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Sample records for antimalarial quinoline methanols

  1. Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution.

    Science.gov (United States)

    Gildenhuys, Johandie; Sammy, Chandre J; Müller, Ronel; Streltsov, Victor A; le Roex, Tanya; Kuter, David; de Villiers, Katherine A

    2015-10-14

    The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(iii)PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(iii)PPIX in acetonitrile. The length of the iron(iii)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(iii)PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(iii)PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(iii)PPIX-drug complex. We propose that formation of the drug-Fe(iii)PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.

  2. Design and Synthesis of Some New Quinoline Based 1,2,3-Triazoles as Antimicrobial and Antimalarial Agents

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    Parthasaradhi Y.

    2015-09-01

    Full Text Available A series of novel 6-bromo-2-chloro-3-(4-phenyl-[1,2,3]triazol-1-ylmethyl-quinoline and its derivatives (5a-j were synthesized in good yields from the intermediates (6-bromo-2-chloro-quinolin-3-yl-methanol (2, methanesulfonic acid (6-bromo-2-chloroquinolin-3-ylmethyl methanesulfonate (3 and 3-azidomethyl-6-bromo-2-chloro-quinoline (4. The synthetic route leading to the title compounds is commenced from commercially available 6-bromo-2-chloro-quinolin-3-carbaldehyde (1. The chemical structures of the newly synthesized compounds were elucidated by their IR, 1H and 13C NMR, mass spectral data and elemental analysis. Further, all the target compounds were screened for their antimicrobial activity against various microorganisms and antimalarial activity towards P. falciparum. DOI: http://dx.doi.org/10.17807/orbital.v7i3.692 

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

    OpenAIRE

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

    2010-01-01

    International audience; 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 eff...

  4. 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.

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

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    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.

  6. Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols

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    Melendez Victor

    2010-02-01

    Full Text Available Abstract Background The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier. Methods A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed. Results The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs. The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability. Conclusions A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified.

  7. Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice

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    Shackleford David M

    2011-06-01

    Full Text Available Abstract Background The clinical use of mefloquine (MQ has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs that do not accumulate in the central nervous system (CNS to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization. Experimental design The plasma and brain levels of MQ and twenty five, 4-position modified NGQMs were determined using LCMS/MS at 5 min, 1, 6 and 24 h after IV administration (5 mg/kg to male FVB mice. Fraction unbound in brain tissue homogenate was assessed in vitro using equilibrium dialysis and this was then used to calculate brain-unbound concentration from the measured brain total concentration. A five-fold reduction CNS levels relative to mefloquine was considered acceptable. Additional pharmacological properties such as permeability and potency were determined. Results The maximum brain (whole/free concentrations of MQ were 1807/4.9 ng/g. Maximum whole brain concentrations of NGQMs were 23 - 21546 ng/g. Maximum free brain concentrations were 0.5 to 267 ng/g. Seven (28% and two (8% compounds exhibited acceptable whole and free brain concentrations, respectively. Optimization of maximum free brain levels, IC90s (as a measure or potency and residual plasma concentrations at 24 h (as a surrogate for half-life in the same molecule may be feasible since they were not correlated. Diamine quinoline methanols were the most promising lead compounds. Conclusion Reduction of CNS levels of NGQMs relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols.

  8. Enantiopure inherently chiral calix[4]arene derivatives containing quinolin-2-yl-methanol moiety:Synthesis and application in the catalytic asymmetric addition of diethylzinc to benzaldehyde

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    A series of novel N,O-type chiral ligands derived from enantiopure inherently chiral calix[4]arenes containing quinolin-2-yl-methanol moiety in the cone or partialcone conformation have been synthe-sized and characterized. Moreover,they have been applied to the catalytic asymmetric addition of diethylzinc to benzaldehyde,which represents the first example that the inherently chiral calixarene can be used as the chiral ligands for the catalytic asymmetric synthesis.

  9. Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Svenson, M; Theander, T G;

    1987-01-01

    Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...... mononuclear cells of the various antimalarial drugs and the potential adverse effects of antimalarial chemotherapy are discussed.......Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...... levels suppressed the lymphocytes' proliferation, but not their IL-2 production. All three quinolines suppressed the proliferation of lymphocytes, but not equally, with mefloquine having the strongest effect. Quinine suppressed the growth at therapeutic concentrations. The IL-2 production was suppressed...

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

    Science.gov (United States)

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

    2015-06-01

    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.

  11. Recent progress in the development of anti-malarial quinolones.

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    Beteck, Richard M; Smit, Frans J; Haynes, Richard K; N'Da, David D

    2014-08-30

    Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.

  12. Quinolinemethanol Antimalarials.

    Science.gov (United States)

    1974-12-01

    COC1121Br 106-163 5 CjirO ad 6-Me Ph1F COCI1213r 13-4-136 72 CInl133rFNO 5e 7-CF, H COCH ,Br 203-205 deck 63 C,,l1,lrF3NO*HBrl 7& 7-CFs H CH-CH, 60-621 72 C...and II, starting from the corresponding quinoline-l- R R\\ H carboxylic acids (IV), is outlined in Scheme I and re- LICocII, cocH , duces the number of

  13. Wet oxidation of quinoline

    DEFF Research Database (Denmark)

    Thomsen, A.B.; Kilen, H.H.

    1998-01-01

    The influence of oxygen pressure (0.4 and 2 MPa). reaction time (30 and 60 min) and temperature (260 and 280 degrees C) on the wet oxidation of quinoline has been studied. The dominant parameters for the decomposition of quinoline were oxygen pressure and reaction temperature. whereas the reaction...... time was less important within the range studied. Nitrifying bacteria were used to measure the inhibition from wet oxidative-treated samples to study the effect of the (wet oxidation) reaction conditions. Wet oxidation made quinoline more toxic to Nitrosomonas. This was observed for Nitrobacter as well....... The combined wet oxidation and biological treatment of reaction products resulted in 91% oxidation of the parent compound to CO2 and water. Following combined wet oxidation and biological treatment the sample showed low toxicity towards Nitrosomonas and no toxicity towards Nitrobacter. (C) 1998 Elsevier...

  14. Synthesis of 4-hydroxy-2(1H)-quinolone derived chalcones, pyrazolines and their antimicrobial, in silico antimalarial evaluations.

    Science.gov (United States)

    Sarveswari, S; Vijayakumar, V; Siva, R; Priya, R

    2015-01-01

    A few derivatives of 3-(4,5-dihydro-5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-hydroxyquinolin-2(1H)-ones (5a-j) that are synthesized from 4-hydroxy-3-(3-arylacryloyl)quinolin-2(1H)-ones (4a-j) by microwave-assisted synthesis are screened for their antimicrobial, in silico antimalarial activities. Among the tested compounds 4h and 5d were found to have a potent antimalarial activity than the standards, and the others are found to show considerable antimalarial activity and moderate antimicrobial activity.

  15. Novel Synthesis of Quinoline-7,8-diol Derivative

    Institute of Scientific and Technical Information of China (English)

    HE,Juan; WANG,Xue-Bin; WAN,Zheng-Kai

    2004-01-01

    @@ Quinoline 7,8-diol derivatives can be expected to form metal complexes, and are the moiety of marine alkaloid,which exhibits strong cytotoxic activity against several human tumor. Our synthesis of 6 commences from L-dopa (1)(Scheme 1). Esterification of 2 with methanol and treatment of the resulting ester 3 with trichloroethoxycarbonyl (Troc)chloride yielded the N-protected amino acid ester 4. Treatment of 4 with acrolein in 1.3 mol/L methanolic HCl for 4 d at room temperature yielded the quinoline derivative 5, which was dissolved in 25% aq. HBr and the resulting solution was heated at reflux for 6 h to afford compound 6.

  16. 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.

  17. Hydrodenitrogenation of quinoline and acridine

    Energy Technology Data Exchange (ETDEWEB)

    Reiff, Jr., E. K.

    1977-06-01

    The hydrodenitrogenation of quinoline and of acridine was studied in a batch autoclave reactor between 342 and 353/sup 0/C and between 500 and 2000 psig. The several commercial hydrotreating catalysts examined decreased in activity in the following order for quinoline hydrodenitrogenation: Ni--Mo/Al/sub 2/O/sub 3/, Ni--W/Al/sub 2/O/sub 3/, Ni--W/SiO/sub 2/--Al/sub 2/O/sub 3/, and Co--Mo/Al/sub 2/O/sub 3/. The total nitrogen removal rate for quinoline was slightly greater than that for acridine and both followed pseudo first-order kinetics over a conversion range of 0 to 50%. Hydrogenation and cracking steps were both kinetically limiting. Nitrogen-containing reaction products for quinoline hydrodenitrogenation were 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, decahydroquinoline and o-propylaniline. At 342/sup 0/C and 500 psig quinoline and 1,2,3,4-tetrahydroquinoline were in thermodynamic equilibrium, and the disappearance of the lumped group of quinoline plus 1,2,3,4-tetrahydroquinoline followed pseudo first-order kinetics. Sixteen nitrogen-containing reaction products were found for acridine hydrodenitrogenation, including 1,2,3,4-tetrahydroacridine, 1,2,3,4,9,10,13,14-octahydroacridine, sym-octahydroacridine, perhydroacridine, and o-(methylenecyclohexane)aniline. The hydrogenolysis step for both quinoline and acridine appears to be through hydrogenated forms of these compounds. This is supported by bond strength arguments.

  18. Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines.

    Science.gov (United States)

    Saunthwal, Rakesh K; Patel, Monika; Verma, Akhilesh K

    2016-05-06

    A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)methanol, and 1,4-bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies.

  19. Antimalarial activity of cedronin.

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    Moretti, C; Deharo, E; Sauvain, M; Jardel, C; David, P T; Gasquet, M

    1994-06-01

    Cedronin was isolated from Simaba cedron Planchon (Simaroubaceae), a species popularly believed in South America to have antimalarial properties. It was examined for in vitro and in vivo antimalarial activities and for cytotoxicity against KB cells. Experimental results showed that cedronin was active against chloroquine-sensitive and resistant strain, with an IC50 of 0.25 micrograms/ml (0.65 mumol/ml). It was also found to be active in vivo against Plasmodium vinkei with an IC50 of 1.8 mg/kg (4.7 nM/kg) in the classic 4-day test. Cedronin belongs to the small group of quassinoids with a C19 basic skeleton and shows a rather low cytotoxicity against KB cells (IC50 = 4 micrograms/ml, 10.4 microM) as compared with C20 biologically active quassinoids; however its toxic/therapeutic ratio (10/1.8) remains lower than chloroquine (10/0.5).

  20. Glycoconjugates of Quinolines: Application in Medicinal Chemistry.

    Science.gov (United States)

    Oliveri, Valentina; Vecchio, Graziella

    2016-09-02

    Compounds with the quinoline scaffold are widely investigated and offer a variety of therapeutical properties. A number of quinoline derivatives have been synthesized and among these there are glycoconjugated derivatives. Based on the interest for this family of compounds, we reviewed the different biological activities (molecular probes, antiinfective, antiproliferative, antiaggregant and antioxidant) and the potential applications in medicinal chemistry of quinoline glycoconjugates. This review wants to show an example of the glycoconjugation strategy which arose not only to modify the water solubility of the quinolines but also to influence their activity and targeting properties.

  1. World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs

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    Olliaro Piero

    2007-09-01

    Full Text Available Abstract The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

  2. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

    Science.gov (United States)

    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.

  3. Microbial transformation of antimalarial terpenoids.

    Science.gov (United States)

    Parshikov, Igor A; Netrusov, Alexander I; Sutherland, John B

    2012-01-01

    The fungal and bacterial transformation of terpenoids derived from plant essential oils, especially the sesquiterpenoid artemisinin from Artemisia annua, has produced several new candidate drugs for the treatment of malaria. Obtaining new derivatives of terpenoids, including artemisinin derivatives with increased antimalarial activity, is an important goal of research in microbial biotechnology and medicinal chemistry.

  4. Antimalarial activity of extracts and alkaloids isolated from six plants used in traditional medicine in Mali and Sao Tome.

    Science.gov (United States)

    Ancolio, C; Azas, N; Mahiou, V; Ollivier, E; Di Giorgio, C; Keita, A; Timon-David, P; Balansard, G

    2002-11-01

    Methanol and chloroform extracts were prepared from various parts of four plants collected in Mali: Guiera senegalensis (Gmel.) Combretaceae, Feretia apodanthera (Del.) Rubiaceae, Combretum micranthum (Don.) Combretaceae, Securidaca longepedunculata (Fres.) Polygalaceae and two plants -collected in Sao Tome: Pycnanthus angolensis (Welw.) Myristicaceae and Morinda citrifolia (Benth.) Rubiaceae were assessed for their in vitro antimalarial activity and their cytotoxic effects on human monocytes (THP1 cells) by flow cytometry. The methanol extract of leaves of Feretia apodanthera and the chloroform extract of roots of Guiera senegalensis exhibited a pronounced antimalarial activity. Two alkaloids isolated from the active extract of Guiera senegalensis, harman and tetrahydroharman, showed antimalarial activity (IC(50) lower than 4 microg/mL) and displayed low toxicity against THP1. Moreover, the decrease of THP1 cells in S phase of the cell cycle, after treatment with harman and tetrahydroharman, was probably due to an inhibition of total protein synthesis.

  5. Difluoro[2-(quinolin-2-ylphenolato]borane

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    Xi Yang

    2011-05-01

    Full Text Available The title compound, C15H10BF2NO, was synthesized by the reaction of 2-(quinolin-2-ylphenol and boron trifluoride etherate. The quinoline ring system and the benzene ring are twisted, making a dihedral angle of 8.3 (2°. In the crystal, π–π interactions between the aromatic rings [centroid–centroid distance = 3.638 (9 Å] link the molecules into chains propagating in [100].

  6. Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.

    Science.gov (United States)

    Sullivan, David J; Liu, Yi; Mott, Bryan T; Kaludov, Nikola; Martinov, Martin N

    2015-01-01

    Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.

  7. Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.

    Directory of Open Access Journals (Sweden)

    David J Sullivan

    Full Text Available Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.

  8. Cannizzaro reaction of 2-chloro-3-formylquinolines and its synthetic utility for 2-acetylfuro[2,3-]quinolines: The alkaloid analogues

    Indian Academy of Sciences (India)

    Devadoss Karthik Kumar; Rajakandhan Shankar; Subramaniam Parameswaran Rajendran

    2012-09-01

    Cannizzaro reaction of 2-chloro-3-formylquinolines was investigated under two different conditions. Under both conditions, redox and methoxylation proceeded simultaneously and gave 2-methoxy- 3-formylquinolines, 2-methoxyquinolin-3-yl-methanols and 2-methoxyquinoline-3-carboxylic acids. The synthesized 2-methoxy-3-formylquinolines were then condensed with acetone in the presence of sulphuric acid to give 4-(2-methoxy-quinolin-3-yl)-but-3-en-2-ones which in turn were bromocyclized and dehydrobrominated to get 2-acetylfuro[2,3-]quinolines.

  9. Antimalarial natural products: a review

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    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.

  10. Benzylchloridobis(quinolin-8-olatotin(IV

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    Qibao Wang

    2009-08-01

    Full Text Available In the title compound, [Sn(C7H7(C9H6NO2Cl], the SnIV ion is in a distorted octahedral coordination environment formed by the O and N atoms of two bis-chelating quinolin-8-olate ligands, a Cl atom and a C atom from a benzyl ligand. The axial sites are occupied by an N atom of a quinolinate ligand and the C atom of the benzyl ligand. The axial Sn—N bond is slightly shorter than the equatorial Sn—N bond.

  11. 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.

  12. Syntheses and antimalarial activities of N-substituted 11-azaartemisinins.

    Science.gov (United States)

    Torok, D S; Ziffer, H; Meshnick, S R; Pan, X Q; Ager, A

    1995-12-22

    A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

  13. N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity.

    Science.gov (United States)

    Figueiras, Marta; Coelho, Lis; Wicht, Kathryn J; Santos, Sofia A; Lavrado, João; Gut, Jiri; Rosenthal, Philip J; Nogueira, Fátima; Egan, Timothy J; Moreira, Rui; Paulo, Alexandra

    2015-04-01

    We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

  14. Separation and preconcentration of U(VI) on XAD-4 modified with 8-hydroxy quinoline.

    Science.gov (United States)

    Singh, B N; Maiti, B

    2006-04-15

    Amberlite XAD-4 adsorber resin was modified with 8-hydroxy quinoline (Oxine) by equilibrating with methanol solution of the reagent and the modified resin was used as a support material for the solid phase extraction and preconcentration of UO(2)(2+) from aqueous solution at pH between 4 and 5.5. Ten micrograms of uranium from 300 ml of aqueous phase could be quantitatively extracted in to 1g of the modified resin giving an enrichment of 200. Uranium collected in the column could be eluted out with methanol-HCl mixture and determined spectrophotometrically using arsenazo(III) as the chromogenic reagent. The preconcentration could be made selective to uranium by using EDTA as a masking agent for transition metal ions and Th(IV).

  15. 15-(4-Chlorophenyl-6b-hydroxy-17-methyl-6b,7,16,17-tetrahydro-7,14a-methanonaphtho[1′,8′:1,2,3]pyrrolo[3′,2′:8,8a]azuleno[5,6-b]quinolin-14(15H-one methanol hemisolvate

    Directory of Open Access Journals (Sweden)

    J. M. Joseph

    2016-04-01

    Full Text Available In the title solvate, C35H25ClN2O3·0.5CH3OH, the conformation of the central 1-methylpyrrolidine ring is best described as an envelope with the N atom as the flap. The cyclopentane ring adopts a twist conformation on the CH—CH2 bond and the cyclohexane ring has an envelope conformation with the CH2 atom as the flap. The pyrrolidine ring makes dihedral angles of 40.87 (12, 67.89 (11, 81.86 (9 and 70.86 (12° with the mean planes of the cyclopentane, cyclohexane, acenaphthylene and chlorobenzene rings, respectively. The quinoline ring system is inclined to the naphthalene ring system by 54.14 (6°. There is a short O—H...N contact in the molecule making an S(5 ring motif. In the crystal, there is a disordered and partially occupied ethan-1,2-diol solvent molecule present, located about an inversion centre, which links the title molecules via O—H...O and C—H...O hydrogen bonds, forming chains propagating along the a-axis direction.

  16. New quinoline alkaloid from Ruta graveolens aerial parts and evaluation of the antifertility activity.

    Science.gov (United States)

    Salib, Josline Y; El-Toumy, Sayed A; Hassan, Emad M; Shafik, Nabila H; Abdel-Latif, Sally M; Brouard, Ignacio

    2014-01-01

    Bioassay-guided isolation of methanol extract of Ruta graveolens L. leaves yielded a new quinoline alkaloid, (4S) 1,4-dihydro-4-methoxy-1,4-dimethyl-3-(3-methylbut-2-enyl)quinoline 2,7-diol, and nine phenolic compounds including rutin as a major compound. Structures of the isolated compounds were determined by using chromatography, UV, HR-ESI-MS and 1D/2D (1)H/(13)C NMR spectroscopy. The uterotonic activity of methanol extract fractions (ethyl acetate, n-butanol and aqueous fraction) as well as the isolated major compounds was tested in the isolated mouse uterus in vitro. The n-butanol-soluble fraction was found to demonstrate the most potent uterotonic activity in a dose-dependent manner, also the major isolated compound rutin revealed the occurrence of an uterotonic response, which was maximum at a concentration level of 0.25 mg/mL, accounting for 68.7% of that exhibited by the chosen concentration of oxytocin.

  17. trans-Dichloridobis(quinoline-κNplatinum(II

    Directory of Open Access Journals (Sweden)

    Kwang Ha

    2012-05-01

    Full Text Available In the title complex, trans-[PtCl2(C9H7N2], the PtII ion is four-coordinated in an essentially square-planar coordination environment defined by two N atoms from two quinoline (qu ligands and two Cl− anions. The Pt atom is located on an inversion centre and thus the asymmetric unit contains one half of the complex; the PtN2Cl2 unit is exactly planar. The dihedral angle between the PtN2Cl2 unit and the quinoline ligand is 85.1 (1°. In the crystal, the complex molecules are stacked into columns along the b axis. In the columns, several intermolecular π–π interactions between the six-membered rings are present, the shortest ring centroid–centroid distance being 3.733 (5 Å between pyridine rings.

  18. Method for making methanol

    Science.gov (United States)

    Mednick, R. Lawrence; Blum, David B.

    1986-01-01

    Methanol is made in a liquid-phase methanol reactor by entraining a methanol-forming catalyst in an inert liquid and contacting said entrained catalyst with a synthesis gas comprising hydrogen and carbon monoxide.

  19. Hydrotalcite-quinolinate composites as catalysts in a coupling reaction.

    Science.gov (United States)

    Ríos, Eloisa; Hernández, Magali; Ibarra, Ilich A; Guzmán, Ariel; Lima, Enrique

    2016-01-01

    Samples of layered double hydroxides were prepared by a sol-gel procedure. Quinolinate Al(C9H6NO)3 units were added during the synthesis, leading to composite quinolinate hydrotalcite-like compounds. The amount of quinolinate was varied, showing that the number of organic building blocks determines the physicochemical properties of materials, which differ significantly from those commonly reported for hydrotalcites without any quinolinate. The order of layers, specific surface area and coordination of aluminium were the parameters most significantly influenced by the presence of the quinolinate as a part of the brucite-like layers. The composite quinolinate-hydrotalcite materials were tested to catalyse the Kabachnik-Fields reaction.Graphical abstractAdding of quinolinate Al(C9H6NO)3 to hydrotalcite-like compounds creates disorder in the stack of brucite-like layers, leading to a significant modification of structural, textural and catalytic properties. The presence of quinolinate inhibits the enchainment of octahedral blocks in hydrotalcite but develop specific surface areas as high as 600 m(2)g(-1).

  20. Transformation of indole and quinoline by Desulfobacterium indolicum (DSM 3383)

    DEFF Research Database (Denmark)

    Licht, D.; Johansen, S.S.; Arvin, E.

    1996-01-01

    Degradation of indole and quinoline by Desulfobacterium indolicum was studied in batch cultures. The first step in the degradation pathway of indole and quinoline was a hydroxylation at the 2 position to oxindole and 2-hydroxyquinoline respectively. These hydroxylation reactions followed saturati...

