj, Ramprasad; Jayakumar, Vasanthan; Damodaran, Anand C; Rao, Sudha Narayana; Katta, Mohan A V S K; Gopinathan, Sreeja; Sarma, Santosh Prasad; Senthilkumar, Vanitha; Niranjan, Vidya; Gopinath, Ashok; Mugasimangalam, Raja C

    2013-01-01

    Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  20. Analysis of the electrochemical reactivity of natural hemozoin and {beta}-hemozoin in the presence of antimalarial drugs

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    Esteban Reyes-Cruz, Victor, E-mail: reyescruz16@yahoo.com [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Urbano Reyes, Gustavo, E-mail: gurbano2003@yahoo.com.mx [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Veloz Rodriguez, Maria Aurora, E-mail: maveloz70@yahoo.com.mx [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Imbert Palafox, Jose Luis, E-mail: imbertox@hotmail.com [Area Academica de Medicina, Instituto de Ciencias de la Salud, Universidad Autonoma del Estado de Hidalgo (Mexico)

    2011-11-30

    We report an evaluation of the reactivity of hemozoin (HZ) and {beta}-hemozoin ({beta}-HZ) obtained from the Triatoma Meccus longipennis, alone and in combination with quinine and amodiaquine. Using cyclic voltammetry and carbon paste electrodes, the redox processes that these compounds undergo were analysed. The results indicated that the atom Fe presence, the substance concentration, the drugs existence and the nature of the electrolytic medium are important in the redox processes. The strongest reactivity was for {beta}-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of {beta}-HZ and indicates that like HZ, {beta}-HZ could be associate with phospholipid bilayers and interfere with their physical and chemical integrity, contributing to membrane breakdown and hyper-oxidation of molecules. It was further observed that when measuring the reactivity of HZ and {beta}-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the {beta}-HZ, which could explain the effectiveness of amodiaquine as a better antimalarial drug. Finally, it was concluded that electrochemical evaluation may be a convenient tool in determining the efficiency of antimalarial drugs and the identification of their redox processes.

  1. Further Validation of a Rapid Screening Semiquantitative Thin-Layer Chromatographic Method for Marketed Antimalarial Medicines for Adoption in Malawi

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    Dorcas Osei-Safo

    2018-01-01

    Full Text Available A recently developed semiquantitative thin-layer chromatographic (SQ-TLC assay has been employed in postmarketing surveillance of antimalarial medicines used in Malawi prior to HPLC assay. Both methods gave analogous results in a significant majority of the samples, with a good correlation (r = 0.9012 for the active pharmaceutical ingredients of the dosage forms assayed. Artemether-containing medicines had the highest percentage (92.67% of samples with comparable results for both assays. The lowest percentage (66.67% was observed in artesunate-containing medicines. The SQ-TLC method was validated for specificity, accuracy, precision, linearity, and stability according to the International Conference on Harmonisation guidelines, with the results falling within acceptable limits. For specificity, retention factor values of the test samples and reference standards were comparable, while accuracy and precision of 91.1 ± 5.7% were obtained for all samples. The method was linear in the range 1.0–2.0 µg/spot with a correlation coefficient of r = 0.9783. Stability tests also fell within acceptable limits. In this study, we present the validation of the SQ-TLC method and propose its adoption as a rapid screening tool for field estimation of the quality of antimalarial and other essential medicines in Malawi and other parts of the developing world prior to a more accurate HPLC assay.

  2. Anti-malarial activity of 6-(8'Z-pentadecenyl-salicylic acid from Viola websteri in mice

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    Park Won-Hwan

    2009-07-01

    Full Text Available Abstract Background Petroleum ether extracts of Viola websteri Hemsl (Violaceae were reported to have anti-plasmodial activity against Plasmodium falciparum in vitro, with this activity being largely attributable to 6-(8'Z-pentadecenyl-salicylic acid (6-SA. Methods The schizontocidal activity of 6-SA on early Plasmodium berghei infections was evaluated in a four-day test. The possible 'repository' activity of 6-SA was assessed using the method described by Peters. The median lethal dose (LD50 of 6-SA, when given intraperitoneally, was also determined using uninfected ICR mice and the method of Lorke. Results In the present study, 6-SA was found to have anti-malarial activity in vivo, when tested against P. berghei in mice. 6-SA at 5, 10 and 25 mg/kg·day exhibited a significant blood schizontocidal activity in four-day early infections, repository evaluations and established infections with a significant mean survival time comparable to that of the standard drug, chloroquine (5 mg/kg·day. Conclusion 6-SA possesses a moderate anti-malarial activity that could be exploited for malaria therapy.

  3. An ethnobotanical study of anti-malarial plants among indigenous people on the upper Negro River in the Brazilian Amazon.