  1. Optimization of propafenone analogues as antimalarial leads.

    Science.gov (United States)

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

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  2. The quality of antimalarials available in Yemen

    Directory of Open Access Journals (Sweden)

    Atta Hoda

    2005-06-01

    Full Text Available Abstract Background Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Methods Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only in comparison to standard specifications for these products in the relevant pharmacopoeia. Results The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. Conclusion There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This

  3. The sensitivity and selectivity properties of a fluorescence sensor based on quinoline-Bodipy

    Energy Technology Data Exchange (ETDEWEB)

    Nuri Kursunlu, Ahmed, E-mail: ankursunlu@gmail.com; Guler, Ersin

    2014-01-15

    A novel florescence sensor (Q-BODIPY) based on quinoline-Bodipy (quinoline-boradiazaindacene) was prepared by ‘click chemistry’ in several stages. The sensing actions of Q-BODIPY were confirmed by UV–vis titration, emission and excitation spectroscopic studies in presence of Mn{sup 2+}, Co{sup 2+}, Ni{sup 2+}, Cu{sup 2+}, Zn{sup 2+}, Cd{sup 2+}, Sn{sup 2+}, Hg{sup 2+}, Pb{sup 2+}, La{sup 3+}, Ga{sup 3+}, Er{sup 3+} and Yb{sup 3+} ions in methanol:H{sub 2}O (1:1) medium. Whereas some metal ions can only cause quenching effect on the fluorescence intensity of Q-BODIPY, some of them show an increase in fluorescence intensity. The stoichiometry of host–guest complexes formed was determined by Job′s plot method. The binding constants were calculated by Stern–Volmer method. As a fluorescence sensor, Q-BODIPY shows the best selectivity performance against Zn{sup 2+} ions in according to all spectroscopic data. -- Highlights: • Q-BODIPY prepared by several techniques shows a fluorescent behavior toward p, d and f block metal ions. • Q-BODIPY has both a more sensitivity and more effective ability for the detection of Zn(II) ion. • The synthesis strategies to produce Bodipy′s with metal coordinating offer a new approach for the design of novel fluorescence sensors.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. New pyrone and quinoline alkaloid from Almeidea rubra and their trypanocidal activity

    Energy Technology Data Exchange (ETDEWEB)

    Ambrozin, Alessandra R.P.; Mafezoli, Jair; Vieira, Paulo C.; Fernandes, Joao B.; Silva, M. Fatima das G.F. da [Sao Carlos Univ., SP (Brazil). Dept. de Quimica]. E-mail: paulo@dq.ufscar.br; Ellena, Javier A. [Sao Paulo Univ., Sao Carlos, SP (Brazil). Inst. de Fisica; Albuquerque, Sergio de [Sao Paulo Univ., Ribeirao Preto, SP (Brazil). Faculdade de Ciencias Farmaceuticas. Dept. de Analises Clinicas, Toxicologicas, Bromatologicas

    2005-05-15

    The investigation of the ethyl acetate fraction of methanol extract from leaves of Almeidea rubra A. St.-Hil. (Rutaceae) afforded two new compounds 4-methoxy-6-[2-(methylamino)phenyl]-2Hpyran- 2-one and rel-(7R,8R)-8-[(E)-3-hydroxy-3-methyl-1-butenyl]-4,8-dimethoxy-5,6,7,8- tetrahydrofuro[2,3-b]quinoline-7-yl acetate, along with the known compounds arborinine, N-methyl- 1-hydroxy-3-methoxyacridone, skimmianine, kokusagine, isodutaduprine, isoskimmianine, and isokokusagine. Their structures were established based on their spectral data, and for the new compounds these data are described herein. Additionally, these compounds were assayed on the tripomastigote forms of Trypanosoma cruzi showing moderate trypanocidal activity. (author)

  6. Expanding the Antimalarial Drug Arsenal—Now, But How?

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    Rajeev K. Mehlotra

    2011-04-01

    Full Text Available The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii repurposing drugs that are currently used to treat other infections or diseases; (iii chemically modifying existing antimalarial compounds; (iv exploring natural sources; (v large-scale screening of diverse chemical libraries; and (vi through parasite genome-based (“targeted” discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum, and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs, and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now and “long term” (5. Next generation of

  7. Thermodynamics of organic mixtures containing amines. VIII. Systems with quinoline

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez, Juan Antonio [G.E.T.E.F., Grupo Especializado en Termodinamica de Equilibrio entre Fases, Departamento de Fisica Aplicada, Facultad de Ciencias, Universidad de Valladolid, E-47071 Valladolid (Spain)], E-mail: jagl@termo.uva.es; Domanska, Urszula; Zawadzki, Maciej [Physical Chemistry Division, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw (Poland)

    2008-08-15

    (Solid + liquid) equilibrium temperatures for mixtures containing quinoline and 1-dodecanol, 1-hexadecanol, or 1-octadecanol have been measured using a dynamic method. (Quinoline + benzene, +alkane, or +1-alkanol) systems were investigated using DISQUAC. The corresponding interaction parameters are reported. The model yields a good representation of molar excess Gibbs free energies, G{sup E}, molar excess enthalpies, H{sup E}, and of the (solid + liquid) equilibria, SLE. Interactional and structural effects were analysed comparing H{sup E} and the molar excess internal energy at constant volume, U{sub V}{sup E}. It was encountered that structural effects are very important in systems involving alkanes or 1-alkanols. Interactions between amine molecules are stronger in mixtures with quinoline than in those containing pyridine, which was ascribed to the higher polarizability of quinoline.

  8. 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.

  9. Xanthone as Antimalarial: QSAR Analysis, Synthesis, Molecular Docking and In-vitro Antimalarial Evaluation

    Directory of Open Access Journals (Sweden)

    Jufrizal Syahri

    2017-02-01

    Full Text Available The rational design of eighteen new antimalarial compounds from xanthone derivatives has been conducted based on Quantitative Structure-Activity Relationship(QSAR calculation using semi-empirical AM1 methods. The best equation model obtained from QSAR calculation was Log pIC50 = 2.997 - 29.256 (qO8 - 138.234 (qC9 - 6.882 (qC12 - 107.836 (qC14 + 48.764 (qO15. Among the designed compounds, 3,6-dihydroxy-9H-xanthen-9-one (26 and 3,4,6-trihydroxy-9H-xanthen-9-one (27 have been synthesized and investigated their in-vitro antimalarial activities against the chloroquine-sensitive 3D7 strain. An in-vitro antimalarial activity of compound 26 and 27 showed to be highly potential as antimalarial compounds with IC50 of 0.71 and 0.11 µM respectively. Molecular docking studies of compound 26 and 27 showed the formation of a binding interaction between the compounds with the amino acids Ala16, Ser108, Phe58, Asp54 and Leu46, which is the crucial amino acids for antimalarial activity based on the protein-ligand co-crystal structure of WR99210(1,3,5-triazine, a pre-clinical molecule as P. falciparum DHFR-TS inhibitor.

  10. World Antimalarial Resistance Network (WARN II: In vitro antimalarial drug susceptibility

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2007-09-01

    Full Text Available Abstract Intrinsic resistance of Plasmodium falciparum is clearly a major determinant of the clinical failure of antimalarial drugs. However, complex interactions between the host, the parasite and the drug obscure the ability to define parasite drug resistance in vivo. The in vitro antimalarial drug susceptibility assay determines ex-vivo growth of parasite in the presence of serial drug concentrations and, thus, eliminates host effects, such as drug metabolism and immunity. Although the sensitivity of the parasite to various antimalarials provided by such a test provides an important indicator of intrinsic parasite susceptibility, there are fundamental methodological issues that undermine comparison of in vitro susceptibility both between laboratories and within a single laboratory over time. A network of laboratories is proposed that will agree on the basic parameters of the in vitro test and associated measures of quality control. The aim of the network would be to establish baseline values of sensitivity to commonly used antimalarial agents from key regions of the world, and create a global database, linked to clinical, molecular and pharmacology databases, to support active surveillance to monitor temporal trends in parasite susceptibility. Such a network would facilitate the rapid detection of strains with novel antimalarial resistance profiles and investigate suitable alternative treatments with retained efficacy.

  11. 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.

  12. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate

    Science.gov (United States)

    Mishra, Kirti; Dash, Aditya P.; Dey, Nrisingha

    2011-01-01

    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. PMID:21760808

  13. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate

    Directory of Open Access Journals (Sweden)

    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.

  14. Evaluation of antimalarial, free-radical-scavenging and insecticidal activities of Artemisia scoparia and A. Spicigera, Asteraceae

    Directory of Open Access Journals (Sweden)

    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.

  15. [Historical overview of antimalarials used in Venezuela].

    Science.gov (United States)

    Zerpa de Artiles, N

    1993-06-01

    A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs.

  16. Antimalarial pharmacology and therapeutics of atovaquone.

    Science.gov (United States)

    Nixon, Gemma L; Moss, Darren M; Shone, Alison E; Lalloo, David G; Fisher, Nicholas; O'Neill, Paul M; Ward, Stephen A; Biagini, Giancarlo A

    2013-05-01

    Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.

  17. Antimalarial compounds from Kniphofia foliosa roots.

    Science.gov (United States)

    Wube, Abraham Abebe; Bucar, Franz; Asres, Kaleab; Gibbons, Simon; Rattray, Lauren; Croft, Simon L

    2005-06-01

    During the course of screening Ethiopian medicinal plants for their antimalarial properties, it was found that the dichloromethane extract of the roots of Kniphofia foliosa Hochst. (Asphodelaceae), which have long been used in the traditional medicine of Ethiopia for the treatment of abdominal cramps and wound healing, displayed strong in vitro antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum with an ED50 value of 3.8 microg/mL and weak cytotoxic activity against KB cells with an ED50 value of 35.2 microg/mL. Five compounds were isolated from the roots and evaluated for their in vitro antimalarial activity. Among the compounds tested, 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin, showed a high inhibition of the growth of the malaria parasite, P. falciparum with ED50 values of 0.260 and 0.537 microg/mL, respectively, while the naphthalene derivative, 2-acetyl-1-hydroxy-8-methoxy-3-methylnaphthalene, exhibited a less significant antimalarial activity with an ED50 value of 15.4 microg/mL. To compare the effect on the parasite with toxicity to mammalian cells, the cytotoxic activities of the isolated compounds against the KB cell line were evaluated and 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin displayed very low toxicity with ED50 values of 104 and 90 microg/mL, respectively. This is the first report of the inhibition of the growth of P. falciparum by anthraquinone-anthrone dimers and establishes them as a new class of potential antimalarial compounds with very little host cell toxicity.

  18. 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.

  19. A novel way to grow hemozoin-like crystals in vitro and its use to screen for hemozoin inhibiting antimalarial compounds.

    Directory of Open Access Journals (Sweden)

    Vincent Thomas

    Full Text Available BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. METHODS: We investigated the use of a new assay based on naturally occurring "self-replicating" particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit "self-replication" (crystallisation of these particles. RESULTS: We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC. HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. CONCLUSIONS: The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins

  20. Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

    NARCIS (Netherlands)

    Ginsburg, H.; Demel, R.A.

    1984-01-01

    Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pre

  1. Direct 2-acetoxylation of quinoline N-oxides via copper catalyzed C-H bond activation.

    Science.gov (United States)

    Chen, Xuan; Zhu, Chongwei; Cui, Xiuling; Wu, Yangjie

    2013-08-07

    An efficient and direct 2-acetoxylation of quinoline N-oxides via copper(I) catalyzed C-H bond activation has been developed. This transformation was achieved using TBHP as an oxidant in the cross-dehydrogenative coupling (CDC) reaction of quinoline N-oxides with aldehydes, and provided a practical pathway to 2-acyloxyl quinolines.

  2. 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.

  3. Antimalarial properties of imipramine and amitriptyline

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

    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 ..mu..M) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring (/sup 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 (/sup 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/sup 0/C with variable concentrations of drugs and/or FP (1-7 ..mu..M). Both drugs at 10 to 100 ..mu..M 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.

  4. 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.

  5. The Methanol Miracle

    Institute of Scientific and Technical Information of China (English)

    1995-01-01

    Methanol already makes a good fuel for camp stoves and even for a few cars. But in the future,say botanist Arthur Nonomura and biochemist Andrew Benson,methanol may fuel an agricultural revolution in hot and dry regions of the world. When the researchers recently sprayed diluted solutions of methanol on crops at Nonomura’s Arizona farm,they found they could double yields in some cases and halve water consumption in others.

  6. Methanol Asinger's vision today

    CERN Document Server

    Bertau, Martin; Plass, Ludolf; Schmidt, Friedrich; Wernicke, Hans-Jürgen

    2014-01-01

    Methanol - The Chemical and Energy Feedstock of the Future offers a visionary yet unbiased view of methanol technology. Based on the groundbreaking 1986 publication ""Methanol"" by Friedrich Asinger, this book includes contributions by more than 40 experts from industry and academia. The authors and editors provide a comprehensive exposition of methanol chemistry and technology which is useful for a wide variety of scientists working in chemistry and energy related industries as well as academic researchers and even decision-makers and organisations concerned with the future of chemical and e

  7. The Methanol Economy Project

    Energy Technology Data Exchange (ETDEWEB)

    Olah, George [Univ. of Southern California, Los Angeles, CA (United States); Prakash, G. K. [Univ. of Southern California, Los Angeles, CA (United States)

    2014-02-01

    The Methanol Economy Project is based on the concept of replacing fossil fuels with methanol generated either from renewable resources or abundant natural (shale) gas. The full methanol cycle was investigated in this project, from production of methanol through bromination of methane, bireforming of methane to syngas, CO2 capture using supported amines, co-electrolysis of CO2 and water to formate and syngas, decomposition of formate to CO2 and H2, and use of formic acid in a direct formic acid fuel cell. Each of these projects achieved milestones and provided new insights into their respective fields.

  8. The regioselective iodination of quinolines, quinolones, pyridones, pyridines and uracil.

    Science.gov (United States)

    Dutta, Uttam; Deb, Arghya; Lupton, David W; Maiti, Debabrata

    2015-12-28

    A radical based direct C-H iodination protocol for quinolines, quinolones, pyridones, pyridines, and uracil has been developed. The iodination occurs in a C3 selective manner for quinolines and quinolones. Pyridones and pyridines undergo C3 and C5 iodination, while dimethyl uracil undergoes C5 iodination. Scope of the method was demonstrated through the rapid synthesis of both electron rich as well as electron poor heteroaromatic iodides. The protocol was found to be scalable and general, while a mechanism has been proposed.

  9. Benzylchloridobis(quinolin-8-olato)tin(IV)

    OpenAIRE

    Qibao Wang

    2009-01-01

    In the title compound, [Sn(C7H7)(C9H6NO)2Cl], the SnIV ion is in a distorted octahedral coordination environment formed by the O and N atoms of two bis-chelating quinolin-8-olate ligands, a Cl atom and a C atom from a benzyl ligand. The axial sites are occupied by an N atom of a quinolinate ligand and the C atom of the benzyl ligand. The axial Sn—N bond is slightly shorter than the equatorial Sn—N bond.

  10. Benzyl-chloridobis(quinolin-8-olato)tin(IV).

    Science.gov (United States)

    Wang, Qibao

    2009-07-11

    In the title compound, [Sn(C(7)H(7))(C(9)H(6)NO)(2)Cl], the Sn(IV) ion is in a distorted octa-hedral coordination environment formed by the O and N atoms of two bis-chelating quinolin-8-olate ligands, a Cl atom and a C atom from a benzyl ligand. The axial sites are occupied by an N atom of a quinolinate ligand and the C atom of the benzyl ligand. The axial Sn-N bond is slightly shorter than the equatorial Sn-N bond.

  11. Benzyl­chloridobis(quinolin-8-olato)tin(IV)

    OpenAIRE

    Wang, Qibao

    2009-01-01

    In the title compound, [Sn(C7H7)(C9H6NO)2Cl], the SnIV ion is in a distorted octa­hedral coordination environment formed by the O and N atoms of two bis-chelating quinolin-8-olate ligands, a Cl atom and a C atom from a benzyl ligand. The axial sites are occupied by an N atom of a quinolinate ligand and the C atom of the benzyl ligand. The axial Sn—N bond is slightly shorter than the equatorial Sn—N bond.

  12. 2-(Methoxycarbonylquinolinium tetrachlorido(quinoline-2-carboxylato-κ2N,Ostannate(IV methanol solvate

    Directory of Open Access Journals (Sweden)

    Marzieh Vafaee

    2010-04-01

    Full Text Available In the title salt, (C11H10NO2[SnCl4(C10H6NO2]·CH3OH, the Sn atom is chelated by the quinolincarboxylate unit and it exists in a distorted octahedral coordination geometry. The cation is linked to the solvent molecule by an N—H...O hydrogen bond; the solvent molecule is linked to the anion by an O—H...O hydrogen bond.

  13. Phenylpropanoids and furanocoumarins as antibacterial and antimalarial constituents of the Bhutanese medicinal plant Pleurospermum amabile.

    Science.gov (United States)

    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.

  14. Bioremediation of Quinoline-contaminated Soil Using Bioaugmentation in Slurry-phase Reactor

    Institute of Scientific and Technical Information of China (English)

    JIAN-LONG WANG; ZE-YU MAO; LI-PING HAN; YI QIAN

    2004-01-01

    Objective To investigate the possibility of using bioaugmentation as a strategy for remediating quinoline-contaminated soil. Methods Microorganisms were introduced to the soil to assess the feasibility of enhancing the removal of quinoline from quinoline-contaminated soil. Slurry-phase reactor was used to investigate the bioremediation of quinoline-contaminated soil. HPLC (Hewlett-Packard model 5050 with an UV detector) was used for analysis of quinoline concentration. Results The biodegradation rate of quinoline was increased through the introduction of Burkholderia pickettii. Quinoline, at a concentration of 1 mg/g soil, could be removed completely within 6 and 8 hours with and without combined effect of indigenous microbes, respectively. Although the indigenous microbes alone had no quinoline-degrading ability, they cooperated with the introduced quinoline-degrader to remove quinoline more quickly than the introduced microbes alone. Bioaugmentaion process was accelerated by the increase of inoculum size and bio-stimulation. The ratio of water to soil in slurry had no significant impact on bioremediation results. Conclusion Bioaugmetation is an effective way for bioremediation of quinoline-contaminated soil.

  15. Hemozoin Formation as a Target for Antimalarial Drug Design

    Science.gov (United States)

    2005-02-01

    AD Award Number: DAMD17-03-1-0030 TITLE: Hemozoin Formation as a Target for Antimalarial Drug Design PRINCIPAL INVESTIGATOR: Michael K. Riscoe, Ph.D...Formation as a Target for Antimalarial Drug Design DAMD17-03-1-0030 6. A UTHOR(S) Michael K. Riscoe, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S) AND ADDRESS...Report: by Principal Investigator - Michael K. Riscoe, Ph.D. DAMD1 7-03-1-0030: "Hemozoin Formation as a Target for Antimalarial Drug Design " INTRODUCTION

  16. Methanol partial oxidation reformer

    Science.gov (United States)

    Ahmed, Shabbir; Kumar, Romesh; Krumpelt, Michael

    1999-01-01

    A partial oxidation reformer comprising a longitudinally extending chamber having a methanol, water and an air inlet and an outlet. An igniter mechanism is near the inlets for igniting a mixture of methanol and air, while a partial oxidation catalyst in the chamber is spaced from the inlets and converts methanol and oxygen to carbon dioxide and hydrogen. Controlling the oxygen to methanol mole ratio provides continuous slightly exothermic partial oxidation reactions of methanol and air producing hydrogen gas. The liquid is preferably injected in droplets having diameters less than 100 micrometers. The reformer is useful in a propulsion system for a vehicle which supplies a hydrogen-containing gas to the negative electrode of a fuel cell.

  17. An efficient synthesis of quinolines under solvent-free conditions

    Indian Academy of Sciences (India)

    Mihir K Chaudhuri; Sahid Hussain

    2006-03-01

    An efficient synthesis of substituted quinolines has been achieved in a one-pot reaction from -nitrobenzaldehyde and enolizable ketones using SnCl2.2H2O as the reductant under microwave irradiation without any solvent or catalyst.

  18. Dasycarine, a New Quinoline Alkaloid from Dictamnus dasycarpus

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Dasycarine, a new quinoline alkaloid along with five known compounds, dictamine, dihydroobacunone, obacunone, fraxinellone and b -sitosterol, were isolated from Dictamnus dasycarpus. The structure of dasycarine was identified as 4, 5, 8- trimethoxyl -3- (3- methyl -2- butenyl)- 2- quinone by 1D and 2D NMR techniques.

  19. A combination of the leaves and tuber of Icacina senegalensis A. Juss (Icacinaceae improves the antimalarial activity of the plant in mice

    Directory of Open Access Journals (Sweden)

    Esien David-Oku

    2015-10-01

    Full Text Available Objective: To investigate the possibility of increased antimalarial activity of Icacina senegalensis A. Juss (Icacinaceae upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice. Methods: Chloroquine sensitive ANKA clones of Plasmodium berghei were used to develop experimental models based on intraperitoneal injection of 107 parasitized erythrocytes in phosphate buffer saline (pH 7.2 and subsequent development of parasitemia. The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuberleaf methanol extracts of the plant at selected dosages (25, 50 and 100 mg/kg body weight. Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies. Results: Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites, with higher activity and mean survival time exhibited by the combined extract. Conclusions: Anti-plasmodia activity has been discovered in methanol extract of Icacina senegalensis tuber extract. The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.

  20. Drug Discovery and Development of Antimalarial Agents: Recent Advances.

    Science.gov (United States)

    Thota, Sreekanth; Yerra, Rajeshwar

    2016-01-01

    Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic countries. Most of the malarial infections and deaths are due to Plasmodium falciparum and Plasmodium vivax species. The recent emergence of resistance necessitates the search for new antimalarial drugs, which overcome the resistance and act through new mechanisms. Although much effort has been directed towards the discovery of novel antimalarial drugs. 4-anilino quinolone triazines as potent antimalarial agents, their in silico modelling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors has been reported. This review is primarily focused on the drug discovery of the recent advances in the development of antimalarial agents and their mechanism of action.

  1. Dietary methanol and autism.

    Science.gov (United States)

    Walton, Ralph G; Monte, Woodrow C

    2015-10-01

    The authors sought to establish whether maternal dietary methanol during pregnancy was a factor in the etiology of autism spectrum disorders. A seven item questionnaire was given to women who had given birth to at least one child after 1984. The subjects were solicited from a large primary care practice and several internet sites and separated into two groups - mothers who had given birth to a child with autism and those who had not. Average weekly methanol consumption was calculated based on questionnaire responses. 550 questionnaires were completed by women who gave birth to a non-autistic child. On average these women consumed 66.71mg. of methanol weekly. 161 questionnaires were completed by women who had given birth to an autistic child. The average estimated weekly methanol consumption for this group was 142.31mg. Based on the results of the Wilcoxon rank sum-test, we see a significant difference between the reported methanol consumption rates of the two groups. This study suggests that women who have given birth to an autistic child are likely to have had higher intake of dietary sources of methanol than women who have not. Further investigation of a possible link of dietary methanol to autism is clearly warranted.

  2. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    OpenAIRE

    Norazsida Ramli; Pakeer Oothuman Syed Ahamed; Hassan Mohamed Elhady; Muhammad Taher

    2014-01-01

    Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral t...

  3. Synthesis of triazol derivatives of lupeol with potential antimalarial activity

    OpenAIRE

    Tatiane Freitas Borgati; Guilherme Rocha Pereira; Geraldo Célio Brandão; Alaíde Braga Oliveira; José Dias Souza Filho

    2012-01-01

    The goal of this project is synthesize and characterization of derivatives of lupeol and evaluated antimalarial activity. Historically, plants are important source of antimalarial medicines, highlighting quinine (1) (Figure 1), an important      alkaloid from the Cinchona calisaya bark. This compound was an important model for cloroquine  synthesis, a drug that was widely used in malaria treatment. In addition, one of the principal medicines used today is artemisinine, isolated from the Chine...

  4. New approaches in antimalarial drug discovery and development: a review

    Directory of Open Access Journals (Sweden)

    Anna Caroline C Aguiar

    2012-11-01

    Full Text Available Malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. This problem has since been aggravated by a decreased sensitivity of Plasmodium vivax to chloroquine. This review discusses strategies for evaluating the antimalarial activity of new compounds in vitro and in animal models ranging from conventional tests to the latest high-throughput screening technologies. Antimalarial discovery approaches include the following: the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking. Using these approaches, thousands of new drugs with known molecular specificity and active against P. falciparum have been selected. The inhibition of haemozoin formation in vitro, an indirect test that does not require P. falciparum cultures, has been described and this test is believed to improve antimalarial drug discovery. Clinical trials conducted with new funds from international agencies and the participation of several industries committed to the eradication of malaria should accelerate the discovery of drugs that are as effective as artemisinin derivatives, thus providing new hope for the control of malaria.

  5. How do antimalarial drugs reach their intracellular targets?

    Directory of Open Access Journals (Sweden)

    Katherine eBasore

    2015-05-01

    Full Text Available Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.

  6. Methanol Cannon Demonstrations Revisited.

    Science.gov (United States)

    Dolson, David A.; And Others

    1995-01-01

    Describes two variations on the traditional methanol cannon demonstration. The first variation is a chain reaction using real metal chains. The second example involves using easily available components to produce sequential explosions that can be musical in nature. (AIM)

  7. A novel endogenous antimalarial: Fe(II)-protoporphyrin IX alpha (heme) inhibits hematin polymerization to beta-hematin (malaria pigment) and kills malaria parasites.

    Science.gov (United States)

    Monti, D; Vodopivec, B; Basilico, N; Olliaro, P; Taramelli, D

    1999-07-13

    The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX] to inert hemozoin (malaria pigment) is a crucial and unique process for intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins have been shown to block polymerization by forming electronic pi-pi interactions with heme monomers. Here, we report the identification of ferrous-protoporphyrin IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules, released from the proteolysis of hemoglobin, are first oxidized and then polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by cyclic voltammetry. Polymerization assays at acidic pH were conducted with the resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization adapted to anaerobic conditions and the products characterized by infrared spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover, Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave similar results: a dose-dependent inhibition of heme polymerization was observed using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L-cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological target.

  8. Synthesis, photochemistry, DNA cleavage/binding and cytotoxic properties of fluorescent quinoxaline and quinoline hydroperoxides.

    Science.gov (United States)

    Chowdhury, Nilanjana; Gangopadhyay, Moumita; Karthik, S; Pradeep Singh, N D; Baidya, Mithu; Ghosh, S K

    2014-01-01

    Novel fluorescent quinoxaline and quinoline hydroperoxides were shown to perform dual role as both fluorophores for cell imaging and photoinduced DNA cleaving agents. Photophysical studies of newly synthesized quinoxaline and quinoline hydroperoxides showed that they all exhibited moderate to good fluorescence. Photolysis of quinoxaline and quinoline hydroperoxides in acetonitrile using UV light above 350nm resulted in the formation of corresponding ester compounds via γ-hydrogen abstraction by excited carbonyl chromophore. Single strand DNA cleavage was achieved on irradiation of newly synthesized hydroperoxides by UV light (⩾350nm). Both hydroxyl radicals and singlet oxygen were identified as reactive oxygen species (ROS) responsible for the DNA cleavage. Further, we showed quinoline hydroperoxide binds to ct-DNA via intercalative mode. In vitro biological studies revealed that quinoline hydroperoxide has good biocompatibility, cellular uptake property and cell imaging ability. Finally, we showed that quinoline hydroperoxide can permeate into cells efficiently and may cause cytotoxicity upon irradiation by UV light.

  9. Assessment of Antimalarial Activity against Plasmodium falciparum and Phytochemical Screening of Some Yemeni Medicinal Plants

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    Mohammed A. Alshawsh

    2009-01-01

    Full Text Available Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III according to World Health Organization (WHO 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides.

  10. Determination of acrolein in urine by liquid chromatography and fluorescence detection of its quinoline derivative.

    Science.gov (United States)

    al-Rawithi, S; el-Yazigi, A; Nicholls, P J

    1993-11-01

    We describe an assay for acrolein in urine, employing derivatization with m-aminophenol in the presence of ferrous sulfate solution in sulfuric acid. The derivative (7-OH quinoline; DER) and the internal standard (quinine-bisulfate; IS) were separated on a 10-micron particle, 8 mm x 10-cm C18 cartridge in conjunction with a radial compression system using a mixture of 0.05 M dibasic ammonium phosphate solution (pH 2.5):acetonitrile:methanol (92:6:2) at a flow rate of 3 mL/min as a mobile phase. The effluent was monitored fluorometrically at excitation and emission wavelengths of 360 and 495 nm, respectively. The retention times of DER and IS under these conditions were 4.3 and 26 min, respectively, and no interference in the assay from any endogenous substance or other concomitantly used drug was observed. The assay was highly linear (r > 0.994) in the range 1-20 micrograms/mL of acrolein in urine (CV at different concentrations, < or = 7.9%). This method can serve to monitor acrolein pharmacokinetics in patients.

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

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    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

  12. Quinoline-2-thiol Derivatives as Fluorescent Sensors for Metals, pH and HNO

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    Naphtali A. O’Connor

    2014-06-01

    Full Text Available A tautomeric equilibrium exists for quinoline-2-thiol and quinoline-2(1H-thione. Quantum mechanical calculations predict the thione is the major tautomer and this is confirmed by the absorption spectra. The utility of quinolone-2-thiol/quinoline-2(1H-thione as a chromophore for developing fluorescent sensors is explored. No fluorescence is observed when excited at absorption maxima, however a fluorescence increase is observed when exposed to HNO, a molecule of import as a cardiovascular therapeutic. Alkylated quinoline-2-thiol derivatives are found to be fluorescent and show a reduction in fluorescence when exposed to metals and changes in pH.

  13. Quinoline based receptor in fluorometric discrimination of carboxylic acids

    Directory of Open Access Journals (Sweden)

    2008-12-01

    Full Text Available Quinoline and naphthalene-based fluororeceptors 1 and 2 have been designed and synthesized for detection of hydroxy carboxylic acids in less polar solvents. The receptor 1 shows monomer emission quenching followed by excimer emission upon hydrogen bond-mediated complexation of carboxylic acids. The excimer emission distinguishes aromatic dicarboxylic acids from aliphatic dicarboxylic acids and even long chain aliphatic dicarboxylic acids from short chain aliphatic dicarboxylic acids. The receptor 1 is found to be selective for citric acid with a strong excimer emission in CHCl3. On the contrary, the receptor 2 exhibited less binding constant value and did not form any excimer upon complexation with the same acids under similar conditions. This established the role of quinoline ring nitrogen in binding with the acids.

  14. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  15. Gold-catalyzed oxidative cycloadditions to activate a quinoline framework.

    Science.gov (United States)

    Huple, Deepak B; Ghorpade, Satish; Liu, Rai-Shung

    2013-09-23

    Going for gold! Gold-catalyzed reactions of 3,5- and 3,6-dienynes with 8-alkylquinoline oxides results in an oxidative cycloaddition with high stereospecificity (see scheme; EWG = electron-withdrawing group); this process involves a catalytic activation of a quinoline framework. The reaction mechanism involves the intermediacy of α-carbonyl pyridinium ylides (I) in a concerted [3+2]-cycloaddition with a tethered alkene.

  16. Synthesis of triazol derivatives of lupeol with potential antimalarial activity

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    Tatiane Freitas Borgati

    2012-06-01

    Full Text Available The goal of this project is synthesize and characterization of derivatives of lupeol and evaluated antimalarial activity. Historically, plants are important source of antimalarial medicines, highlighting quinine (1 (Figure 1, an important      alkaloid from the Cinchona calisaya bark. This compound was an important model for cloroquine  synthesis, a drug that was widely used in malaria treatment. In addition, one of the principal medicines used today is artemisinine, isolated from the Chinese plant Artemisia annua L (2 (Figure 1, and their semi synthetic derivatives (artesunate, artemeter, arteter. However, the malaria parasite has already shown resistance    to most of these current drugs and  the search for new candidates is essential. Lupeol (3 (Figura 1 is a compound that occurs in many plant species and discloses antimalarial, antiinflamatoryl and antitumoral activities. Considering its potential as a lead antimalarial molecule, we focused our work in the synthesis of new lupeol derivatives with increased antimalarial activity(scheme 1.

  17. Direct Methanol Fuel Cell, DMFC

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    Amornpitoksuk, P.

    2003-09-01

    Full Text Available Direct Methanol Fuel Cell, DMFC is a kind of fuel cell using methanol as a fuel for electric producing. Methanol is low cost chemical substance and it is less harmful than that of hydrogen fuel. From these reasons it can be commercial product. The electrocatalytic reaction of methanol fuel uses Pt-Ru metals as the most efficient catalyst. In addition, the property of membrane and system designation are also effect to the fuel cell efficient. Because of low power of methanol fuel cell therefore, direct methanol fuel cell is proper to use for the energy source of small electrical devices and vehicles etc.

  18. Synthesis, Crystal and Molecular Structure Studies and DFT Calculations of Phenyl Quinoline-2-Carboxylate and 2-Methoxyphenyl Quinoline-2-Carboxylate; Two New Quinoline-2 Carboxylic Derivatives

    Directory of Open Access Journals (Sweden)

    Edakot Fazal

    2015-02-01

    Full Text Available The crystal and molecular structures of the title compounds, phenyl quinoline-2-carboxylate and 2-methoxyphenyl quinoline-2-carboxylate, two new derivatives of quinolone-2-carboxylic acid, are reported and confirmed by single crystal X-ray diffraction and spectroscopic data. Compound (I, C16H11NO2, crystallizes in the monoclinic space group P21/c, with 8 molecules in the unit cell. The unit cell parameters are a = 14.7910(3 Å; b = 5.76446(12 Å; c = 28.4012(6 Å; β = 99.043(2°; V = 2391.45(9 Å3. Compound (II, C17H13NO5, crystallizes in the monoclinic space group P21/n with 4 molecules in the unit cell. The unit cell parameters are a = 9.6095(3 Å; b = 10.8040(3 Å; c = 13.2427(4 Å; β = 102.012(3°; V = 1344.76(7 Å3. Density functional theory (DFT geometry optimized molecular orbital calculations were performed and frontier molecular orbitals of each compound are displayed. Correlation between the calculated molecular orbital energies (eV for the surfaces of the frontier molecular orbitals to the electronic excitation transitions from the absorption spectra of each compound has been proposed. Additionally, similar correlations observed among six closely related compounds examining small structural differences to their frontier molecular orbital surfaces and from their DFT molecular orbital energies, provide further support for the suggested assignments of the title compounds.

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

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    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. Potent antimalarial 4-pyridones with improved physico-chemical properties.

    Science.gov (United States)

    Bueno, José M; Manzano, Pilar; García, María C; Chicharro, Jesús; Puente, Margarita; Lorenzo, Milagros; García, Adolfo; Ferrer, Santiago; Gómez, Rubén M; Fraile, María T; Lavandera, José L; Fiandor, José M; Vidal, Jaume; Herreros, Esperanza; Gargallo-Viola, Domingo

    2011-09-15

    Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

  1. 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...

  2. Medical need, scientific opportunity and the drive for antimalarial drugs.

    Science.gov (United States)

    Ridley, Robert G

    2002-02-07

    Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.

  3. A correlation study of quinoline derivatives and their pharmaceutical behavior by ab initio calculated NQR parameters.

    Science.gov (United States)

    Rafiee, Marjan A; Hadipour, Nasser L; Naderi-manesh, Hossein

    2004-03-01

    In this paper, ab initio calculated NQR parameters for some quinoline-containing derivatives are presented. The calculations are carried out in a search for the relationships between the charge distribution of these compounds and their ability to interact with haematin. On the basis of NQR parameters, pi-electron density on the nitrogen atom of the quinoline ring plays a dominant role in determining the ability of quinolines to interact with haematin. This point was confirmed with investigation of Fe+3 cation-pi quinoline ring interactions in 2- and 4-aminoquinoline. However, our results do not show any preference for those carbon atoms of the quinoline ring which previous reports have noted. In order to calculate the NQR parameters, the electric field gradient (EFG) should be evaluated at the site of a quadrupolar nucleus in each compound. EFGs are calculated by the Gaussian 98 program using the B3LYP/6-31 G* level of theory.

  4. In vitro Potentiation of Antimalarial Activities by Daphnetin Derivatives Against Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    FANG HUANG; LIN-HUA TANG; LIN-QIAN YU; YI-CHANG NI; QIN-MEI WANG; FA-JUN NAN

    2006-01-01

    Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum (FCC1) was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodium falciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

  5. Development and validation of a generic liquid chromatographic method for the simultaneous determination of five commonly used antimalarial drugs: Application to pharmaceutical formulations and human plasma.

    Science.gov (United States)

    Mannemala, Sai Sandeep; Nagarajan, Janaki Sankarachari Krishnan

    2015-05-01

    A simple, sensitive, and rapid liquid chromatographic method was developed and validated using diode array detection for the determination of five commonly used antimalarial drugs in pharmaceutical formulations and in human plasma. Chromatographic separation of antimalarial drugs and internal standard (ibuprofen) was achieved on a C18 column with a mobile phase composed of 10 mM dipotassium orthophosphate at pH 3.0, methanol, and acetonitrile in a ratio of 20:38:42 v/v, at a flow rate of 1 mL/min. The analytes were monitored at 220 nm and separated in ˂10 min. The method was validated for linearity, accuracy, precision, limit of quantification, and robustness. Both intra- and interday precisions (in terms of %RSD) were lower than 3% and accuracy ranged from 98.1 to 104.5%. Extraction recoveries were ≥96% in plasma. The limits of quantitation for artemether, lumefantrine, pyrimethamine, sulfadoxine, and mefloquine were 0.3, 0.03, 0.06, 0.15, and 0.15 μg/mL in human plasma. Stability under various conditions was also investigated. The method was successfully applied for quantification of antimalarial drugs in marketed formulations and in spiked human plasma. The method can be employed for routine QC purposes and in pharmacokinetic investigations.

  6. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    Science.gov (United States)

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  7. 7-[(Morpholin-4-yl(phenylmethyl]quinolin-8-ol

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    A. Crochet

    2013-01-01

    Full Text Available In the title compound, C20H20N2O2, the quinoline ring system makes dihedral angles of 81.05 (4 and 61.16 (5° with the mean planes of the benzene and morpholine rings, respectively; the mean planes of the latter two rings make a dihedral angle of 83.59 (4°. In the crystal, pairs of O—H...N hydrogen bonds link neighbouring molecules related by a twofold rotation axis, generating R22(10 motifs.

  8. Neurotoxicity of Quinolinic Acid to Spiral Ganglion Cells in Rats

    Institute of Scientific and Technical Information of China (English)

    肖红俊; 杨琛; 何圆圆; 郑娜

    2010-01-01

    Our study investigated the neurotoxicity of quinolinic acid(QA) to spiral ganglion cells(SGCs),observed the protective effects of N-methyl-D-aspartate(NMDA) receptor antagonist MK-801 and magnesium ions on the QA-induced injury to SGCs,and analyzed the role of QA in otitis media with effusion(OME)-induced sensorineural hearing loss(SNHL).After culture in vitro for 72 h,SGCs were exposed to different media and divided into 4 groups:the blank control group,the QA injury group,the MK-801 treatment group,and th...

  9. UV action spectroscopy of protonated PAH derivatives. Methyl substituted quinolines

    DEFF Research Database (Denmark)

    Klærke, Benedikte; Holm, Anne; Andersen, Lars Henrik

    2011-01-01

    Aims. We investigate the production of molecular photofragments upon UV excitation of PAH derivatives, relevant for the interstellar medium. Methods. The action absorption spectra of protonated gas-phase methyl-substituted quinolines (CH3−C9H7NH+) have been recorded in the 215–338 nm spectral ran...... the estimated IR relaxation time. Photophysical properties of both nitrogen containing and methyl-substituted PAHs are interesting in an astrophysical context in connection with identifying the aromatic component of the interstellar medium....

  10. The toxicity of methanol

    Energy Technology Data Exchange (ETDEWEB)

    Tephly, T.R. (Univ. of Iowa, Iowa City (USA))

    1991-01-01

    Methanol toxicity in humans and monkeys is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in humans and monkeys, a feature not seen in lower animals. The accumulation of formate is due to a deficiency in formate metabolism which is, in turn, related, in part, to low hepatic tetrahydrofolate (H{sub 4}folate). An excellent correlation between hepatic H{sub 4} folate and formate oxidation rates has been shown within and across species. Thus, humans and monkeys possess low hepatic H{sub 4}folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in monkeys in the absence of metabolic acidosis. In addition to low hepatic H{sub 4}folate concentrations, monkeys and humans also have low hepatic 10-formyl H{sub 4}folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. This review presents the basis for the role of folic acid-dependent reactions in the regulation of methanol toxicity.

  11. Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest.

    Science.gov (United States)

    Duran, Leidy Tatiana Díaz; Rincón, Nathalia Olivar; Galvis, Carlos Eduardo Puerto; Kouznetsov, Vladimir V; Lorenzo, Jorge Luis Fuentes

    2015-03-01

    Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis.

  12. True Niacin Deficiency in Quinolinic Acid Phosphoribosyltransferase (QPRT) Knockout Mice.

    Science.gov (United States)

    Shibata, Katsumi

    2015-01-01

    Pyridine nucleotide coenzymes (PNCs) are involved in over 500 enzyme reactions. PNCs are biosynthesized from the amino acid L-tryptophan (L-Trp), as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-) or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and the qprt(+/-) mice. On the other hand, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (pniacin such as blood and liver NAD concentrations were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of quinolinic acid was greater in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice (pniacin-deficient mice.

  13. Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria.

    Directory of Open Access Journals (Sweden)

    Chimere Obiora Agomo

    Full Text Available The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1 and type 1 antifolate antimalarial medicines (Pfdhfr.Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72-76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt gene by real time polymerase chain reaction (PCR using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1 gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.Two haplotypes of Pfcrt (n = 54 were observed: CVMNK 13(24.2% and CVIET 41 (75.9% of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28 haplotypes were NYSND 15(53.6%, YYSND 5(17.9%, NFSND 6(21.4% and YFSND 2(7.1%. The Pfdhfr (n = 15 were ACNCSVI 4(26.7%, and ACICNSVI 1(6.7% and ACIRNVI 10 (66.7%. The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Y and 184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024 while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006. The median parasitaemia were similar (P>0.05 in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt

  14. Atmospheric methanol measurement using selective catalytic methanol to formaldehyde conversion

    Directory of Open Access Journals (Sweden)

    S. J. Solomon

    2005-01-01

    Full Text Available A novel atmospheric methanol measurement technique, employing selective gas-phase catalytic conversion of methanol to formaldehyde followed by detection of the formaldehyde product, has been developed and tested. The effects of temperature, gas flow rate, gas composition, reactor-bed length, and reactor-bed composition on the methanol conversion efficiency of a molybdenum-rich, iron-molybdate catalyst [Mo-Fe-O] were studied. Best results were achieved using a 1:4 mixture (w/w of the catalyst in quartz sand. Optimal methanol to formaldehyde conversion (>95% efficiency occurred at a catalyst housing temperature of 345°C and an estimated sample-air/catalyst contact time of <0.2 seconds. Potential interferences arising from conversion of methane and a number of common volatile organic compounds (VOC to formaldehyde were found to be negligible under most atmospheric conditions and catalyst housing temperatures. Using the new technique, atmospheric measurements of methanol were made at the University of Bremen campus from 1 to 15 July 2004. Methanol mixing ratios ranged from 1 to 5 ppb with distinct maxima at night. Formaldehyde mixing ratios, obtained in conjunction with methanol by periodically bypassing the catalytic converter, ranged from 0.2 to 1.6 ppb with maxima during midday. These results suggest that selective, catalytic methanol to formaldehyde conversion, coupled with existing formaldehyde measurement instrumentation, is an inexpensive and effective means for monitoring atmospheric methanol.

  15. Atmospheric methanol measurement using selective catalytic methanol to formaldehyde conversion

    Directory of Open Access Journals (Sweden)

    S. J. Solomon

    2005-05-01

    Full Text Available A novel atmospheric methanol measurement technique, employing selective gas-phase catalytic conversion of methanol to formaldehyde followed by detection of the formaldehyde product, has been developed and tested. The effects of temperature, gas flow rate, gas composition, reactor-bed length, and reactor-bed composition on the methanol conversion efficiency of a molybdenum-rich, iron-molybdate catalyst [Mo-Fe-O] were studied. Best results were achieved using a 1:4 mixture (w/w of the catalyst in quartz sand. Optimal methanol to formaldehyde conversion (>95% efficiency occurred at a catalyst housing temperature of 345°C and an estimated sample-air/catalyst contact time of <0.2 s. Potential interferences arising from conversion of methane and a number of common volatile organic compounds (VOC to formaldehyde were found to be negligible under most atmospheric conditions and catalyst housing temperatures. Using the new technique, atmospheric measurements of methanol were made at the University of Bremen campus from 1 to 15 July 2004. Methanol mixing ratios ranged from 1 to 5 ppb with distinct maxima at night. Formaldehyde mixing ratios, obtained in conjunction with methanol by periodically bypassing the catalytic converter, ranged from 0.2 to 1.6 ppb with maxima during midday. These results suggest that selective, catalytic methanol to formaldehyde conversion, coupled with existing formaldehyde measurement instrumentation, is an inexpensive and effective means for monitoring atmospheric methanol.

  16. Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs.

    Science.gov (United States)

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

    2017-01-14

    The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

  17. Fake anti-malarials: start with the facts.

    Science.gov (United States)

    Kaur, Harparkash; Clarke, Siȃn; Lalani, Mirza; Phanouvong, Souly; Guérin, Philippe; McLoughlin, Andrew; Wilson, Benjamin K; Deats, Michael; Plançon, Aline; Hopkins, Heidi; Miranda, Debora; Schellenberg, David

    2016-02-13

    This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.

  18. Coordination chemistry and biological activity of 5'-OH modified quinoline-B12 derivatives.

    Science.gov (United States)

    Zelenka, Karel; Brandl, Helmut; Spingler, Bernhard; Zelder, Felix

    2011-10-14

    The consequences of structural modifications at the 5'-OH ribofuranotide moiety of quinoline modified B12 derivatives are discussed in regard of the coordination chemistry, the electrochemical properties and the biological behaviour of the compound.

  19. Facile and efficient synthesis of quinoline-4-carboxylic acids under microwave irradiation

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A facile and efficient method for the preparation of 2-non-substituted quinoline-4-carboxylic acids is described via the Pfitzinger reaction of isatins with sodium pyruvate following consequent decarboxylation under microwave irradiation.

  20. Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

    Science.gov (United States)

    Le Chapelain, Camille; Groll, Michael

    2016-05-23

    One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle.

  1. 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.

  2. Antimalarial diterpene alkaloids from the seeds of Caesalpinia minax.

    Science.gov (United States)

    Ma, Guoxu; Sun, Zhaocui; Sun, Zhonghao; Yuan, Jingquan; Wei, Hua; Yang, Junshan; Wu, Haifeng; Xu, Xudong

    2014-06-01

    Two new diterpene alkaloids, caesalminines A (1) and B (2), possessing a tetracyclic cassane-type furanoditerpenoid skeleton with γ-lactam ring, were isolated from the seeds of Caesalpinia minax. Their structures were determined by different spectroscopic methods and ECD calculation. The plausible biosynthetic pathway of caesalminines A and B was proposed. The anti-malarial activity of compounds 1 and 2 is presented with IC50 values of 0.42 and 0.79 μM, respectively.

  3. 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

    2016-01-01

    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 [3H]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. PMID:27139466

  4. Potential antimalarials from African natural products: A reviw.

    Science.gov (United States)

    Lawal, Bashir; Shittu, Oluwatosin Kudirat; Kabiru, Adamu Yusuf; Jigam, Ali Audu; Umar, Maimuna Bello; Berinyuy, Eustace Bonghan; Alozieuwa, Blessing Uchenna

    2015-01-01

    Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health, and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in vivo or in vitro against malaria parasite. Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, and Science domain) that report on antiplasmodial activity of natural products from differernts Africa region. A total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%), Fababceae (8.128%), Euphorbiaceae (5.52%), Rubiaceas (5.52%), and Apocyanaceae (5.214%), have received more scientific validation than others. African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against Plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products are of paramount importance.