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    Frausin, Gina; Hidalgo, Ari de Freitas; Lima, Renata Braga Souza; Kinupp, Valdely Ferreira; Ming, Lin Chau; Pohlit, Adrian Martin; Milliken, William

    2015-11-04

    In this article we present the plants used for the treatment of malaria and associated symptoms in Santa Isabel do Rio Negro in the Brazilian Amazon. The region has important biological and cultural diversities including more than twenty indigenous ethnic groups and a strong history in traditional medicine. The aims of this study are to survey information in the Baniwa, Baré, Desana, Piratapuia, Tariana, Tukano, Tuyuca and Yanomami ethnic communities and among caboclos (mixed-ethnicity) on (a) plant species used for the treatment of malaria and associated symptoms, (b) dosage forms and (c) distribution of these anti-malarial plants in the Amazon. Information was obtained through classical ethnobotanical and ethnopharmacological methods from interviews with 146 informants in Santa Isabel municipality on the upper Negro River, Brazil. Fifty-five mainly native neotropical plant species from 34 families were in use. The detailed uses of these plants were documented. The result was 187 records (64.5%) of plants for the specific treatment of malaria, 51 records (17.6%) of plants used in the treatment of liver problems and 29 records (10.0%) of plants used in the control of fevers associated with malaria. Other uses described were blood fortification ('dar sangue'), headache and prophylaxis. Most of the therapeutic preparations were decoctions and infusions based on stem bark, root bark and leaves. These were administered by mouth. In some cases, remedies were prepared with up to three different plant species. Also, plants were used together with other ingredients such as insects, mammals, gunpowder and milk. This is the first study on the anti-malarial plants from this region of the Amazon. Aspidosperma spp. and Ampelozizyphus amazonicus Ducke were the most cited species in the communities surveyed. These species have experimental proof supporting their anti-malarial efficacy. The dosage of the therapeutic preparations depends on the kind of plant, quantity of plant

  4. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

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    Ronn Anita

    2011-08-01

    Full Text Available Abstract Background In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1 therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma. Methods A monoclonal antibody (MAb that reacts with the N-side chain of the CQ molecule was prepared by use of a CQ analogue. A specific and reliable ELISA for detection of CQ was developed. The developed assay was validated by measuring CQ in tablets sold in Denmark, India and Sudan. Furthermore, kinetics of CQ concentrations in plasma of four volunteers, who ingested two tablets of Malarex® containing, 250 mg CQ base, were measured before drug intake, three hours later and thereafter at days 1, 3, 7, 14, 21 and 28. The same plasma samples were simultaneously measured by high performance liquid chromatography (HPLC. Results The ELISA proved an easy-to-handle and very sensitive tool for the detection of CQ with a lower limit of detection at 3.9 ng/ml. ELISA levels of CQ in plasma showed high agreement with the levels obtained by HPLC (r = 0.98. The specificity in the negative control group was 100%. Conclusion The developed ELISA can be used for quality screening of CQ in pharmaceutical formulations and for drug monitoring in malaria and in other infectious diseases, such as HIV, where CQ proved to be an effective therapeutic agent. The methodology has been exploited to develop monoclonal

  5. Antimalarial drug susceptibility testing of Plasmodium falciparum in Brazil using a radioisotope method

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    Cerutti Junior Crispim

    1999-01-01

    Full Text Available From March 1996 to August 1997, a study was carried out in a malaria endemic area of the Brazilian Amazon region. In vivo sensitivity evaluation to antimalarial drugs was performed in 129 patients. Blood samples (0.5 ml were drawn from each patient and cryopreserved to proceed to in vitro studies. In vitro sensitivity evaluation performed using a radioisotope method was carried out with the cryopreserved samples from September to December 1997. Thirty-one samples were tested for chloroquine, mefloquine, halofantrine, quinine, arteether and atovaquone. Resistance was evidenced in 96.6% (29/30 of the samples tested for chloroquine, 3.3% (1/30 for quinine, none (0/30 for mefloquine and none for halofantrine (0/30. Overall low sensitivity was evidenced in 10% of the samples tested for quinine, 22.5% tested for halofantrine and in 20% tested for mefloquine. Means of IC 50 values were 132.2 (SD: 46.5 ng/ml for chloroquine, 130.6 (SD: 49.6 ng/ml for quinine, 3.4 (SD: 1.3 ng/ml for mefloquine, 0.7 (SD: 0.3 ng/ml for halofantrine, 1 (SD: 0.6 ng/ml for arteether and 0.4 (SD: 0.2 ng/ml for atovaquone. Means of chloroquine IC 50 of the tested samples were comparable to that of the chloroquine-resistant strain W2 (137.57 ng/ml and nearly nine times higher than that of the chloroquine-sensitive strain D6 (15.09 ng/ml. Means of quinine IC 50 of the tested samples were 1.7 times higher than that of the low sensitivity strain W2 (74.84 ng/ml and nearly five times higher than that of the quinine-sensitive strain D6 (27.53 ng/ml. These results disclose in vitro high resistance levels to chloroquine, low sensitivity to quinine and evidence of decreasing sensitivity to mefloquine and halofantrine in the area under evaluation.

  6. Alternatives to currently used antimalarial drugs: in search of a magic bullet.

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    Bhagavathula, Akshaya Srikanth; Elnour, Asim Ahmed; Shehab, Abdulla

    2016-11-04

    Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners' collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic

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