  5. Antimalarial effect of agmatine on Plasmodium berghei K173 strain

    Institute of Scientific and Technical Information of China (English)

    SURui-Bin; WEIXiao-Li; LIUYin; LIJin

    2003-01-01

    AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.

  6. Anti-Malarial Plants of Jonai, India: an Ethnobotanical Approach

    Directory of Open Access Journals (Sweden)

    Tonlong WANGPAN

    2016-03-01

    Full Text Available North-East India represents a unique ecosystem with treasured medicinal plant wealth closely related with Folk medicines. A large number of plants having medicinal properties and their folk uses have remained confined to the natives of this region. The tribal community of Jonai, Assam was explored to expose the indigenous herbal remedy for malaria. Sixteen antimalarial plants belonging to 13 families were reported. The analysis revealed highest fidelity level (FL value for Ajuga integrifolia (100% followed by Ricinus communis (94%, Alstonia scholaris (88%, Oroxylum indicum (86% and Achyranthes aspera (82%. The percentage of respondent’s knowledge (PRK about anti-malarial plants showed Alstonia scholaris as the most commonly known antimalarial species (53% within this region. Preference ranking (PR unveiled eight species to be very effective against malarial parasite, which includes Allium sativum, Artemisia indica, Azadirachta indica, Carica papaya, Clerodendrum glandulosum, Ocimum tenuiflorum, Oroxylum indicum, Piper longum and Piper nigrum. All medicine preparations are made using water as the medium and are orally administered in the form of crude extract, powder, juice and decoction. Overall analysis suggested Ajuga integrifolia, Achyranthes aspera, Alstonia scholaris, Artemisia indica, Oroxylum indicum and Ricinus communis to be used for the development of novel, economical, effective and ecofriendly herbal formulations for healthcare management.

  7. Review of pyronaridine anti-malarial properties and product characteristics

    Directory of Open Access Journals (Sweden)

    Croft Simon L

    2012-08-01

    Full Text Available Abstract Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. In vitro susceptibility of Plasmodium vivax to antimalarials in Colombia.

    Science.gov (United States)

    Fernández, Diana; Segura, César; Arboleda, Margarita; Garavito, Giovanny; Blair, Silvia; Pabón, Adriana

    2014-11-01

    The in vitro susceptibilities of 30 isolates of Plasmodium vivax to a number of antimalarials (chloroquine [CQ], mefloquine, amodiaquine, quinine, and artesunate [AS]) were evaluated. The isolates came from the region of Urabá in Colombia, in which malaria is endemic, and were evaluated by the schizont maturation test. The 50% inhibitory concentration (IC50) was 0.6 nM (95% confidence interval [CI], 0.3 to 1.0 nM) for artesunate, 8.5 nM (95% CI, 5.6 to 13.0 nM) for amodiaquine, 23.3 nM (95% CI, 12.4 to 44.1 nM) for chloroquine, 55.6 nM (95% CI, 36.8 to 84.1 nM) for mefloquine, and 115.3 nM (95% CI, 57.7 to 230.5 nM) for quinine. The isolates were classified according to whether the initial parasites were mature or immature trophozoites (Tfz). It was found that the IC50s for chloroquine and artesunate were significantly different in the two aforementioned groups (P Colombia, P. vivax continues to be susceptible to antimalarials. This is the first report, to our knowledge, showing in vitro susceptibilities of P. vivax isolates to antimalarials in Colombia.

  10. Antimalarials and the fight against malaria in Brazil

    Directory of Open Access Journals (Sweden)

    Luiz MA Carmargo

    2009-04-01

    Full Text Available Luiz MA Carmargo1, Saulo de Oliveira2, Sergio Basano3, Célia RS Garcia21ICBV-USP, Monte Negro, Rondônia, Brasil; 2Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, SP, Brazil; 3CEMETRON, Porto Velho, Guaporé, BrazilAbstract: 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.Keywords: Plasmodium falciparum, malaria, antimalarials, calcium

  11. Antimalarial activity of newly synthesized chalcone derivatives in vitro.

    Science.gov (United States)

    Yadav, Neesha; Dixit, Sandeep K; Bhattacharya, Amit; Mishra, Lokesh C; Sharma, Manish; Awasthi, Satish K; Bhasin, Virendra K

    2012-08-01

    Twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC(50) (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-1-one with IC(50) of 1.1 μg/mL, while that of the natural phytochemical, licochalcone A is 1.43 μg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy-substituted chalcones. Furthermore, 3, 4, 5-trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity.

  12. A quinoline based pH sensitive ratiometric fluorescent sensor: Structure and spectroscopy

    Indian Academy of Sciences (India)

    Soma Mukherjee; Amit Kumar Paul; Helen Stoeckli-Evans

    2015-09-01

    A new quinoline based hydrazone was synthesized via a condensation reaction and characterized by NMR, mass and single crystal X-ray diffraction studies. It was investigated for suitability as a reversible ratiometric fluorescent pH sensor in acidic pH region. The sensor exhibits intramolecular charge transfer (ICT) type photophysical changes upon protonation of the quinoline ring. No significant interference on emission behavior was observed in the presence of various metal ions.

  13. 4-Hy-droxy-1-methyl-3-phenyl-quinolin-2(1H)-one.

    Science.gov (United States)

    Kafka, Stanislav; Pevec, Andrej; Proisl, Karel; Kimmel, Roman; Košmrlj, Janez

    2013-02-01

    In the title compound, C(16)H(13)NO(2), the quinoline system is approximately planar with a maximum deviation from the least-squares plane of 0.059 (1) Å for the N atom. The phenyl ring is rotated by 62.16 (4)° with respect to the plane of the quinoline system. In the crystal, O-H⋯O hydrogen bonds link mol-ecules into infinite chains running along the b-axis direction.

  14. Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

    Directory of Open Access Journals (Sweden)

    Rafael Lugo-Huitrón

    2013-01-01

    Full Text Available Quinolinic acid (QUIN, a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.

  15. Determination of aniline and quinoline compounds in textiles.

    Science.gov (United States)

    Luongo, Giovanna; Iadaresta, Francesco; Moccia, Emanuele; Östman, Conny; Crescenzi, Carlo

    2016-11-04

    A simple method for simultaneous determination of twenty-one analytes, belonging to two classes of compounds, aromatic amines and quinolines, is presented. Several of the analytes considered in this study frequently occur in textiles goods on the open market and have been related to allergic contact dermatitis and/or are proven or suspected carcinogens. The method includes an efficient clean-up step using graphitized carbon black (GCB) that simplifies and improves the robustness of the subsequent GC-MS analysis. Briefly, after solvent extraction of the textile sample, the extract is passed through a GCB SPE cartridge that selectively retain dyes and other interfering compounds present in the matrix, producing a clean extract, suitable for GC-MS analysis, is obtained. The method was evaluated by spiking blank textiles with the selected analytes. Method quantification limits (MQL) ranged from 5 to 720ng/g depending on the analyte. The linear range of the calibration curves ranged over two order magnitude with coefficients of determination (R(2)) higher than 0.99. Recoveries ranged from 70 to 92% with RSDs 1.7-14%. The effectiveness of the method was tested on a variety of textile materials samples from different origin. In a pilot explorative survey, 2,6-dichloro-4-nitroaniline was detected in all the analysed clothing samples in concentrations ranging from 1.0 to 576μg/g. 2,4-dinitroaniline was detected in four of the seven samples with a highest concentration of 305μg/g. Quinoline was detected in all samples in concentrations ranging from 0.06 to 6.2μg/g.

  16. CO{sub 2} binding in the (quinoline-CO{sub 2}){sup −} anionic complex

    Energy Technology Data Exchange (ETDEWEB)

    Graham, Jacob D.; Buytendyk, Allyson M.; Wang, Yi; Bowen, Kit H., E-mail: kbowen@jhu.edu [Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Kim, Seong K. [Department of Chemistry, Seoul National University, Seoul 151-747 (Korea, Republic of)

    2015-06-21

    We have studied the (quinoline-CO{sub 2}){sup −} anionic complex by a combination of mass spectrometry, anion photoelectron spectroscopy, and density functional theory calculations. The (quinoline-CO{sub 2}){sup −} anionic complex has much in common with previously studied (N-heterocycle-CO{sub 2}){sup −} anionic complexes both in terms of geometric structure and covalent bonding character. Unlike the previously studied N-heterocycles, however, quinoline has a positive electron affinity, and this provided a pathway for determining the binding energy of CO{sub 2} in the (quinoline-CO{sub 2}){sup −} anionic complex. From the theoretical calculations, we found CO{sub 2} to be bound within the (quinoline-CO{sub 2}){sup −} anionic complex by 0.6 eV. We also showed that the excess electron is delocalized over the entire molecular framework. It is likely that the CO{sub 2} binding energies and excess electron delocalization profiles of the previously studied (N-heterocycle-CO{sub 2}){sup −} anionic complexes are quite similar to that of the (quinoline-CO{sub 2}){sup −} anionic complex. This class of complexes may have a role to play in CO{sub 2} activation and/or sequestration.

  17. Quinolines in clothing textiles--a source of human exposure and wastewater pollution?

    Science.gov (United States)

    Luongo, Giovanna; Thorsén, Gunnar; Ostman, Conny

    2014-05-01

    A production process in which the use of various types of chemicals seems to be ubiquitous makes the textile industry a growing problem regarding both public health as well as the environment. Among several substances used at each stage, the present study focuses on the quinolines, a class of compounds involved in the manufacture of dyes, some of which are skin irritants and/or classified as probable human carcinogens. A method was developed for the determination of quinoline derivatives in textile materials comprising ultrasound-assisted solvent extraction, solid phase extraction cleanup, and final analysis by gas chromatography/mass spectrometry. Quinoline and ten quinoline derivatives were determined in 31 textile samples. The clothing samples, diverse in color, material, brand, country of manufacture, and price, and intended for a broad market, were purchased from different shops in Stockholm, Sweden. Quinoline, a possible human carcinogen, was found to be the most abundant compound present in almost all of the samples investigated, reaching a level of 1.9 mg in a single garment, and it was found that quinoline and its derivatives were mainly correlated to polyester material. This study points out the importance of screening textiles with nontarget analysis to investigate the presence of chemicals in an unbiased manner. Focus should be primarily on clothing worn close to the body.

  18. Methylnaltrexone bromide methanol monosolvate

    Directory of Open Access Journals (Sweden)

    Xinbo Zhou

    2012-03-01

    Full Text Available In the title compound [systematic name: (4R,4aS,7aR,12bS-3-cyclopropylmethyl-4a,9-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium bromide methanol monosolvate], C21H26NO4+·Br−·CH3OH, two of the three six-membered rings adopt chair conformations while the third, which contains a C=C double bond, adopts an approximate half-boat conformation. The 2,3-dihydrofuran ring adopts an envelope conformation. In the crystal, the components are linked by O—H...O and O—H...Br hydrogen bonds. The absolute stereochemistry was inferred from one of the starting materials.

  19. Methanol synthesis beyond chemical equilibrium

    NARCIS (Netherlands)

    van Bennekom, J. G.; Venderbosch, R. H.; Winkelman, J. G. M.; Wilbers, E.; Assink, D.; Lemmens, K. P. J.; Heeres, H. J.

    2013-01-01

    In commercial methanol production from syngas, the conversion is thermodynamically limited to 0.3-0.7 leading to large recycles of non-converted syngas. This problem can be overcome to a significant extent by in situ condensation of methanol during its synthesis which is possible nowadays due to the

  20. Methanol as an energy carrier

    Energy Technology Data Exchange (ETDEWEB)

    Biedermann, P.; Grube, T.; Hoehlein, B. (eds.)

    2006-07-01

    For the future, a strongly growing energy demand is expected in the transport sector worldwide. Economically efficient oil production will run through a maximum in the next decade. Higher fuel prices and an environmentally desirable reduction of emissions will increase the pressure for reducing fuel consumption and emissions in road traffic. These criteria show the urgent necessity of structural changes in the fuel market. Due to its advantages concerning industrial-scale production, storage and global availability, methanol has the short- to medium-term potential for gaining increased significance as a substitution product in the energy market. Methanol can be produced both from fossil energy sources and from biomass or waste materials through the process steps of synthesis gas generation with subsequent methanol synthesis. Methanol has the potential to be used in an environmentally friendly manner in gasoline/methanol mixtures for flexible fuel vehicles with internal combustion engines and in diesel engines with pure methanol. Furthermore, it can be used in fuel cell vehicles with on-board hydrogen production in direct methanol fuel cell drives, and in stationary systems for electricity and heat generation as well as for hydrogen production. Finally, in portable applications it serves as an energy carrier for electric power generation. In this book, the processes for the production and use of methanol are presented and evaluated, markets and future options are discussed and issues of safety and environmental impacts are addressed by a team of well-known authors. (orig.)

  1. Crystal Structures of the Iron–Sulfur Cluster-Dependent Quinolinate Synthase in Complex with Dihydroxyacetone Phosphate, Iminoaspartate Analogues, and Quinolinate

    Energy Technology Data Exchange (ETDEWEB)

    Fenwick, Michael K. [Cornell Univ., Ithaca, NY (United States); Ealick, Steven E. [Cornell Univ., Ithaca, NY (United States)

    2016-07-12

    The quinolinate synthase of prokaryotes and photosynthetic eukaryotes, NadA, contains a [4Fe-4S] cluster with unknown function. We report crystal structures of Pyrococcus horikoshii NadA in complex with dihydroxyacetone phosphate (DHAP), iminoaspartate analogues, and quinolinate. DHAP adopts a nearly planar conformation and chelates the [4Fe-4S] cluster via its keto and hydroxyl groups. The active site architecture suggests that the cluster acts as a Lewis acid in enediolate formation, like zinc in class II aldolases. The DHAP and putative iminoaspartate structures suggest a model for a condensed intermediate. The ensemble of structures suggests a two-state system, which may be exploited in early steps.

  2. Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery

    OpenAIRE

    Marques, Joana; Valle-Delgado, Juan J.; Urbán, Patricia; Baró, Elisabet; Prohens, Rafel; Mayor, Alfredo; Cisteró, Pau; Delves, Michael; Robert E Sinden; Grandfils, Christian; de Paz, José L.; García-Salcedo, José A.; Fernández-Busquets, Xavier

    2016-01-01

    The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial dru...

  3. Antimaláricos e Ototoxicidade Antimalarials and Ototoxicity

    Directory of Open Access Journals (Sweden)

    Marcelo Cardoso Figueiredo

    2004-06-01

    Full Text Available Os antimaláricos, como o difosfato de cloroquina, têm sido usados amplamente no tratamento não só da malária, mas também de doenças reumatológicas como a síndrome de Sjögren (SS, artrite reumatóide (AR e lúpus eritematoso sistêmico (LES. Essas drogas são usadas cronicamente e, em conseqüência do acúmulo nos melanócitos, podem causar hiperpigmentação cutânea, retinopatia e lesão no ouvido interno. Como o protocolo do uso de antimaláricos só envolve a avaliação oftalmológica e das enzimas hepáticas, esta revisão discute a necessidade de novos estudos da avaliação periódica da audição desses pacientes.Antimalarials such as chloroquine diphosphate have been widely used not only for the treatment of malaria, but also for several rheumatic diseases such as Sjögren's syndrome (SS, rheumatoid arthritis (RA and Systemic Lupus Erythematosus (SLE. These drugs are used on a long-term basis and, due to melanocytes' accumulation, can cause cutaneous hyperpigmentation, retinopathy and internal ear damage. As the antimalarials' user follow-up protocol recommends only periodic eye exams and liver function testing, we reviewed the literature questioning whether new studies on the periodic hearing evaluation are required for antimalarials' users.

  4. Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.

    Science.gov (United States)

    Sonoiki, Ebere; Palencia, Andres; Guo, Denghui; Ahyong, Vida; Dong, Chen; Li, Xianfeng; Hernandez, Vincent S; Zhang, Yong-Kang; Choi, Wai; Gut, Jiri; Legac, Jennifer; Cooper, Roland; Alley, M R K; Freund, Yvonne R; DeRisi, Joseph; Cusack, Stephen; Rosenthal, Philip J

    2016-08-01

    There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

  5. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Norazsida Ramli

    2014-01-01

    Full Text Available Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group during early, established and residual infections. Results: The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000, 200 (P = 0.000 and 400 mg/kg doses (P = 0.000 in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. Conclusion: Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection.

  6. 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

  7. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Directory of Open Access Journals (Sweden)

    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. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  9. A Novel Preparation of 2,4-Disubstituted Quinolines Catalyzed by FeCl3 ·6H2O in Ionic Liquids

    Institute of Scientific and Technical Information of China (English)

    FAN Xue-Sen; ZHANG Xin-Ying

    2003-01-01

    @@ Quinolines and their derivatives occur in numerous natural products. Many quinolines display interesting physi ological activities and have found attractive applications as pharmaceuticals and agrochemicals as well as being general synthetic building blocks. [1] Many synthetic methods have been developed for quinolines, [2] but due to their great importance, the development of novel synthetic methods remains an active research area. [3

  10. Acute methanol toxicity in minipigs

    Energy Technology Data Exchange (ETDEWEB)

    Dorman, D.C.; Dye, J.A.; Nassise, M.P.; Ekuta, J.; Bolon, B.

    1993-01-01

    The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuroocular toxicosis.

  11. Accidental methanol ingestion: Case report

    Directory of Open Access Journals (Sweden)

    Bakker Jan

    2010-02-01

    Full Text Available Abstract Background The incidence of methanol (CH3OH intoxication differs enormously from country to country. Methanol intoxication is extremely rare in the Dutch population. Even a low dose can already be potentially lethal. Patients are conventionally treated with hemodialysis. Therefore we'd like to present a report of a foreign sailor in Rotterdam who accidentally caused himself severe methanol intoxication, with a maximum measured concentration of 4.4 g/L. Case presentation The patient presented with hemodynamic instability and severe metabolic acidosis with pH 6.69. The anion gap was 39 mmol/L and the osmol gap 73 mosmol/kg. Treatment with ethanol and continuous venovenous hemodiafiltration (CVVH-DF was initiated. Despite the hemodynamic instability it is was possible to achieve rapid correction of pH and methanol concentration with CVVH-DF while maintaining a stable and therapeutic ethanol serum concentration. Despite hemodynamic and acid-base improvement, our patient developed massive cerebral edema leading to brain death. Permission for organ donation was unfortunately not ascertained. Conclusions We conclude that in a hemodynamic instable situation high methanol concentrations and methanol-induced derangements of homeostasis are safely and effectively treated with CVVH-DF and that severe cerebral edema is another possible cause of death rather than the classical bleeding in the putamen area.

  12. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

    Science.gov (United States)

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-01-01

    A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.

  13. Characterization of Strain Pseudomonas sp.Q1 in Microbial Fuel Cell for Treatment of Quinoline-Contaminated Water

    Institute of Scientific and Technical Information of China (English)

    ZHANG Cui-Ping; CHEN Shan-Shan; LIU Guang-Li; ZHANG Ren-Duo; XIE Jian

    2012-01-01

    To find new strain in the microbial fuel cell (MFC) for quinoline removal from wastewater and soil,a facultative anaerobic bacterium strain was isolated from the anode of MFC,utilizing quinoline as the carbon source and electron donor.Based on the 16S rRNA sequence analysis,the bacterium strain was Gram-negative and identified as Pseudomonas sp.Q1 according to its morphology and physiochemical properties.The strain was inoculated into a double-chambered MFC using various quinoline concentratious (0,50,75,86,100,150,200 and 300 mg L-1) combining with 300 mg L-1 glucose as the fuel.Results showed that electricity was generated from the MFC,in which quinoline was degraded simultaneously.The values of Coulombic efficiency (CE) increased with the increase of quinoline concentrations from 0 to 100 mg L-1 then decreased with the increase of quinoline concentration from 100 to 300 mg L-1,and the maximum CE 36.7% was obtained at the quinoline concentration of 100 mg L-1.The cyclic voltammetry analysis suggested that the mechanism of electron transfer was through excreting mediators produced by the strain Q1.The MFC should be a potential method for the treatment of quinoline-contaminated water and soil.

  14. Quinolinic acid induces oxidative stress in rat brain synaptosomes.

    Science.gov (United States)

    Santamaría, A; Galván-Arzate, S; Lisý, V; Ali, S F; Duhart, H M; Osorio-Rico, L; Ríos, C; St'astný, F

    2001-03-26

    The oxidative action of quinolinic acid (QUIN), and the protective effects of glutathione (GSH), and 2-amino-5-phosphonovaleric acid (APV), were tested in rat brain synaptosomes, Reactive oxygen species (ROS) formation was quantified after the exposure of synaptosomes to increasing concentrations of QUIN (25-500 microM). The potency of QUIN to induce lipid peroxidation (LP) was tested as a regional index of thiobarbituric acid-reactive substances (TBARS) production, and the antioxidant actions of both GSH (50 microM) and APV (250 microM) on QUIN-induced LP were evaluated in synaptosomes prepared from different brain regions. QUIN induced concentration-dependent increases in ROS formation and TBARS in all regions analyzed, but increased production of fluorescent peroxidized lipids only in the striatum and the hippocampus, whereas both GSH and APV decreased this index. These results suggest that the excitotoxic action of QUIN involves regional selectivity in the oxidative status of brain synaptosomes, and may be prevented by substances exhibiting antagonism at the NMDA receptor.

  15. Antimalarial drug resistance in Bangladesh, 1996-2012.

    Science.gov (United States)

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.

  16. Maximizing antimalarial efficacy and the importance of dosing strategies.

    Science.gov (United States)

    Beeson, James G; Boeuf, Philippe; Fowkes, Freya J I

    2015-05-09

    Artemisinin-based combination therapies (ACTs) are the cornerstone for the treatment of malaria. However, confirmed resistance to artemisinins in South-East Asia, and reports of reduced efficacy of ACTs raise major concerns for malaria treatment and control. Without new drugs to replace artemisinins, it is essential to define dosing strategies that maximize therapeutic efficacy, limit the spread of resistance, and preserve the clinical value of ACTs. It is important to determine the extent to which reduced efficacy of ACTs reflects true resistance versus sub-optimal dosing, and quantify other factors that determine treatment failure. Pooled analyses of individual patient data from multiple clinical trials, by investigators in the Worldwide Antimalarial Resistance Network, have shown high overall efficacy for three widely used ACTs, artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. Analyses also highlight that suboptimal dosing leads to increased risk of treatment failure, especially among children. In the most recent study, an analysis of clinical trials of artesunate-amodiaquine, widely used among children in Africa, revealed a superior efficacy for fixed-dose combination tablets compared to loose non-fixed dose combinations. This highlights the benefits of fixed-dose combinations as a practical strategy for ensuring optimal antimalarial dosing and maximizing efficacy. Please see related article: http://www.biomedcentral.com/1741-7015/13/66.

  17. The role of antimalarial treatment in the elimination of malaria.

    Science.gov (United States)

    Gosling, R D; Okell, L; Mosha, J; Chandramohan, D

    2011-11-01

    With declining transmission of malaria in several regions of the world and renewed interest in the elimination of malaria, strategies for malaria control using antimalarial drugs are being revisited. Drug-based strategies to reduce transmission of malaria need to target the asymptomatic carriers of infection. Drugs that are effective against gametocytes are few in number, but it may be possible to reduce gametocyte production by killing the asexual stages, for which more drugs are available. Drugs for use in large-scale programmes must be safe and tolerable. Strategies include improving access to treatment for malaria with an efficacious drug, intermittent-treatment programmes, and mass drug administration, with and without screening for malaria. Recent proposals have targeted high-risk groups for interventions. None of the strategies has been rigorously tested with appropriate control groups for comparison. Because of the lack of field evidence, modelling has been used. Models have shown, first, that for long-lasting effects, drug administration programmes should be linked with vector control, and second, that if elimination is the aim, programmes are likely to be more successful when applied to smaller populations of a few thousand or less. In order to sustain the gains following the scaling up of vector control and use of artemisinin combination therapies (ACTs), strategies that use antimalarials effectively need to be devised and evidence generated for the most cost-efficient way forward.

  18. 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 Garcinia 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 (IC50 level: concentration that inhibits parasite growth by 50%) and 30 µg/mL (IC90 level: 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 IC50 concentration, about 82% of the expressed parasite proteins were matched with the control (non-exposed), while at the IC90 concentration, only 15% matched proteins were found. The selected protein spots from parasite exposed to the plant extract at the concentration of 12 µg/mL were identified as enzymes that play role in glycolysis pathway, i.e., phosphoglycerate mutase putative, L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase/phosphoglycerate kinase. The proteosome was found in parasite exposed to 30 µg/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).

  19. 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).

  20. Quantifying the pharmacology of antimalarial drug combination therapy

    Science.gov (United States)

    Hastings, Ian M.; Hodel, Eva Maria; Kay, Katherine

    2016-01-01

    Most current antimalarial drugs are combinations of an artemisinin plus a ‘partner’ drug from another class, and are known as artemisinin-based combination therapies (ACTs). They are the frontline drugs in treating human malaria infections. They also have a public-health role as an essential component of recent, comprehensive scale-ups of malaria interventions and containment efforts conceived as part of longer term malaria elimination efforts. Recent reports that resistance has arisen to artemisinins has caused considerable concern. We investigate the likely impact of artemisinin resistance by quantifying the contribution artemisinins make to the overall therapeutic capacity of ACTs. We achieve this using a simple, easily understood, algebraic approach and by more sophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the two approaches gave consistent results. Surprisingly, the artemisinin component typically makes a negligible contribution (≪0.0001%) to the therapeutic capacity of the most widely used ACTs and only starts to make a significant contribution to therapeutic outcome once resistance has started to evolve to the partner drugs. The main threat to antimalarial drug effectiveness and control comes from resistance evolving to the partner drugs. We therefore argue that public health policies be re-focussed to maximise the likely long-term effectiveness of the partner drugs. PMID:27604175

  1. 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

    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, e.g. the drug concentrations in whole blood, plasma, and urin...... summarized. Finally, the main problems that the researchers have dealt with are highlighted. This information will aid analytical chemists in the development of novel methods for determining existing antimalarials and upcoming new drugs.......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, e.g. the drug concentrations in whole blood, plasma, and urine...

  2. Unusual case of methanol poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, L.; Henderson, M. (St. James' s Univ. Hospital, Leeds (United Kingdom). Dept. of Chemical Pathology); Madi, S.; Mellor, L. (St. James' s Univ. Hospital, Leeds (United Kingdom). Dept. of Medicine, and Pharmacy)

    1993-01-09

    A 31-year-old man with a history of alcohol abuse presented to the accident and emergency department complaining of blurred vision. 4 h previously he had drunk 300 mL de-icer fluid. Electrolytes, urea, creatinine, glucose, and blood-gas analysis were normal. Measured osmolality, however, was 368 mosmol/kg with a calculated osmolality of 300 mosmol/kg, which indicated a greatly increased osmolar gap. He was therefore given 150 mL whisky and admitted. Methanol was later reported as 200 mg/dL. Ethylene glycol was not detected, but another glycol, propylene glycol, was present at 47 mg/dL. 10 h after ingestion an intravenous infusion of ethanol was started and he was hemodialysed for 7 h. After dialysis he was given a further 100 mL whisky and the rate of ethanol infusion was reduced to 11 g per h. Methanol and ethanol were measured twice daily until methanol was under 10/mg/dL: The recommendation is that blood ethanol be maintained between 100 and 200 mg/dL during treatment of methanol poisoning. This concentration was not achieved, presumably because of the high rate of ethanol metabolism often found in alcoholics. Antifreeze solutions commonly contain methanol and ethylene glycol. Sometimes propylene glycol is substituted because it has properties similar to those of ethylene glycol but is less toxic. The authors postulate that propylene glycol inhibited the metabolism of methanol in the patient, thus sparing him from the toxic effects of methanol.

  3. Bis(quinolin-8-olsilver(I 2-hydroxy-3,5-dinitrobenzoate

    Directory of Open Access Journals (Sweden)

    Fang-Fang Jian

    2009-12-01

    Full Text Available The title compound, [Ag(C9H7NO2](C7H3N2O7, was prepared from 3,5-dinitrosalicylic acid (DNS, quinolin-8-ol and AgNO3. The AgI atom is coordinated by two N atoms and two O atoms from two quinolin-8-ols in a roughly planar [maximum deviation = 0.223 (2 Å] environment. The two quinolin-8-ol ligands are bent slightly with respect to each other, making a dihedral angle of 9.55 (9°. The DNS anion interacts with the silver complex through O—H...O hydrogen bonds

  4. Anion- interactions in layered structures of salts of 5-(hydroxyimino) quinolin-8-one and related salts

    Indian Academy of Sciences (India)

    Prithiviraj Khakhlary; Jubaraj B Baruah

    2015-01-01

    Relevance of anion- interactions in chloride, bromide, nitrate and perchlorate salts of 5-(hydroxyimino)quinolin-8-one are discussed. Structures of nitrate salt of 5-aminoquinoline as well as nitrate salt of 4-hydroxyquinazoline are compared with the structure of nitrate salt of 5-(hydroxyimino)quinolin-8-one. From such a comparison, two different arrangements of nitrate ions with respect to the respective cations are discerned. Nitrate ions are sandwiched between aromatic planes of cations in nitrate salts of 5-(hydroxyimino)quinolin-8-one or 4-hydroxyquinazoline; whereas, nitrate ions are in oblique positions with respect to aromatic planes of counter cations in nitrate salt of 5-aminoquinoline. Binding constants of different nitrate salts in solution are determined by UV-visible spectroscopic titrations. Solution study shows formation of ion-pairs of these salts in solution.

  5. Chemical consequences of pyrazole orientation in Ru(II) complexes of unsymmetric quinoline-pyrazole ligands.

    Science.gov (United States)

    Hedberg Wallenstein, Joachim; Fredin, Lisa A; Jarenmark, Martin; Abrahamsson, Maria; Persson, Petter

    2016-08-07

    A series of homoleptic Ru(II) complexes including the tris-bidentate complexes of a new bidentate ligand 8-(1-pyrazol)-quinoline (Q1Pz) and bidentate 8-(3-pyrazol)-quinoline (Q3PzH), as well as the bis-tridentate complex of bis(quinolinyl)-1,3-pyrazole (DQPz) was studied. Together these complexes explore the orientation of the pyrazole relative to the quinoline. By examining the complexes structurally, photophysically, photochemically, electrochemically, and computationally by DFT and TD-DFT, it is shown that the pyrazole orientation has a significant influence on key properties. In particular, its orientation has noticeable effects on oxidation and reduction potentials, photostability and proton sensitivity, indicating that [Ru(Q3PzH)3](2+) is a particularly good local environment acidity-probe candidate.

  6. Novel quinolines carrying pyridine, thienopyridine, isoquinoline, thiazolidine, thiazole and thiophene moieties as potential anticancer agents

    Directory of Open Access Journals (Sweden)

    Ghorab Mostafa M.

    2016-06-01

    Full Text Available As a part of ongoing studies in developing new anticancer agents, novel 1,2-dihydropyridine 4, thienopyridine 5, isoquinolines 6–20, acrylamide 21, thiazolidine 22, thiazoles 23–29 and thiophenes 33–35 bearing a biologically active quinoline nucleus were synthesized. The structure of newly synthesized compounds was confirmed on the basis of elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. 2,3-Dihydrothiazole-5-carboxamides 27, 25, 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (34, 1,2-dihydroisoquinoline-7-carbonitrile (7, 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (35, 1,2-dihydroisoquinoline-7-carbonitrile (6, 2-cyano-3-(dimethylamino-N-(quinolin-3-ylacrylamide (21, 1,2-dihydroisoquinoline-7-carbonitriles (11 and (8 exhibited higher activity (IC50 values of 27–45 μmol L–1 compared to doxorubicin (IC50 47.9 μmol L–1. LQ quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (12, 2-thioxo-2,3-dihydrothiazole-5-carboxamide (28 and quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (15 show activity comparable to doxorubicin, while (quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (9, 2,3-dihydrothiazole-5-carboxamide (24, thieno [3,4-c] pyridine-4(5H-one (5, cyclopenta[b]thiophene-3-carboxamide (33 and (quinolin-3-yl-6-stryl-1,2-dihydroisoquinoline-7-carbonitrile (10 exhibited moderate activity, lower than doxorubicin.

  7. The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain.

    Science.gov (United States)

    Swathy, S S; Indira, M

    2010-01-01

    One of the mechanisms of neurotoxicity is the induction of oxidative stress. There is hardly any cure for neurotoxicity in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. The aim of our study was to evaluate the effect of Ksheerabala on quinolinic acid-induced toxicity in rat brain. The optimal dose of Ksheerabala was found from a dose escalation study, wherein it was found that Ksheerabala showed maximum protection against quinolinic acid-induced neurotoxicity at a dose of 15 microL/100 g body weight/day, which was selected for further experiments. Four groups of female albino rats were maintained for 21 days as follows: 1. Control group, 2. Quinolinic acid (55 microg/100 g body weight), 3. Ksheerabala (15 microL/100 g body weight), 4. Ksheerabala (15 microL/100 g body weight) + Quinolinic acid (55 microg/100 g body weight). At the end of the experimental period, levels of lipid peroxidation products, protein carbonyls, and activities of scavenging enzymes were analyzed. The results revealed that quinolinic acid intake caused enhanced lipid and protein peroxidation as evidenced by increased levels of peroxidation products such as malondialdehyde, hydroperoxide, conjugated dienes, and protein carbonyls. On the other hand, the activities of scavenging enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase as well as the concentration of glutathione were reduced. On coadminstration of Ksheerabala along with quinolinic acid, the levels of all the biochemical parameters were restored to near-normal levels, indicating the protective effect of the drug. These results were reinforced by histopathological studies.

  8. Metabolic pathways of quinoline, indole and their methylated analogs by Desulfobacterium indolicum (DSM 3383)

    DEFF Research Database (Denmark)

    Johansen, S.S.; Licht, D.; Arvin, E.

    1997-01-01

    The transformation of quinoline, isoquinoline and 3-, 4-, 6- and 8-methylquinoline by Desulfobacterium indolicum was compared with that of the N-containing analogues indole and 1-, 2-, 3- and 7-methylindole. The metabolites were identified using high-performance liquid chromatography with UV...... detection, thin-layer chromatography, combined gas chromatography/mass spectrometry and proton NMR spectroscopy. All degraded compounds were initially hydroxylated at position 2 by D. indolicum. A new degradation product of quinoline was observed in the second transformation step, where 3,4-dihydro-2...

  9. Deuterium isotope effects on 13C chemical shifts of 10-Hydroxybenzo[h]quinolines

    DEFF Research Database (Denmark)

    Hansen, Poul Erik; Kamounah, Fadhil S.; Gryko, Daniel T.

    2013-01-01

    Deuterium isotope effects on 13C-NMR chemical shifts are investigated in a series of 10-hydroxybenzo[h]quinolines (HBQ’s) The OH proton is deuteriated. The isotope effects on 13C chemical shifts in these hydrogen bonded systems are rather unusual. The formal four-bond effects are found to be nega......Deuterium isotope effects on 13C-NMR chemical shifts are investigated in a series of 10-hydroxybenzo[h]quinolines (HBQ’s) The OH proton is deuteriated. The isotope effects on 13C chemical shifts in these hydrogen bonded systems are rather unusual. The formal four-bond effects are found...

  10. Jusbetonin, the first indolo[3,2-b]quinoline alkaloid glycoside, from Justicia betonica.

    Science.gov (United States)

    Subbaraju, Gottumukkala V; Kavitha, Jakka; Rajasekhar, Dodda; Jimenez, Jorge I

    2004-03-01

    A new indolo[3,2-b]quinoline alkaloid glycoside, jusbetonin (1), and three known alkaloids, namely, 10H-quindoline (2), 6H-quinindoline (3), and 5H,6H-quinindolin-11-one (4), have been isolated from the leaves of Justicia betonica. The structure of 1 was established on the basis of 1D and 2D NMR ((1)H-(1)H COSY, HMQC, and HMBC) and HRFABMS data. Compound 1 is the first example of a glycosylated indolo[3,2-b]quinoline alkaloid, while compound 4 was isolated for the first time from a natural source.

  11. Structural study on few co-crystals and a salt of quinoline derivatives having amide bond

    Science.gov (United States)

    Karmakar, Anirban; Kalita, Dipjyoti; Baruah, Jubaraj B.

    2009-10-01

    The N-[2-(4-Methoxy-phenyl)-ethyl]-2-(quinolin-8-yloxy)-acetamide forms 1:1 co-crystals with aromatic diols namely 1,4-dihydroxybenzene, 1,5-dihydroxynaphthalene. In the later case co-crystal is formed in hydrated form. The hydrated form of co-crystal with 1,5-naphthalenediol has two symmetry independent host molecules in its unit cell, whereas such phenomenon in the co-crystal 1,4-dihydroxybenzene is not observed. The crystal structure of perchloric acid salt of (Quinolin-8-ylamino)-acetic acid is determined and this salt also shows two symmetry independent parent molecules in unit cell.

  12. Vibronic Spectroscopy of a Structural Isomer of Quinoline: -

    Science.gov (United States)

    Mehta-Hurt, Deepali N.; Korn, Joseph A.; Zwier, Timothy S.

    2013-06-01

    This talk will present results of a gas phase, jet-cooled vibronic spectroscopy study of (Z)-phenylvinylnitrile ((Z)-C_6H_5-CH=CH-C=N, (Z)-PVN). With a substituent locked into a cis conformation with respect to the aromatic ring, (Z)-PVN is postulated to be a molecule with an ideal functionality to isomerize to quinoline upon photoexcitation. As such, (Z)-PVN is particularly relevant to Titan's nitrile-containing atmosphere, where much of the chemistry is photochemically driven. As a first step towards such photochemical studies, a fluorescence excitation spectrum of a mixture of (E)- and (Z)-PVN was collected spanning the range 33,300-35,580 cm^{-1} (300.0-281.0 nm). Previous investigations in the Zwier group pertaining to the vibronic spectroscopy of (E)-PVN allowed for the identification of peaks in the (E)- and (Z)-PVN composite spectrum that were solely due to (Z)-PVN, and the S_0-S_1 origin of (Z)-PVN was identified as a dominant band that occurs at 33,706 cm^{-1}. For additional confirmation, ultraviolet depletion spectroscopy (UVD) was used to obtain an isomer specific spectrum of (Z)-PVN as well as search for non-radiative transitions. Dispersed fluorescence spectra that characterize the vibronic activity have also been acquired. A comparison between the vibronic spectroscopy of (Z)-PVN with both (E)-PVN and (Z)-phenylvinylacetylene ((Z)-PVA), the hydrocarbon analog of (Z)-PVN, will be made in this talk.

  13. Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

    Directory of Open Access Journals (Sweden)

    Laurent Calcul

    2013-12-01

    Full Text Available We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18 were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14, which was found to display the most favorable bioactivity profile.

  14. 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.

  15. 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)

  16. Characterization of counterfeit artesunate antimalarial tablets from southeast Asia.

    Science.gov (United States)

    Hall, Krystyn Alter; Newton, Paul N; Green, Michael D; De Veij, Marleen; Vandenabeele, Peter; Pizzanelli, David; Mayxay, Mayfong; Dondorp, Arjen; Fernandez, Facundo M

    2006-11-01

    In southeast Asia, the widespread high prevalence of counterfeits tablets of the vital antimalarial artesunate is of great public health concern. To assess the seriousness of this problem, we quantified the amount of active ingredient present in artesunate tablets by liquid chromatography coupled to mass spectrometry. This method, in conjunction with analysis of the packaging, classified tablets as genuine, substandard, or fake and validated results of the colorimetric Fast Red TR test. Eight (35%) of 23 fake artesunate samples contained the wrong active ingredients, which were identified as different erythromycins and paracetamol. Raman spectroscopy identified calcium carbonate as an excipient in 9 (39%) of 23 fake samples. Multivariate unsupervised pattern recognition results indicated two major clusters of artesunate counterfeits, those with counterfeit foil stickers and containing calcium carbonate, erythromycin, and paracetamol, and those with counterfeit holograms and containing starch but without evidence of erythromycin or paracetamol.

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

    Science.gov (United States)

    Islahudin, Farida; Tindall, Sarah M; Mellor, Ian R; Swift, Karen; Christensen, Hans E M; Fone, Kevin C F; Pleass, Richard J; Ting, Kang-Nee; Avery, Simon V

    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 neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

  18. Differential speciation of ferriprotoporphyrin IX in the presence of free base and diprotic 4-aminoquinoline antimalarial drugs

    Science.gov (United States)

    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

  19. Synthesis and structure of interaction products of quinoline-2(1H)-thione with molecular iodine.

    Science.gov (United States)

    Chernov'yants, Margarita S; Starikova, Zoya A; Kolesnikova, Tatiana S; Karginova, Anastasia O; Lyanguzov, Nikolay V

    2015-03-15

    The behavior of quinoline-2(1H)-thione, which is a potential antithyroid drug toward molecular iodine, was investigated. The ability of quinoline-2(1H)-thione to form the outer-sphere charge-transfer complex C9H7NS·I2 with iodine molecular in dilute chloroform solution has been studied by UV-vis spectroscopy (lgβ=3.85). The crystal structure of the new salt 2-(quinoline-2-yldisulfanyl)quinolinium triiodide - product of irreversible oxidation of quinoline-2(1H)-thione was determined by X-ray diffraction. The 2-(quinoline-2-yldisulfanyl)quinolinium cations form dimers through π-π-stacking interaction between quinoline rings. Strong intramolecular interactions are observed between iodine - sulfur atoms and iodine - hydrogen atoms with shortened contacts (less of sum of van der Waals contacts). It is noteworthy that two perfectly centrosymmetrical anions I3(-) form a very short contact I(3)⋯I(3') 3.7550(5) so we can state the formation of the dianion I(6)(2-). Therefore the formation and topology of polyiodide species depend on the characteristics, such as shape, size and charge, etc., of the counter cation, 2-(quinoline-2-yldisulfanyl)quinolinium, which is considered as templating agent.

  20. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  2. In Vitro and In Vivo Antimalarial Evaluations of Myrtle Extract, a Plant Traditionally Used for Treatment of Parasitic Disorders

    Directory of Open Access Journals (Sweden)

    Farzaneh Naghibi

    2013-01-01

    Full Text Available Based on the collected ethnobotanical data from the Traditional Medicine and Materia Medica Research Center (TMRC, Iran, Myrtus communis L. (myrtle was selected for the assessment of in vitro and in vivo antimalarial and cytotoxic activities. Methanolic extract of myrtle was prepared from the aerial parts and assessed for antiplasmodial activity, using the parasite lactate dehydrogenase (pLDH assay against chloroquine-resistant (K1 and chloroquine-sensitive (3D7 strains of Plasmodium falciparum. The 4-day suppressive test was employed to determine the parasitemia suppression of the myrtle extract against P. berghei  in vivo. The IC50 values of myrtle extract were 35.44 µg/ml against K1 and 0.87 µg/ml against 3D7. Myrtle extract showed a significant suppression of parasitaemia (84.8 ± 1.1% at 10 mg/kg/day in mice infected with P. berghei after 4 days of treatment. Cytotoxic activity was carried out against mammalian cell lines using methyl thiazol tetrazolium (MTT assay. No cytotoxic effect on mammalian cell lines up to 100 µg/mL was shown. The results support the traditional use of myrtle in malaria. Phytochemical investigation and understanding the mechanism of action would be in our upcoming project.

  3. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

    NARCIS (Netherlands)

    Rijpma, S.R.; Heuvel, J.J.; Velden, M. van der; Sauerwein, R.W.; Russel, F.G.; Koenderink, J.B.

    2014-01-01

    BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involve

  4. Distillation time as tool for improved antimalarial activity and differential oil composition of cumin seed oil

    Science.gov (United States)

    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...

  5. Degradation of quinoline by wet oxidation - kinetic aspects and reaction mechanisms

    DEFF Research Database (Denmark)

    Thomsen, A.B.

    1998-01-01

    of succinic acid is suggested to be a result of a coupling reaction of the acetic acid radical A reaction mechanism is suggested for the degradation of quinoline: it involves hydroxyl radicals and the possible interaction with autoclave walls is discussed. (C) 1998 Elsevier Science Ltd. All rights reserved....

  6. Synthesis, Characterization and Antibacterial Activity of a New Series of s-Triazines Derived with Quinolines

    Directory of Open Access Journals (Sweden)

    J. J. Vora

    2009-01-01

    Full Text Available 8-Hydroxy quinoline was synthesized using Skraup reaction. This was condensed with trichloro-s-triazine. The product of the above reaction was allowed to react with triazole derivative. Finally, urea derivatives were allowed to react and the products were characterized by conventional and instrumental methods. Their structures were determined and important biochemical properties were studied

  7. Anxiogenic activity of quinolinic acid and kynurenine in the social interaction test in mice.

    Science.gov (United States)

    Lapin, I P; Mutovkina, L G; Ryzov, I V; Mirzaev, S

    1996-01-01

    Quinolinic acid, a metabolite of tryptophan on the kynurenine pathway, shortened the duration of social contacts (sniffings) in C57BL/6 mice which had been previously isolated for 24 h. This effect was observed at the following time intervals after i.c.v. administration: 2-6, 22-26 and 32-36 min. Locomotion was significantly less inhibited and only during the first interval. L-Kynurenine sulphate was less active. It shortened the duration of contacts only during the 32-36 min interval after i.c.v. administration. Grooming was significantly reduced by quinolinic acid at 7-11, 12-16 and 17-21 min after administration. These effects of quinolinic acid in the social interaction test are similar to those of standard anxiogens and suggest that quinolinic acid belongs to the putative endogenous anxiogens (and not only to the endogenous convulsants). The same assumption about L-kynurenine based on data in other models of anxiety has been made previously.

  8. Synthesis and cytotoxic activity of 2,5-disubstituted pyrimido [5,4-c] quinoline derivatives

    Institute of Scientific and Technical Information of China (English)

    Fan Zhang; Xin Zhai; Li Juan Chen; Jian Guo Qi; Bo Cui; Yu Cheng Gu; Ping Gong

    2011-01-01

    A series of 2,5-disubstituted pyrimido[5,4-c]quinoline derivatives were synthesized and their cytotoxic activity against H460, HT-29 and MDA-MB-231 cell lines was evaluated in vitro. It was found that most of the tested compounds especially compound 17, shown stronger activity to the selected three cell lines than ZM447439.

  9. Synthesis, Characterization and Anti-Cancer Activity of Hydrazide Derivatives Incorporating a Quinoline Moiety

    Directory of Open Access Journals (Sweden)

    Murat Bingul

    2016-07-01

    Full Text Available Identification of the novel (E-N′-((2-chloro-7-methoxyquinolin-3-ylmethylene-3-(phenylthiopropanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19–26 were prepared from the corresponding quinoline hydrazones and substituted carboxylic acids using EDC-mediated peptide coupling reactions. Further modification of the parent compound 18 was achieved by replacement of the quinoline moiety with other aromatic systems. All the newly synthesized compounds were evaluated for their anti-cancer activity against the SH-SY5Y and Kelly neuroblastoma cell lines, as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Analogues 19 and 22 significantly reduced the cell viability of neuroblastoma cancer cells with micromolar potency and significant selectivity over normal cells. The quinoline hydrazide 22 also induced G1 cell cycle arrest, as well as upregulation of the p27kip1 cell cycle regulating protein.

  10. Copper(II)-catalyzed electrophilic amination of quinoline N-oxides with O-benzoyl hydroxylamines.

    Science.gov (United States)

    Li, Gang; Jia, Chunqi; Sun, Kai; Lv, Yunhe; Zhao, Feng; Zhou, Kexiao; Wu, Hankui

    2015-03-21

    Copper acetate-catalyzed C-H bond functionalization amination of quinoline N-oxides was achieved using O-benzoyl hydroxylamine as an electrophilic amination reagent, thereby affording the desired products in moderate to excellent yields. Electrophilic amination can also be performed in good yield on a gram scale.

  11. Bis(quinolin-8-ol)silver(I) 2-hydr­oxy-3,5-dinitro­benzoate

    OpenAIRE

    Fang-Fang Jian; Chun-Lan Zhang

    2009-01-01

    The title compound, [Ag(C9H7NO)2](C7H3N2O7), was prepared from 3,5-dinitrosalicylic acid (DNS), quinolin-8-ol and AgNO3. The AgI atom is coordinated by two N atoms and two O atoms from two quinolin-8-ols in a roughly planar [maximum deviation = 0.223 (2) Å] environment. The two quinolin-8-ol ligands are bent slightly with respect to each other, making a dihedral angle of 9.55 (9)°. The DNS anion interacts with the silver complex through O...

  12. Towards a methanol economy based on homogeneous catalysis: methanol to H2 and CO2 to methanol

    DEFF Research Database (Denmark)

    Alberico, E.; Nielsen, Martin

    2015-01-01

    The possibility to implement both the exhaustive dehydrogenation of aqueous methanol to hydrogen and CO2 and the reverse reaction, the hydrogenation of CO2 to methanol and water, may pave the way to a methanol based economy as part of a promising renewable energy system. Recently, homogeneous...

  13. Crystal Structure of Norfloxacin Methanol Solvate: C16H18FN3O3·CH3OH·H2O

    Institute of Scientific and Technical Information of China (English)

    WANG Ying; SUN Li-Wei; WANG Wei; YAN Lian-He

    2005-01-01

    Norfloxacin methanol solvate (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid methanol solvate) has been prepared. The crystal and molecular struc- tures of the title compound, C16H18FN3O3·CH3OH·H2O, were determined by X-ray diffraction me- thod. The compound crystallizes in monoclinic, space group P21/c with a = 7.8660(16), b = 22.525 (5), c = 10.253(2)(A), β = 108.31°, Mr = 369.39, V = 1724.7(6) (A)3, Z = 4, Dc = 1.423 g/cm3, F(000) = 784, R = 0.0557 and wR = 0.1224. The TGA analysis indicates that it decomposes completely at 723.75 ℃.

  14. 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.

  15. The in vitro antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with mefloquine/artesunate.

    Science.gov (United States)

    Chaijaroenkul, Wanna; Na-Bangchang, Kesara

    2014-03-01

    Multidrug resistance Plasmodium falciparum is the major health problem in Thailand. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate the antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with the standard antimalarial drugs mefloquine and artesunate in chloroquine sensitive (3D7) and chloroquine resistant (K1) P. falciparum clones in vitro. Median (range) IC50 (drug concentration which produces 50% parasite growth inhibition) values of the 9-hydroxycalabaxanthone, α-mangostin, artesunate and mefloquine for 3D7 vs K1 clones were 1.5 (0.9-2.1) vs 1.2 (1.1-1.6) μM, 17.9 (15.7.0-20.0) vs 9.7 (6.0-14.0) μM, 1.0 (0.4-3.0) vs 1.7 (1.0-2.5) nM, and 13.3 (11.1-13.3) vs 7.1 (6.7-12.2) nM, respectively. Analysis of isobologram and combination index (CI) of 9-hydroxycalabaxanthone with artesunate or mefloquine showed synergistic and indifference antimalarial interaction, respectively. α-mangostin-artesunate combination exhibited a slight antagonistic effect of antimalarial interaction, whereas α-mangostin and mefloquine combination showed indifference interaction in both clones. The combination of 9-hydroxycalabaxanthone with α-mangostin showed the synergistic antimalarial interaction in both clones.

  16. Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis.

    Science.gov (United States)

    Santos, Cleydson Breno Rodrigues dos; Lobato, Cleison Carvalho; Braga, Francinaldo Sarges; Costa, Josivan da Silva; Favacho, Hugo Alexandre Silva; Carvalho, Jose Carlos Tavares; Macedo, Williams Jorge da Cruz; Brasil, Davi Do Socorro Barros; Silva, Carlos Henrique Tomich de Paula da; Silva Hage-Melim, Lorane Izabel da

    2015-01-01

    Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r(2)), explained variance (adjusted R(2)), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays.

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

    Directory of Open Access Journals (Sweden)

    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. The washout effect during laundry on benzothiazole, benzotriazole, quinoline, and their derivatives in clothing textiles.

    Science.gov (United States)

    Luongo, Giovanna; Avagyan, Rozanna; Hongyu, Ren; Östman, Conny

    2016-02-01

    In two previous papers, the authors have shown that benzothiazole, benzotriazole, quinoline, and several of their derivatives are widespread in clothing textile articles. A number of these compounds exhibit allergenic and irritating properties and, due to their octanol-water partition coefficient, are prone to be absorbed by the skin. Moreover, they are slightly soluble in water, which could make washing of clothes a route of emission into the environment. In the present study, the washout effect of benzothiazole, benzotriazole, quinoline, and some of their derivatives has been investigated. Twenty-seven textile samples were analyzed before, as well as after five and ten times of washing. The most abundant analyte was found to be benzothiazole, which was detected in 85 % of the samples with an average concentration of 0.53 μg/g (median 0.44 μg/g), followed by quinoline, detected in 81 % of the samples with an average concentration of 2.42 μg/g (median 0.21 μg/g). The average decrease in concentration for benzothiazoles was 50 % after ten times washing, while it was around 20 % for quinolines. The average emission to household wastewater of benzothiazoles and quinolines during one washing (5 kg of clothes made from polyester materials) was calculated to 0.5 and 0.24 g, respectively. These results strongly indicate that laundering of clothing textiles can be an important source of release of these compounds to household wastewater and in the end to aquatic environments. It also demonstrates a potential source of human exposure to these chemicals since considerable amounts of the compounds remain in the clothes even after ten times of washing.

  19. ACUTE AND CHRONIC TOXICITY OF PHENYL QUINOLINE ON WATER FLEA DAPHNIA MAGNA

    Directory of Open Access Journals (Sweden)

    Hildebrando Ayala

    2012-06-01

    Full Text Available The aquatic ecotoxicological determination of phytonematicide products using the zooplanktonic cladoceran Daphnia magna is important for environmental risk assessment. Evaluations were made of the acute median lethal concentration (LC50 of phenyl quinoline on D. magna, that was 4.12 ug i.a. L-1 at 48 h of exposure. The chronic effects of phenyl quinoline in the mortality rate of the cladoceran D. magna at 17 d of exposure, with 0.18 ug ai L-1 of LOEC (Lowest Observed Effect Concentration and 0.072 ug ai L-1 of NOEC (No Observed Effect Concentration were determined. Evaluations of the chronic effect of phenyl quinoline on three parameters of growth of D. magna (total length, antenna length and caudal length to 17 d of exposure, only showed significant differences in length of the antenna between the control and 0.072 ug ai L-1 been this the value of LOEC and thus the lower concentration 0.0288 ug ai L-1, the NOEC value for phenyl quinoline. The ratio between acute and chronic toxicity (RAC for the relationship showed acute 48 h exposure on mortality NOEC 17 d a value of 57.22, and for the ratio of acute NOEC on of the length of the antenna to 17 d was a value of 143. The environmental risk assessment (ERA shows that the PEC (Probable Effect Concentration / PNEC (Predicted No-Effect Concentration for acute assay was 582 524 and for the PEC / PNEC for chronic test was 83 333 333. These results demonstrate that phenyl quinoline has a high impact on aquatic biota represented by the trophic level that belongs to D. magna, and therefore shows that the substance is a candidate for a comprehensive ecotoxicological assessment.

  20. Enhanced methanol utilization in direct methanol fuel cell

    Science.gov (United States)

    Ren, Xiaoming; Gottesfeld, Shimshon

    2001-10-02

    The fuel utilization of a direct methanol fuel cell is enhanced for improved cell efficiency. Distribution plates at the anode and cathode of the fuel cell are configured to distribute reactants vertically and laterally uniformly over a catalyzed membrane surface of the fuel cell. A conductive sheet between the anode distribution plate and the anodic membrane surface forms a mass transport barrier to the methanol fuel that is large relative to a mass transport barrier for a gaseous hydrogen fuel cell. In a preferred embodiment, the distribution plate is a perforated corrugated sheet. The mass transport barrier may be conveniently increased by increasing the thickness of an anode conductive sheet adjacent the membrane surface of the fuel cell.

  1. Fermentation of methanol in the sheep rumen.

    OpenAIRE

    Pol, A.; Demeyer, D. I.

    1988-01-01

    Sheep fed a hay-concentrate diet were adapted to pectin administration and ruminal infusion of methanol. Both treatments resulted in a strong increase in the rate of methanogenesis from methanol. Quantitative data show that methanol was exclusively converted into methane. Treatments did not influence ruminal volatile fatty acid percentages.

  2. The fate of methanol in anaerobic bioreactors.

    NARCIS (Netherlands)

    Florencio, L.

    1994-01-01

    Methanol is an important component of certain industrial wastewaters. In anaerobic environments, methanol can be utilized by methanogens and acetogens. In wastewater treatment plants, the conversion of methanol into methane is preferred because this conversion is responsible for chemical oxygen dema

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

    Science.gov (United States)

    Kalani, Komal; Agarwal, Jyoti; Alam, Sarfaraz; Khan, Feroz; Pal, Anirban; Srivastava, Santosh Kumar

    2013-01-01

    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.

  4. Studies on adsorption and corrosion inhibitive properties of quinoline derivatives on N80 steel in 15% hydrochloric acid

    Directory of Open Access Journals (Sweden)

    K.R. Ansari

    2016-12-01

    Full Text Available This paper deals with the N80 steel corrosion protection study in 15% HCl which was carried by three quinoline derivatives namely 3-acetyl-1-(4-methylbenzylideneamino quinolin-2-one (AQ-1, 3-acetyl-1-(4 hydroxy benzylideneamino quinolin-2-one (AQ-2, 3-acetyl-1-(3-nitrobenzylideneamino quinolin-2(1H-one (AQ-3 using gravimetric, electrochemical, and quantum chemical studies. Tafel polarization showed that AQs are mixed type inhibitors but dominantly affect cathodic reaction more. The observed results reveal that AQ-1 is the best inhibitor. All the three inhibitors were found to obey the Langmuir adsorption isotherm. Scanning electron microscopy (SEM micrographs supports the protection of the N80 steel by AQs. Quantum chemical study reveals that the inhibitors have a tendency to get protonated and this protonated form has greater tendency to get adsorbed onto the N80 steel surface.

  5. Genetic relationship of organic bases of the quinoline and isoquinoline series from lignite semicoking tars with the initial biological material

    Energy Technology Data Exchange (ETDEWEB)

    Platonov, V.V.; Proskuryakov, V.A.; Podshibyakin, S.I.; Domogatskii, V.V.; Shvykin, A.Y.; Shavyrina, O.A.; Chilachava, K.B. [Leo Tolstoy State Pedagog University, Tula (Russian Federation)

    2002-07-01

    The genetic relationship of quinoline and isoquinoline compounds present in semicoking tars of Kimovsk lignites (near-Moscow fields) with the initial vegetable material is discussed. Transformation pathways of the native compounds in the course of lignite formation are suggested.

  6. Methanol production method and system

    Science.gov (United States)

    Chen, Michael J.; Rathke, Jerome W.

    1984-01-01

    Ethanol is selectively produced from the reaction of methanol with carbon monoxide and hydrogen in the presence of a transition metal carbonyl catalyst. Methanol serves as a solvent and may be accompanied by a less volatile co-solvent. The solution includes the transition metal carbonyl catalysts and a basic metal salt such as an alkali metal or alkaline earth metal formate, carbonate or bicarbonate. A gas containing a high carbon monoxide to hydrogen ratio, as is present in a typical gasifer product, is contacted with the solution for the preferential production of ethanol with minimal water as a byproduct. Fractionation of the reaction solution provides substantially pure ethanol product and allows return of the catalysts for reuse.

  7. Withanolide artifacts formed in methanol.

    Science.gov (United States)

    Cao, Cong-Mei; Zhang, Huaping; Gallagher, Robert J; Timmermann, Barbara N

    2013-11-22

    Methanol solutions of the main withanolides (6-8) naturally present in Physalis longifolia yielded five artificial withanolides (1-5), including three new compounds (1-3). Withanolides 1 and 2 were identified as intramolecular Michael addition derivatives, while withanolides 3-5 were the result of intermolecular Michael addition. A comprehensive literature investigation was conducted to identify potential withanolide Michael addition artifacts isolated from Solanaceous species to date.

  8. Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2.

    Science.gov (United States)

    Syniugin, Anatolii R; Ostrynska, Olga V; Chekanov, Maksym O; Volynets, Galyna P; Starosyla, Sergiy A; Bdzhola, Volodymyr G; Yarmoluk, Sergiy M

    2016-01-01

    In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 μM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.

  9. 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.

  10. The toxicity of inhaled methanol vapors

    Energy Technology Data Exchange (ETDEWEB)

    Kavet, R.; Nauss, K.M. (Environmental Research Information, Inc., Palo Alto, CA (USA))

    1990-01-01

    Methanol could become a major automotive fuel in the U.S., and its use may result in increased exposure of the public to methanol vapor. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures. Acute methanol toxicity evolves in a well-understood pattern and consists of an uncompensated metabolic acidosis with superimposed toxicity to the visual system. The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. In short, the toxic syndrome sets in if formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at the anticipated levels of exposure to automotive methanol vapor.117 references.

  11. Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites.

    Science.gov (United States)

    Gero, A M; Scott, H V; O'Sullivan, W J; Christopherson, R I

    1989-04-01

    The infection of human erythrocytes by two strains of the human malarial parasite, Plasmodium falciparum (FCQ-27 or the multi-drug-resistant strain K-1), markedly changed the transport characteristics of the nucleosides, adenosine and tubercidin, compared to uninfected erythrocytes. A component of the transport of these nucleosides was insensitive to the classical mammalian nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR). In vitro studies with tubercidin demonstrated ID50 values of 0.43 and 0.51 microM for FCQ-27 and K-1, respectively. In addition, the nucleoside transport inhibitors NBMPR, nitrobenzylthioguanosine (NBTGR), dilazep and dipyridamole also independently exhibited antimalarial activity in vitro. The combination of tubercidin and NBMPR or NBTGR in vitro demonstrated synergistic activity, whilst tubercidin together with dilazep or dipyridamole showed subadditive activity. Analysis by HPLC indicated that NBMPR could permeate the infected cell membrane and provided evidence for the catabolism of NBMPR in vitro, with subsequent alteration of the purine pool in the infected erythrocyte. These observations further indicated the possibility of the utilization of cytotoxic nucleosides against P. falciparum infection in conjunction with a nucleoside transport inhibitor to protect the host tissue.

  12. Small molecule screen for candidate antimalarials targeting Plasmodium Kinesin-5.

    Science.gov (United States)

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

    2014-06-06

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Perspective for the production of antimalarial drugs in Brazil.

    Science.gov (United States)

    Gilbert, B

    1992-01-01

    There appears to be no chemical manufacture of antimalarial drugs in Brazil. Technology at the laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloguanil, 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 registered in the SDI by Roche. A project to produce artemisinine and its derivatives 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 soft-drink production. Since malarial treatment falls largely within the responsibility 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 scarcely viable at the present moment.

  15. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  16. PEG-SO3H as a catalyst in aqueous media: A simple, proficient and green approach for the synthesis of quinoline derivatives

    Indian Academy of Sciences (India)

    M A Nasseri; S A Alavi; B Zakerinasab

    2013-01-01

    A convenient and efficient method was developed for the synthesis of quinolines, an important class of potentially bioactive compounds. The quinoline derivatives were prepared in water, an excellent solvent in terms of environmental impact and with reduced waste production. PEG-SO3H effectively catalysed the one-pot synthesis of quinolines by the condensation of -aminoaryl ketones and carbonyl compound with high yields (75-95%). The compounds were isolated by simple filtration in a high purity form.

  17. Metabolic methanol: molecular pathways and physiological roles.

    Science.gov (United States)

    Dorokhov, Yuri L; Shindyapina, Anastasia V; Sheshukova, Ekaterina V; Komarova, Tatiana V

    2015-04-01

    Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde.

  18. Endogenous methanol regulates mammalian gene activity.

    Directory of Open Access Journals (Sweden)

    Tatiana V Komarova

    Full Text Available We recently showed that methanol emitted by wounded plants might function as a signaling molecule for plant-to-plant and plant-to-animal communications. In mammals, methanol is considered a poison because the enzyme alcohol dehydrogenase (ADH converts methanol into toxic formaldehyde. However, the detection of methanol in the blood and exhaled air of healthy volunteers suggests that methanol may be a chemical with specific functions rather than a metabolic waste product. Using a genome-wide analysis of the mouse brain, we demonstrated that an increase in blood methanol concentration led to a change in the accumulation of mRNAs from genes primarily involved in detoxification processes and regulation of the alcohol/aldehyde dehydrogenases gene cluster. To test the role of ADH in the maintenance of low methanol concentration in the plasma, we used the specific ADH inhibitor 4-methylpyrazole (4-MP and showed that intraperitoneal administration of 4-MP resulted in a significant increase in the plasma methanol, ethanol and formaldehyde concentrations. Removal of the intestine significantly decreased the rate of methanol addition to the plasma and suggested that the gut flora may be involved in the endogenous production of methanol. ADH in the liver was identified as the main enzyme for metabolizing methanol because an increase in the methanol and ethanol contents in the liver homogenate was observed after 4-MP administration into the portal vein. Liver mRNA quantification showed changes in the accumulation of mRNAs from genes involved in cell signalling and detoxification processes. We hypothesized that endogenous methanol acts as a regulator of homeostasis by controlling the mRNA synthesis.

  19. An experimental screen for quinoline/fumaric acid salts and co-crystals

    DEFF Research Database (Denmark)

    Beko, S. L.; Schmidt, M. U.; Bond, A. D.

    2012-01-01

    An experimental screen has been carried out for salts and co-crystals of quinoline (C9H7N) and fumaric acid (C4H4O4), including solution-based co-crystallisation from a variety of solvents, solvent-assisted and solvent-free co-grinding, and direct co-crystallisation of the starting materials....... Characterised products include the previously published 1 : 1 salt, C9H8N+center dot C4H3O4-, and a new 2 : 1 quinoline/fumaric acid co-crystal, (C9H7N)(2)center dot C4H4O4. Attempts to influence the crystallisation outcome by addition of 6-methylquinoline yielded a second co-crystal, also with an inherent 2...

  20. Syntheses and anti-microbial evaluation of new quinoline scaffold derived pyrimidine derivatives

    Directory of Open Access Journals (Sweden)

    Shikha S. Dave

    2016-09-01

    Full Text Available A series of diversely substituted chalcones derived from a quinoline scaffold, e.g. (E-3-(2-chloroquinolin-3-yl-1-(2-hydroxyphenyl prop-2-en-1-one and its pyrimidine analogues e.g. 2-[2-amino-6-(2-chloroquinolin-3-yl-5,6-dihydropyrimidin-4-yl]phenols have been prepared by condensation of 2-chloro-3-formyl quinoline with differently substituted 2-hydroxy acetophenones and further treatment with guanidine carbonate. All the newly synthesized compounds have been evaluated for their in vitro growth inhibitory activity against Escherichia coli, Pseudomonas vulgaris, Bacillus subtilis, Staphylococcus aureus, Staphylococcus typhi, Candida albicans, Aspergillus niger and Pseudomonas chrysogenum.

  1. Synthesis, crystal structure, optical and electrochemical properties of 9,10-dihydroxybenzo[ℎ]quinoline

    Indian Academy of Sciences (India)

    Kew-Yu Chen; Hsing-Yang Tsai; Wei-Chi Lin; Hou-Hsein Chu; Yu-Ching Weng; Chih-Chieh Chan

    2014-07-01

    9,10-Dihydroxybenzo[ℎ]quinoline (1), a 10-hydroxybenzo[ℎ]quinoline (2) derivative, was synthesized and characterized by 1H NMR, 13C NMR, UV-vis and fluorescence spectra, and single-crystal X-ray diffraction. Compound 1 possesses an intramolecular six-membered-ring hydrogen bond, from which excitedstate intramolecular proton transfer (ESIPT) takes place from the phenolic proton to the pyridinic nitrogen, resulting in a proton-transfer tautomer emission of 650 nm in dichloromethane. Its molecular geometry in the ground state has also been calculated using density functional theory (DFT) at the B3LYP/6-31G∗∗ level and compared with its crystal structure. Results show that the optimized geometry can well reproduce the crystal structure. Furthermore, both absorption and emission spectra of 1 and 2 were calculated using time-dependent DFT (TD-DFT) calculations, and were in good agreement with the experimental results.

  2. Optimization of the Separation of Quinolines in Micellar Liquid Chromatography by Experimental Design and Regression Models

    Institute of Scientific and Technical Information of China (English)

    HADJMOHAMMADI,M.R.; KAMEL,K.

    2008-01-01

    The chemometrics approach was applied to the optimization of separation of quinolines in micellar liquid tigated by means of multivariate analysis. The factors considered were the concentration of sodium dodecyl sulfate (SDS), the organic modifier concentration and the length of its alkyl chain, and pH of the mobile phase. The ex-periments were performed according to a face centered cube response surface experimental design. In order to op-timize the separation a Pareto-optimality method was employed. The models were verified, because a good agree-ment was observed between the predicted and experimental values of the chromatographic response function in the optimal condition. The obtained regression models were characterized by both descriptive and predictive ability (R2≥0.97 and R2cv≥0.92) and allowed the chromatographic separation of the quinolines with a good resolution and a total analysis time of 50 min.

  3. Towards a methanol economy based on homogeneous catalysis: methanol to H2 and CO2 to methanol.

    Science.gov (United States)

    Alberico, E; Nielsen, M

    2015-04-21

    The possibility to implement both the exhaustive dehydrogenation of aqueous methanol to hydrogen and CO2 and the reverse reaction, the hydrogenation of CO2 to methanol and water, may pave the way to a methanol based economy as part of a promising renewable energy system. Recently, homogeneous catalytic systems have been reported which are able to promote either one or the other of the two reactions under mild conditions. Here, we review and discuss these developments.

  4. Ionic liquid catalyzed convenient synthesis of imidazo[1,2-a]quinoline under sonic condition

    Energy Technology Data Exchange (ETDEWEB)

    Patel, Devji S.; Avalani, Jemin R.; Raval, Dipak K., E-mail: dipanalka@yahoo.com [Department of Chemistry, Sardar Patel University Gujarat (India)

    2012-10-15

    An efficient protocol for the synthesis of imidazo[1,2-a]quinoline from aldehydes, enaminones, and malononitrile using 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate ([DBU][Ac]) as a catalyst under ultrasound irradiation is described. Compared with other methods, this new method has the advantages of easier work-up, milder reaction conditions, high yields and environmentally benign procedure. (author)

  5. Diiodido[methyl 2-(quinolin-8-yloxyacetate-κN]mercury(II

    Directory of Open Access Journals (Sweden)

    Yu-Hong Wang

    2012-08-01

    Full Text Available In the title mononuclear complex, [HgI2(C12H11NO3], the HgII ion has a distorted trigonal–planar coordination sphere defined by two I− anions and the N atom of a methyl 2-(quinolin-8-yloxyacetate ligand. In the crystal, face-to-face π–π stacking interactions, with a centroid–centroid distance of 3.563 (9 Å, are observed.

  6. ANTICANCER ACTIVITY AND DRUG LIKELINESS OF QUINOLINE THROUGH INSILICO DOCKING AGAINST CERVICAL AND LIVER CANCER RECEPTORS

    OpenAIRE

    M.P.Santhi, G.Bupesh* , V.SenthilKumar*, K.Meenakumari, K.Prabhu, S.Sugunthan, E.Manikandan, K.Saravanan

    2016-01-01

    The oncogenic protein receptors were key molecular targets for cancers. Especially in tumor cells, they were frequently transformed or mutated at abnormal states. The normal cells encounter a programmed cell death (apoptosis). It is an imperative and striking focus for anticancer medication advancement and disclosure. Biophytum sensitivum is a medicinal plant rich in quinoline and amentoflavone.  The aqueous extract of plant was still administered for various ailments in naturopathy medicines...

  7. The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain

    OpenAIRE

    Swathy, S. S.; Indira, M.

    2010-01-01

    One of the mechanisms of neurotoxicity is the induction of oxidative stress. There is hardly any cure for neurotoxicity in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. The aim of our study was to evaluate the effect of Ksheerabala on quinolinic acid-induced toxicity in rat brain. The o...

  8. Antidiarrheal and thrombolytic effects of methanol extract of Wikstroemia indica (L. C. A. Mey leaves

    Directory of Open Access Journals (Sweden)

    Md Khalilur Rahman

    2015-01-01

    Full Text Available Context: Medicinal plants contribute as potential sources of therapeutic uses. Wikstroemia indica, a traditional medicinal plant, has long been used as anti-inflammatory, antiviral, antimalarial, anti-mitotic, antitumor, and anti-HIV in different parts of the world. Aims: The aim was to investigate the antidiarrheal and thrombolytic effect of W. indica leaf extract. Settings and Design: Sample collection, identification, solvent extraction, and crude extract preparations were led to evaluate the antidiarrheal effect in in vivo model and the thrombolytic effect in in vitro model. Materials and Methods: Castor oil-induced diarrhea and enteropooling assays and gastrointestinal motility tests were used to examine the in vivo antidiarrheal activity in Wistar albino rat. In vitro clot lysis model was undertaken to investigate the thrombolytic action of the extract. Data were analyzed using statistical software (Statistical Package for Social Science, SPSS, version 19.0, SPSS Inc., USA. Results: The diarrheal episode was inhibited by 18.64% and 28.96% for the methanol extract at the doses of 200 and 400 mg/kg, respectively. The extract significantly (P < 0.05 reduced the intestinal volume and intestinal transit in comparison to control. The extract also reduced the rate of defecation, accumulation of fluid, and transit of charcoal oil. The extract showed a moderate thrombolytic effect compared to the reference control. Conclusion: Methanol extract of W. indica might be triggered the premonition of novel drug discovery in the future due to its antidiarrheal effect in the animal model.

  9. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure

    Directory of Open Access Journals (Sweden)

    Neelima Mishra

    2016-01-01

    Interpretation & conclusion: 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.

  10. Cost-effectiveness of pre-referral antimalarial, antibacterial, and combined rectal formulations for severe febrile illness.

    OpenAIRE

    Buchanan, J.; Mihaylova, B.; Gray, A; White, N

    2010-01-01

    BACKGROUND: Malaria and bacterial infections account for most infectious disease deaths in developing countries. Prompt treatment saves lives, but rapid deterioration often prevents the use of oral therapies; delays in reaching health facilities providing parenteral interventions are common. Rapidly and reliably absorbed antimalarial/antibacterial rectal formulations used in the community could prevent deaths and disabilities. Rectal antimalarial treatments are currently available; rectal ant...

  11. A tetranuclear cadmium(II) complex based on the 2-(quinolin-8-yloxy)acetonitrile ligand.

    Science.gov (United States)

    Liu, Ming-Liang; Ye, Qiong

    2013-01-01

    The hydrothermal reaction of 2-(quinolin-8-yloxy)acetonitrile and Cd(ClO(4))(2) yielded the noncentrosymmetric coordination complex tetrakis[μ-2-(quinolin-8-yloxy)acetato]tetrakis[μ-2-(quinolin-8-yloxy)acetonitrile]tetracadmium tetrakis(perchlorate) dihydrate, [Cd(4)(C(11)H(8)NO(3))(4)(C(11)H(8)N(2)O)(4)](ClO(4))(4)·2H(2)O. The local coordination environment around the Cd(II) cation can be best described as a capped octahedron defined by two N atoms and five O atoms from three ligands. The Cd(II) cations are linked by the ligands with Cd-O-Cd and Cd-O-C-C-O-Cd bridges, forming tetranuclear units, there being two independent tertranuclear units in the structure. The fourfold rotoinversion centre sits at the centre of each Cd(4) core. The two perchlorate anions in the asymmetric unit are linked by the water molecule through O-H...O hydrogen bonds.

  12. Active-site models for complexes of quinolinate synthase with substrates and intermediates

    Energy Technology Data Exchange (ETDEWEB)

    Soriano, Erika V.; Zhang, Yang; Colabroy, Keri L.; Sanders, Jennie M.; Settembre, Ethan C.; Dorrestein, Pieter C.; Begley, Tadhg P.; Ealick, Steven E., E-mail: see3@cornell.edu [Cornell University, Ithaca, NY 14853-1301 (United States)

    2013-09-01

    Structural studies of quinolinate synthase suggest a model for the enzyme–substrate complex and an enzyme–intermediate complex with a [4Fe–4S] cluster. Quinolinate synthase (QS) catalyzes the condensation of iminoaspartate and dihydroxyacetone phosphate to form quinolinate, the universal precursor for the de novo biosynthesis of nicotinamide adenine dinucleotide. QS has been difficult to characterize owing either to instability or lack of activity when it is overexpressed and purified. Here, the structure of QS from Pyrococcus furiosus has been determined at 2.8 Å resolution. The structure is a homodimer consisting of three domains per protomer. Each domain shows the same topology with a four-stranded parallel β-sheet flanked by four α-helices, suggesting that the domains are the result of gene triplication. Biochemical studies of QS indicate that the enzyme requires a [4Fe–4S] cluster, which is lacking in this crystal structure, for full activity. The organization of domains in the protomer is distinctly different from that of a monomeric structure of QS from P. horikoshii [Sakuraba et al. (2005 ▶), J. Biol. Chem.280, 26645–26648]. The domain arrangement in P. furiosus QS may be related to protection of cysteine side chains, which are required to chelate the [4Fe–4S] cluster, prior to cluster assembly.

  13. Lack of doxycycline antimalarial prophylaxis impact on Staphylococcus aureus tetracycline resistance.

    Science.gov (United States)

    Mende, Katrin; Beckius, Miriam L; Zera, Wendy C; Yu, Xin; Li, Ping; Tribble, David R; Murray, Clinton K

    2016-10-01

    There is concern that susceptibility of Staphylococcus aureus to tetracyclines may decrease due to use of antimalarial prophylaxis (doxycycline). We examined characteristics related to tetracycline resistance, including doxycycline exposure, in S. aureus isolates collected via admission surveillance swabs and inpatient clinical cultures from United States military personnel injured during deployment (June 2009-January 2012). Tetracycline class resistance was determined using antimicrobial susceptibility testing. The first S. aureus isolate from 168 patients were analyzed, of which 38 (23%) isolates were resistant to tetracyclines (class). Tetracycline-resistant isolates had a higher proportion of resistance to clindamycin (P=0.019) compared to susceptible isolates. There was no significant difference in tetracycline resistance between isolates collected from patients with and without antimalarial prophylaxis; however, significantly more isolates had tet(M) resistance genes in the doxycycline exposure group (P=0.031). Despite 55% of the patients receiving doxycycline as antimalarial prophylaxis, there was no association with resistance to tetracyclines.

  14. Resistance to antimalarial drugs: An endless world war against Plasmodium that we risk losing.

    Science.gov (United States)

    Severini, Carlo; Menegon, Michela

    2015-06-01

    The objective of this review was to describe the 'state of the art' of Plasmodium falciparum resistance to the main antimalarial drugs. A brief note on Plasmodium vivax is also included. Resistance of P. falciparum to the various antimalarials has a long history of hits and misses. During the last 60 years, the pace at which this parasite has developed resistance to antimalarial drugs has exceeded the pace at which new drugs have been developed. In the last decade, the introduction of artemisinin-based combination therapies (ACTs) as a first-line drug treatment for non-complicated P. falciparum malaria had led to extraordinary results in disease control, especially in sub-Saharan Africa. However, the emergence and spread of resistance to artemisinin in Southeast Asia jeopardise these results. In conclusion, the possible spread of artemisinin resistance in Africa should be considered as an epochal disaster.

  15. 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.

  16. 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

    BACKGROUND: In recent years it has been controversially discussed in the literature if smoking is associated with the activity of cutaneous lupus erythematosus (CLE) and the efficacy of antimalarial agents. OBJECTIVES: To investigate the influence of smoking on disease severity and antimalarial...... treatment in patients with CLE using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). METHODS: A total of 1002 patients (768 female, 234 male) with different CLE subtypes were included in this cross-sectional study, which was performed in 14 different countries....... 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...

  17. Excited-state intramolecular proton transfer (ESIPT) inspired azole-quinoline based fluorophores: Synthesis and photophysical properties study

    Energy Technology Data Exchange (ETDEWEB)

    Padalkar, Vikas S.; Sekar, Nagaiyan, E-mail: n.sekar@ictmumbai.edu.in

    2014-11-15

    7-Hydroxy-3-(4-nitrophenyl)quinoline-6-carboxylic acid was obtained by the condensation reaction of p-amino salicylic acid and 4-nitrophenylmalonadialdehyde which was obtained from phenylacetonitrile through nitration, hydrolysis and Vilsmeier reaction. 7-Hydroxy-3-(4-nitrophenyl) quinoline-6-carboxylic acid was condensed with different o-aminophenols or o-aminothiophenol in ethanol in the presence of phosphorustrichloride. Synthesized quinoline contained benzimidazole and benzothiazole moieties. Photophysical behaviors of these compounds in solvents of different polarities were studied using UV–vis and fluorescence spectroscopy. The compounds showed single absorption in all the studied solvents. The dual emissions (normal emission and ESIPT emission) as well as large Stokes' shift emission pattern were observed for the synthesized fluorophores. The photophysical study shows that the emission properties of the compounds depend on the solvent polarity. The photophysical properties of the compounds were compared with structurally analogous ESIPT quinoline. Thermal stability of the compounds was studied using thermogravimetric analysis and results show that compounds are thermally stable up to 300 °C. The synthesized quinoline derivatives were characterized using elemental analysis, FT-IR and {sup 1}H –NMR, {sup 13}C –NMR spectroscopy and mass spectral analysis. - Highlights: • First and unique study of quinoline derivatives contain ESIPT azole unit at 6-position and hydroxyl group at 7-position. • Compounds are fluorescent with considerable quantum yields. • All compounds showed absorption in ultraviolet region and emission in visible region with large Stokes' shift. • The photophysical properties of new compounds were compared with reported ESIPT quinoline analogous.

  18. Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector

    Directory of Open Access Journals (Sweden)

    Snow Robert W

    2005-07-01

    Full Text Available Abstract Background Although an important source of treatment for fevers, little is known about the structure of the retail sector in Africa with regard to antimalarial drugs. This study aimed to assess the range, costs, sources and registration of antimalarial drugs in the Kenyan retail sector. Methods In 2002, antimalarial drug registration and trade prices were established by triangulating national registration lists, government gazettes and trade price indices. Data on registration status and trade prices were compared with similar data generated through a retail audit undertaken among 880 randomly sampled retailers in four districts of Kenya. Results Two hundred and eighteen antimalarial drugs were in circulation in Kenya in 2002. These included 65 "sulfur"-pyrimethamine (sulfadoxine-pyrimethamine and sulfalene-pyrimethamine (SP, the first-line recommended drug in 2002 and 33 amodiaquine (AQ, the second-line recommended drug preparations. Only half of SP and AQ products were registered with the Pharmacy and Poisons Board. Of SP and AQ brands at district level, 40% and 44% were officially within legal registration requirements. 29% of retailers at district level stocked SP and 95% stocked AQ. The retail price of adult doses of SP and AQ were on average 0.38 and 0.76 US dollars, 100% and 347% higher than trade prices from manufacturers and importers. Artemether-lumefantrine, the newly announced first-line recommended antimalarial drug in 2004, was found in less than 1% of all retail outlets at a median cost of 7.6 US dollars. Conclusion There is a need to ensure that all antimalarial drugs are registered with the Pharmacy and Poisons Board to facilitate a more stringent post-marketing surveillance system to ensure drugs are safe and of good quality post-registration.

  19. 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

  20. 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

  1. Improvement of biodiesel methanol blends

    Directory of Open Access Journals (Sweden)

    Y. Datta Bharadwaz

    2016-06-01

    Full Text Available The main objective of this work was to improve the performance of biodiesel–methanol blends in a VCR engine by using optimized engine parameters. For optimization of the engine, operational parameters such as compression ratio, fuel blend, and load are taken as factors, whereas performance parameters such as brake thermal efficiency (Bth and brake specific fuel consumption (Bsfc and emission parameters such as carbon monoxide (CO, unburnt hydrocarbons (HC, Nitric oxides (NOx and smoke are taken as responses. Experimentation is carried out as per the design of experiments of the response surface methodology. Optimization of engine operational parameters is carried out using Derringers Desirability approach. From the results obtained it is inferred that the VCR engine has maximum performance and minimum emissions at 18 compression ratio, 5% fuel blend and at 9.03 kg of load. At this optimized operating conditions of the engine the responses such as brake thermal efficiency, brake specific fuel consumption, carbon monoxide, unburnt hydrocarbons, nitric oxide, and smoke are found to be 31.95%, 0.37 kg/kW h, 0.036%, 5 ppm, 531.23 ppm and 15.35% respectively. It is finally observed from the mathematical models and experimental data that biodiesel methanol blends have maximum efficiency and minimum emissions at optimized engine parameters.

  2. Retinal toxicity induced by antimalarial drugs: literature review and case report.

    Science.gov (United States)

    Garza-Leon, Manuel; Flores-Alvarado, Diana Elsa; Muñoz-Bravo, Juan Manuel

    2016-06-17

    Antimalarial drugs are widely used in several countries for control of rheumatologic diseases such as systemic lupus erythematosus and rheumatoid arthritis. They are still used in Mexico because of their low cost and few secondary effects, most of which are mild and reversible. Even so, at an ophthalmological level, they could produce irreversible visual damage, which is why it is important to have ophthalmological evaluation and proper follow up. We present a clinical case as an example of characteristic ophthalmological findings as well as risk factors for retinal toxicity. We then discuss guidelines for diagnosis and follow up of patients who use antimalarial drugs for the treatment of rheumatologic illnesses.

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

    Directory of Open Access Journals (Sweden)

    Dismas Baza

    2011-02-01

    Full Text Available Abstract Background 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. Methods 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. Results 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

  4. A reaction-diffusion system modeling the spread of resistance to an antimalarial drug.

    Science.gov (United States)

    Bacaer, Nicolas; Sokhna, Cheikh

    2005-04-01

    A mathematical model representing the difusion of resistance to an antimalarial drug is developed. Resistance can spread only when the basic reproduction number of the resistant parasites is bigger than the basic reproduction number of the sensitive parasites (which depends on the fraction of infected people treated with the antimalarial drug). Based on a linearization study and on numerical simulations, an expression for the speed at which resistance spreads is conjectured. It depends on the ratio of the two basic reproduction numbers, on a coefficient representing the difusion of mosquitoes, on the death rate of mosquitoes infected by resistant parasites, and on the recovery rate of nonimmune humans infected by resistant parasites.

  5. 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

  6. 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.

  7. An expeditious I sub(2)-catalyzed entry into 6H-indolo[2,3-b]quinoline system of cryptotackieine

    Digital Repository Service at National Institute of Oceanography (India)

    Parvatkar, P.T; Parameswaran, P.S.; Tilve, S.G.

    A synthesis of a series of novel 6H-indolo[2,3-b]- quinolines with different substituents on the quinoline ring is described. The method involves reaction of indole-3-carboxyaldehyde with aryl amines in the presence of a catalytic amount of iodine...

  8. Developmental and Reproductive Toxicology of Methanol

    Science.gov (United States)

    Methanol is a high production volume chemical used as a feedstock for chemical syntheses and as a solvent and fuel additive. Methanol is acutely toxic to humans, causing acidosis, blindness in death at high dosages, but its developmental and reproductive toxicity in humans is poo...

  9. Hydrogenation of carbon dioxide for methanol production

    NARCIS (Netherlands)

    Ham, van der A.G.J.; Berg, van den H.; Benneker, A.; Simmelink, G.; Timmer, J.; Weerden, van S.

    2012-01-01

    A process for the hydrogenation of CO2 to methanol with a capacity of 10 kt/y methanol is designed in a systematic way. The challenge will be to obtain a process with a high net CO2 conversion. From initially four conceptual designs the most feasible is selected and designed in more detail. The feed

  10. Synthesis of 5-iodopyrrolo[1,2-a]quinolines and indolo[1,2-a]quinolines via iodine-mediated electrophilic and regioselective 6-endo-dig ring closure.

    Science.gov (United States)

    Verma, Akhilesh Kumar; Shukla, Satya Prakash; Singh, Jaspal; Rustagi, Vineeta

    2011-07-15

    The endo-cyclic ring closure of 1-(2-(substituted ethynyl)phenyl)-1H-pyrroles 3a-t and 1-(2-(substituted ethynyl)phenyl)-H-indole 4a-o mediated by Lewis acid (I(2)) under mild conditions afforded substituted 5-iodopyrrolo[1,2-a]quinolines 5a-t and 5-iodoindolo[1,2-a]quinolines 6a-o in good to excellent yields. The reaction shows selective C-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized product. Iodo derivatives of pyrrolo- and indoloquinolines allow functional group diversification on the quinoline nucleus, which proves to be highly advantageous for structural and biological activity assessments.

  11. Embryotoxicity and toxicokinetics of the antimalarial artesunate in rats.

    Science.gov (United States)

    Chung, Moon-Koo; Yu, Wook-Joon; Lee, Jin-Soo; Lee, Jong-Hwa

    2013-03-01

    This study was conducted to investigate the potential embryo-fetal toxicity and toxicokinetics of the antimalarial agent artesunate (ARTS) in Sprague-Dawley rats. Pregnant rats were administered ARTS daily from gestational day 6~15 via oral gavage, at test doses of 0, 2, 4, or 8 mg/kg (22 females per group). The fetuses were examined for external, visceral, and skeletal abnormalities on gestational day 20. With regard to the dams, there were no deaths, treatment-related clinical signs, changes in body weight, or food intake in any of the treatment groups. There were no treatment-related gross findings at necropsy in any treatment group. In the 8 mg/kg group, there was a decrease in gravid uterine weight and in the weight of female fetuses. There was also an increase in fetal deaths (primarily late resorptions) and an increase in post-implantation losses (37%) at 8 mg/kg. An increase in the incidence of visceral and skeletal variations at 4 and 8 mg/kg was observed. These defects included minor changes in the appearance of the kidney and thymus, as well as absent ribs or thoracic vertebrae. Toxicokinetics were assessed in a parallel study, using 4 mated females per group. Using liquid chromatography-mass spectrometry (LC-MS) analysis, the concentration of ARTS and its metabolite dihydroartemisinin (DHA) were quantified in plasma from rats on gestational days 5, 6, 10, and 15. Amniotic fluid was assayed for ARTS and DHA on gestational day 15. There was evidence of rapid conversion of ARTS to the metabolite DHA in maternal plasma, since ARTS could not be consistently detected in plasma at the three doses tested. ARTS and DHA were not detected in amniotic fluid at gestational day 15, indicating limited placental transfer of the two agents. The embryofetal no-observable-adverse-effect level (NOAEL) of the test item was considered to be 8 mg/kg/day for dams, and 2 mg/kg/day for embryo-fetal development.

  12. A search for extragalactic methanol masers

    CERN Document Server

    Ellingsen, S P; Whiteoak, J B; Vaile, R A; McCulloch, P M; Price, M

    1994-01-01

    A sensitive search for 6.7--GHz methanol maser emission has been made towards 10 galaxies that have yielded detectable microwave molecular--line transitions. These include several which show OH megamaser or superluminous \\water\\/ maser emission. Within the Galaxy, \\methanol\\/ and OH masers often occur in the same star formation regions and, in most cases, the \\methanol\\/ masers have a greater peak flux density than their OH counterparts. Thus we might expect \\methanol\\/ masers to be associated with extragalactic OH maser sources. We failed to detect any emission or absorption above our 60--mJy detection limit. We conclude that if the physical conditions exist to produce \\methanol\\/ megamaser emission, they are incompatible with the conditions which produce OH megamaser emission.

  13. Recycling of greenhouse gases via methanol

    Energy Technology Data Exchange (ETDEWEB)

    Bill, A. [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Eliasson, B.; Kogelschatz, U. [ABB Corporate Research Center, Baden-Daettwil (Switzerland)

    1997-06-01

    Greenhouse gas emissions to the atmosphere can be mitigated by using direct control technologies (capture, disposal or chemical recycling). We report on carbon dioxide and methane recycling with other chemicals, especially with hydrogen and oxygen, to methanol. Methanol synthesis from CO{sub 2} is investigated on various catalysts at moderate pressures ({<=}30 bar) and temperatures ({<=}300{sup o}C). The catalysts show good methanol activities and selectivities. The conversion of CO{sub 2} and CH{sub 4} to methanol is also studied in a silent electrical discharge at pressures of 1 to 4 bar and temperatures close to room temperature. Methanol yields are given for mixtures of CO{sub 2}/H{sub 2}, CH{sub 4}/O{sub 2} and also for CH{sub 4} and air mixtures. (author) 2 figs., 5 refs.

  14. New catalysts for miniaturized methanol fuel cells

    DEFF Research Database (Denmark)

    Pedersen, Christoffer Mølleskov

    The methanol fuel cell is an interesting energy technology, capable of converting the chemical energy of methanol directly into electricity. The technology is specifically attractive for small mobile applications such as laptops, smartphones, tablets etc. since it offers almost instantaneously...... recharging by simply replacing the methanol liquid. The technology is currently being developed for hearing instruments in order to ease the handling of the device for users complaining about difficulties replacing the very small batteries in the hearing instrument. The technology has already been...... and methanol poisoning of the oxygen reduction are studied. Consequently, promising new candidates for replacing the standard catalyst are identified. One of these, Pt5Gd, exhibits improved oxygen reduction reaction activity even in the presence of methanol, thus making Pt5Gd an interesting candidate...

  15. 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

    2017-01-18

    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 pKa and lower log D7.4 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 D7.4 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.

  16. Fixed dose combination of arterolane and piperaquine: a newer prospect in antimalarial therapy.

    Science.gov (United States)

    Patil, Cy; Katare, Ss; Baig, Ms; Doifode, Sm

    2014-07-01

    Malaria has been very prevalent vector-borne disease in India and until date bears enormous implications on health care services of the country. Over the period of time, the development of resistance to traditional antimalarials like chloroquine has been posed as major deterrent in efforts of malaria control. As the drug resistance is today universally prevalent, especially in Plasmodium falciparum species, major burden of malarial control resides with the new artemisinin drug class. However, arterolane is one of the first fully synthetic non-artemisinin antimalarial compound with rapid schizontocidal activity, hence offering an alternative to artemisinin drugs in malaria control. Piperaquine is a synthetic bisquinoline (4-amioquinoline Antimalarial) with slow and longer schizontocidal activity. Therefore their combination has been shown to provide rapid parasitemic clearance and quick relief of most malaria-related symptoms along with prevention of recrudescences. This combination was approved by Drugs Controller General of India in 2011 for treatment of uncomplicated P. falciparum malaria. The article is aimed at to review this newer prospect in antimalarial therapy for which comprehensive database search was done in Google, Google Scholar, PubMed using the terms "Malaria," "Arterolane," "OZ277," "Piperaquine," and "Artemisinin combination therapy." A total of 323 articles were screened and 28 articles were considered for this review along with the World Health Organization and National malarial program guidelines.

  17. 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 activ

  18. Influence of antimalarial treatment on acquisition of immunity in Plasmodium berghei NK65 malaria.

    Science.gov (United States)

    Long, Ton That Ai; Nakazawa, Shusuke; Huaman, Maria Cecilia; Kanbara, Hiroji

    2002-07-01

    Antimalarial treatments during primary Plasmodium berghei NK65 infection in BALB/c mice influenced the acquisition of protective immunity against reinfection. Among subcurative treatments, lower doses better enable mice to acquire protective immunity than do higher doses. Eradication of parasites from the start of infection did not promote protective immunity.

  19. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai; Sudaratana Rochanakij Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu(Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  20. Antimalarial qinghaosu/artemisinin:The therapy worthy of a Nobel Prize

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  1. 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.

  2. 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.

  3. Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death.

    Science.gov (United States)

    Salas, E; Roy, S; Marsh, T; Rubin, B; Debnath, J

    2016-06-01

    Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.

  4. 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.

  5. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Directory of Open Access Journals (Sweden)

    Jerapan Krungkrai

    2016-05-01

    Full Text Available Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  6. Polyamine quinoline rhodium complexes: synthesis and pharmacological evaluation as antiparasitic agents against Plasmodium falciparum and Trichomonas vaginalis.

    Science.gov (United States)

    Stringer, Tameryn; Taylor, Dale; Guzgay, Hajira; Shokar, Ajit; Au, Aaron; Smith, Peter J; Hendricks, Denver T; Land, Kirkwood M; Egan, Timothy J; Smith, Gregory S

    2015-09-07

    A series of mono- and bis-salicylaldimine ligands and their corresponding Rh(i) complexes were prepared. The compounds were characterised using standard spectroscopic techniques including NMR, IR spectroscopy and mass spectrometry. The salicylaldimine ligands and complexes were screened for antiparasitic activity against two strains of Plasmodium falciparum i.e. the NF54 CQ-sensitive and K1 CQ-resistant strain as well as against the G3 isolate of Trichomonas vaginalis. The monomeric salicylaldimine quinolines exhibited good activity against the NF54 strain and the dimeric salicylaldimine quinolines exhibited no cross resistance across the two strains. The binuclear 5-chloro Rh(i) complex displayed the best activity against the Trichomonas vaginalis parasite, possibly a consequence of its enhanced lipophilicity. The compounds were also screened for cytotoxicity in vitro against WHCO1 oesophageal cancer cells. The monomeric salicylaldimine quinolines exhibited high selectivity towards malaria parasites compared to cancer cells, while the dimeric compounds were less selective.

  7. GAS PHASE SYNTHESIS OF (ISO)QUINOLINE AND ITS ROLE IN THE FORMATION OF NUCLEOBASES IN THE INTERSTELLAR MEDIUM

    Energy Technology Data Exchange (ETDEWEB)

    Parker, Dorian S. N.; Kaiser, Ralf I. [Department of Chemistry, University of Hawaii at Manoa, Honolulu, HI 96822 (United States); Kostko, Oleg; Troy, Tyler P.; Ahmed, Musahid [Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Mebel, Alexander M. [Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199 (United States); Tielens, Alexander G. G. M. [Leiden Observatory, University of Leiden, Leiden (Netherlands)

    2015-04-20

    Nitrogen-substituted polycyclic aromatic hydrocarbons (NPAHs) have been proposed to play a key role in the astrochemical evolution of the interstellar medium, yet the formation mechanisms of even their simplest prototypes—quinoline and isoquinoline—remain elusive. Here, we reveal a novel concept that under high temperature conditions representing circumstellar envelopes of carbon stars, (iso)quinoline can be synthesized via the reaction of pyridyl radicals with two acetylene molecules. The facile gas phase formation of (iso)quinoline in circumstellar envelopes defines a hitherto elusive reaction class synthesizing aromatic structures with embedded nitrogen atoms that are essential building blocks in contemporary biological-structural motifs. Once ejected from circumstellar shells and incorporated into icy interstellar grains in cold molecular clouds, these NPAHs can be functionalized by photo processing forming nucleobase-type structures as sampled in the Murchison meteorite.

  8. Zanthoxoaporphines A–C: Three new larvicidal dibenzo[de,g]quinolin-7-one alkaloids from Zanthoxylum paracanthum (Rutaceae

    Directory of Open Access Journals (Sweden)

    Fidelis N. Samita

    2013-02-01

    Full Text Available The bioassay-guided purification of Zanthoxylum paracanthum (Rutaceae extracts led to the isolation of three new alkaloids, namely 1-hydroxy-10-methoxy-7H-dibenzo[de,g]quinolin-7-one (zanthoxoaporphine A, 2, 1-hydroxy-7H-dibenzo[de,g]quinolin-7-one (zanthoxoaporphine B, 3 and 1,8-dihydroxy-9-methoxy-7H-dibenzo[de,g]quinolin-7-one (zanthoxaporphine C, 4, and a known lignan identified as sesamin (1. Isolation and purification of the constituent compounds was achieved through conventional chromatographic methods. The chemical structures of the isolated compounds were determined on the basis of UV, IR, NMR and MS data, and confirmed by comparison with those reported in the literature. The larvicidal activity of some of the isolated compounds was investigated by using third-instar Anopheles gambiae larvae.

  9. Experimental and quantum chemical studies on corrosion inhibition performance of quinoline derivatives for MS in 1N HCl

    Indian Academy of Sciences (India)

    B M Mistry; N S Patel; S Sahoo; S Jauhari

    2012-06-01

    The corrosion inhibition effect of two quinoline derivatives, viz. 2-chloro quinoline 3-carbaldehyde (CQC) and (2-chloro-quinoline-3ylmethyl)--tolyl-amine (CQA) have been investigated against mild steel (MS) in 1N HCl solution using conventional weight loss, potentiodynamic polarization, linear polarization and electrochemical impedance spectroscopy. The losses in weights of MS samples have proved that both CQC and CQA are efficient inhibitors of corrosion. The mixed mode of inhibition was confirmed by electrochemical polarizations. The results of electrochemical impedance spectroscopy have showed changes in the impedance parameters like charge transfer resistance and double-layer capacitance that confirmed strong adsorption of inhibitors on the MS surface. The inhibition action of these compounds was assumed to occur via adsorption on the steel surface through the active centres contained in the molecules. Furthermore, quantum chemical calculations have been performed at B3LYP/6-31G( , ) level to complement the experimental evidence.

  10. Bis(quinolin-8-ol)silver(I) 2-hydr-oxy-3,5-dinitro-benzoate.

    Science.gov (United States)

    Zhang, Chun-Lan; Jian, Fang-Fang

    2009-11-07

    The title compound, [Ag(C(9)H(7)NO)(2)](C(7)H(3)N(2)O(7)), was prepared from 3,5-dinitro-salicylic acid (DNS), quinolin-8-ol and AgNO(3). The Ag(I) atom is coordinated by two N atoms and two O atoms from two quinolin-8-ols in a roughly planar [maximum deviation = 0.223 (2) Å] environment. The two quinolin-8-ol ligands are bent slightly with respect to each other, making a dihedral angle of 9.55 (9)°. The DNS anion inter-acts with the silver complex through O-H⋯O hydrogen bonds.

  11. Analysis of denitrifier community in a bioaugmented sequencing batch reactor for the treatment of coking wastewater containing pyridine and quinoline

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Yaohui; Xing, Rui; Wen, Donghui; Tang, Xiaoyan [Peking Univ., Beijing (CN). Key Lab. of Water and Sediment Sciences (Ministry of Education); Sun, Qinghua [Peking Univ., Beijing (CN). Key Lab. of Water and Sediment Sciences (Ministry of Education); Chinese Center for Disease Control and Prevention, Beijing (China). Inst. of Environmental Health and Related Product Safety

    2011-05-15

    The denitrifier community and associated nitrate and nitrite reduction in the bioaugmented and general sequencing batch reactors (SBRs) during the treatment of coking wastewater containing pyridine and quinoline were investigated. The efficiency and stability of nitrate and nitrite reduction in SBR was considerably improved after inoculation with four pyridine- or quinoline-degrading bacterial strains (including three denitrifying strains). Terminal restriction fragment length polymorphism (T-RFLP) based on the nosZ gene revealed that the structures of the denitrifier communities in bioaugmented and non-bioaugmented reactors were distinct and varied during the course of the experiment. Bioaugmentation protected indigenous denitrifiers from disruptions caused by pyridine and quinoline. Clone library analysis showed that one of the added denitrifiers comprised approximately 6% of the denitrifier population in the bioaugmented sludge. (orig.)

  12. Quinoline alkaloids and friedelane-type triterpenes isolated from leaves and wood of Esenbeckia alata kunt (Rutaceae

    Directory of Open Access Journals (Sweden)

    Luis Enrique Cuca-Suarez

    2011-01-01

    Full Text Available This work describes the phytochemical exploration of the ethanol extract from leaves and wood of Esenbeckia alata, leading to the isolation and identification of quinoline alkaloids 4-methoxy-3-(3'-methyl-but-2'-enyl-N-methyl-quinolin-2(1 H-one, N-methylflindersine, dictamine, kokusaginine, Γ-fagarine, flindersiamine, as well as the fridelane-type triterpenes, frideline, fridelanol and its acetate derivative. Identification of these compounds was based on full analyses of spectroscopic data (¹H, 13C, 1D, 2D, IR, MS and comparison with data reported in literature. Compound 4-methoxy-3-(3'-methyl-but-2'-enyl-N-methyl-quinolin-2(1 H-one is reported for the first time for the genus Esenbeckia.

  13. Quinoline alkaloids and friedelane-type triterpenes isolated from leaves and wood of Esenbeckia alata Kunt (Rutaceae)

    Energy Technology Data Exchange (ETDEWEB)

    Cuca-Suarez, Luis Enrique; Barrera, Ericsson David Coy [Universidad Nacional de Colombia, Bogota (Colombia). Dept. de Quimica; Alvarez Caballero, Juan Manuel [Universidad del Magdalena, Santa Marta DTCH (Colombia). Facultad de Ciencias Basicas

    2011-07-01

    This work describes the phytochemical exploration of the ethanol extract from leaves and wood of Esenbeckia alata, leading to the isolation and identification of quinoline alkaloids 4-methoxy-3-(3'-methyl-but-2'-enyl)-N-methyl-quinolin-2(1 H)-one, N-methylflindersine, dictamine, kokusaginine, G-fagarine, flindersiamine, as well as the fridelane-type triterpenes, frideline, fridelanol and its acetate derivative. Identification of these compounds was based on full analyses of spectroscopic data ({sup 1}H, {sup 13}C, {sup 1}D, {sup 2}D, IR, MS) and comparison with data reported in literature. Compound 4-methoxy-3-(3'-methyl-but-2'-enyl)-N-methyl-quinolin-2(1 H)-one is reported for the first time for the genus Esenbeckia. (author)

  14. 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.

  15. Efficient example of cross-linked polymeric catalysed synthesis of 7-benzo[ℎ]indeno[1,2-]quinolin-8-one and 8-naphtho[2,3-ℎ]indeno[1,2-]quinolin-9-one

    Indian Academy of Sciences (India)

    Reza Sandaroos; Mehdi Vadi; Saman Damavandi

    2013-11-01

    Cross-linked poly(2-acrylamido-2-methyl propane sulphonic acid) (AMPS) was found to be an efficient heterogeneous catalyst for direct synthesis of 7-benzo[ℎ]indeno[1, 2-]quinolin-8-one and 8-naphtho[2, 3-ℎ]indeno[1, 2-]quinolin-9-one derivatives through one-pot condensation of aromatic aldehydes, 1, 3-indandione and 1-naphthylamine or 1-antharacylamine. The catalyst could be recovered conveniently and reused without any loss of activity. Mild conditions, short reaction times, simplicity, easy workup, and good to excellent yields can be mentioned as the advantages of this research.

  16. 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

  17. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

    Directory of Open Access Journals (Sweden)

    Lee Sue J

    2009-11-01

    Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with

  18. Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana

    Directory of Open Access Journals (Sweden)

    M. El-Duah & K. Ofori-Kwakye

    2012-09-01

    Full Text Available Background & objectives: The artemisinin-based antimalarial medicines are first line medicines in the treatmentof severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in variouscountries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and qualityof selected brands of artemisinin-based antimalarial medicines marketed in Ghana.Methods: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P and licensedchemical shops (LCSs in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layerchromatography were employed in determining the authenticity of the samples. Important quality assessmenttests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of activepharmaceutical ingredients (APIs were determined.Results: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of masstest while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strengthtest. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength anddisintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs.The other 13 artemisinin products contained either a lower (underdose or higher (overdose amount of thespecified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemicalshops.Interpretation & conclusion: All the artemisinin-based medicines tested (except AL1 were of substandardquality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalentin Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Synthesis of C-glycosyl triazolyl quinoline-based fluorescent sensors for the detection of mercury ions.

    Science.gov (United States)

    Wang, Linfang; Jin, Jianzhong; Zhao, Linwei; Shen, Hongyun; Shen, Chao; Zhang, Pengfei

    2016-10-01

    A series of novel C-glycosyl triazolyl quinoline-based fluorescent sensors have been synthesized via click chemistry. It was found that novel sensors exhibited good selectivity for Hg(2+) over many other metal ions. The glucose framework was introduced to increase the water-solubility of the fluorescent sensors and broaden its application for the detection of Hg(II) in the water-solubility biological systems. The mechanism of the chemodosimetric behavior of the sensors has been attributed to a binding mode of triazolyl quinoline with Hg(2+) which has been characterized by a number of spectroscopic techniques.

  1. Thermo-optical properties of 1H[3,4-b] quinoline films used in electroluminescent devices

    Science.gov (United States)

    Jaglarz, Janusz; Kępińska, Mirosława; Sanetra, Jerzy

    2014-06-01

    Electroluminescence cells with H[3,4-b] quinoline layers are promising devices for a blue light emitting EL diode. This work measured the optical reflectance as a function of temperature in copolymers PAQ layers deposited on Si crystalline substrate. Using the extended Cauchy dispersion model of the film refractive index we determined the thermo-optical coefficients for quinoline layers in the temperature range of 76-333 K from combined ellipsometric and spectrofotometric studies. The obtained values of thermo-optical coefficients of thin PAQ film, were negative and ranged in 5-10 × 10-4 [1/K].

  2. Engineering Escherichia coli for methanol conversion.

    Science.gov (United States)

    Müller, Jonas E N; Meyer, Fabian; Litsanov, Boris; Kiefer, Patrick; Potthoff, Eva; Heux, Stéphanie; Quax, Wim J; Wendisch, Volker F; Brautaset, Trygve; Portais, Jean-Charles; Vorholt, Julia A

    2015-03-01

    Methylotrophic bacteria utilize methanol and other reduced one-carbon compounds as their sole source of carbon and energy. For this purpose, these bacteria evolved a number of specialized enzymes and pathways. Here, we used a synthetic biology approach to select and introduce a set of "methylotrophy genes" into Escherichia coli based on in silico considerations and flux balance analysis to enable methanol dissimilation and assimilation. We determined that the most promising approach allowing the utilization of methanol was the implementation of NAD-dependent methanol dehydrogenase and the establishment of the ribulose monophosphate cycle by expressing the genes for hexulose-6-phosphate synthase (Hps) and 6-phospho-3-hexuloisomerase (Phi). To test for the best-performing enzymes in the heterologous host, a number of enzyme candidates from different donor organisms were selected and systematically analyzed for their in vitro and in vivo activities in E. coli. Among these, Mdh2, Hps and Phi originating from Bacillus methanolicus were found to be the most effective. Labeling experiments using (13)C methanol with E. coli producing these enzymes showed up to 40% incorporation of methanol into central metabolites. The presence of the endogenous glutathione-dependent formaldehyde oxidation pathway of E. coli did not adversely affect the methanol conversion rate. Taken together, the results of this study represent a major advancement towards establishing synthetic methylotrophs by gene transfer.

  3. Alteration of kainic acid and quinolinic acid toxicity by neostriatal transplants in vitro.

    Science.gov (United States)

    Whetsell, W O; Allen, G S; Tulipan, N B

    1989-01-02

    Mature (greater than 21 days in vitro) organotypic corticostriatal cultures prepared from newborn rat brain were incubated in either kainic acid (KA) 10(-3) M or quinolinic acid (QUIN) 10(-3) M for up to 48 h. Other identical cultures were similarly incubated immediately after they had received one or two additional explants of neonatal striatal tissue placed beside each corticostriatal culture. The cultures incubated with either KA or QUIN in the presence of the neonatal striatal tissue showed better preservation than cultures incubated with KA or QUIN alone. Results suggest that the neonatal striatal explants or 'transplants' afford some protective effect against the toxicity or either KA or QUIN.

  4. The discovery of quinoline based single-ligand human H1 and H3 receptor antagonists.

    Science.gov (United States)

    Procopiou, Panayiotis A; Ancliff, Rachael A; Gore, Paul M; Hancock, Ashley P; Hodgson, Simon T; Holmes, Duncan S; Keeling, Steven P; Looker, Brian E; Parr, Nigel A; Rowedder, James E; Slack, Robert J

    2016-12-15

    A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.

  5. Synthesis of (iso)quinoline, (iso)coumarin and (iso)chromene derivatives from acetylene compounds

    Science.gov (United States)

    Ryabukhin, D. S.; Vasilyev, A. V.

    2016-06-01

    Published data on the methods of synthesis of quinoline, isoquinoline, coumarin, isocoumarin, chromene and isochromene derivatives from acetylene compounds are summarized. The reactions catalyzed by metal complexes (Pd, Pt, Ru, Rh, Au, Ag, Ni, Cu, etc.) and transformations induced by various electrophilic reagents (Brynsted and Lewis acids) are considered. Moieties of the mentioned heterocyclic systems are present in many biologically active natural products and pharmaceutical agents. Besides, derivatives of these heterocycles are used in the manufacture of catalysts, dyes, perfumery and cosmetic products, corrosion inhibitors and so on. The bibliography includes 211 references.

  6. Synthesis of new biphenyl-substituted quinoline derivatives, preliminary screening and docking studies

    Indian Academy of Sciences (India)

    Nellisara D Shashikumar; Ganganaika Krishnamurthy; Halehatti S Bhojyanaik; Mayasandra R Lokesh; Kaginalli S Jithendrakumara

    2014-01-01

    New quinoline derivatives containing biphenyl ring were synthesized and characterized by IR, 1H NMR and mass spectral studies. The synthesized compounds were screened for antimicrobial, anthelmintic activities as well as free radical scavenging property against the DPPH radical. The minimum inhibition concentration values showed promising inhibiting activity and are potent biological agents. The compounds showed minimum binding energy towards -tubulin. The compounds 11a, 11c, 13c and 13d have good affinity towards the active pocket and may be considered as a good inhibitor of -tubulin.

  7. (Methoxo-κO)oxidobis(quinolin-8-olato-κ2N,O)vanadium(V)

    OpenAIRE

    Zhenghua Guo; Lianzhi Li; Chengyuan Wang; Tao Xu; Jinghong Li

    2009-01-01

    In the title complex, [V(C9H6NO)2(CH3O)O], the central VV atom is coordinated by the O atoms from the oxido and methoxo ligands and the N and O atoms of two bis-chelating quinolin-8-olate ligands, forming a distorted octahedral environment. In the crystal structure, weak intermolecular C—H...O hydrogen bonds connect molecules into centrosymmetric dimers which are, in turn, linked by weak C—H...π interactions into chains along the b axis.

  8. (Methoxo-κO)oxidobis(quinolin-8-olato-κN,O)vanadium(V).

    Science.gov (United States)

    Guo, Zhenghua; Li, Lianzhi; Wang, Chengyuan; Xu, Tao; Li, Jinghong

    2009-08-15

    In the title complex, [V(C(9)H(6)NO)(2)(CH(3)O)O], the central V(V) atom is coordinated by the O atoms from the oxido and methoxo ligands and the N and O atoms of two bis-chelating quinolin-8-olate ligands, forming a distorted octa-hedral environment. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds connect mol-ecules into centrosymmetric dimers which are, in turn, linked by weak C-H⋯π inter-actions into chains along the b axis.

  9. (Methoxo-κOoxidobis(quinolin-8-olato-κ2N,Ovanadium(V

    Directory of Open Access Journals (Sweden)

    Zhenghua Guo

    2009-09-01

    Full Text Available In the title complex, [V(C9H6NO2(CH3OO], the central VV atom is coordinated by the O atoms from the oxido and methoxo ligands and the N and O atoms of two bis-chelating quinolin-8-olate ligands, forming a distorted octahedral environment. In the crystal structure, weak intermolecular C—H...O hydrogen bonds connect molecules into centrosymmetric dimers which are, in turn, linked by weak C—H...π interactions into chains along the b axis.

  10. (Methoxo-κO)oxidobis(quinolin-8-olato-κ2 N,O)vanadium(V)

    OpenAIRE

    Guo, Zhenghua; Li, Lianzhi; Wang, Chengyuan; Xu, Tao; Li, Jinghong

    2009-01-01

    In the title complex, [V(C9H6NO)2(CH3O)O], the central VV atom is coordinated by the O atoms from the oxido and methoxo ligands and the N and O atoms of two bis-chelating quinolin-8-olate ligands, forming a distorted octa­hedral environment. In the crystal structure, weak inter­molecular C—H⋯O hydrogen bonds connect mol­ecules into centrosymmetric dimers which are, in turn, linked by weak C—H⋯π inter­actions into chains along the b axis.

  11. Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor.

    Science.gov (United States)

    Burch, Jason D; Farand, Julie; Colucci, John; Sturino, Claudio; Ducharme, Yves; Friesen, Richard W; Lévesque, Jean-François; Gagné, Sébastien; Wrona, Mark; Therien, Alex G; Mathieu, Marie-Claude; Denis, Danielle; Vigneault, Erika; Xu, Daigen; Clark, Patsy; Rowland, Steve; Han, Yongxin

    2011-02-01

    Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.

  12. Sorption phenomena of methanol on heat treated coal; Netsushori wo hodokoshita sekitan no methanol kyuchaku tokusei

    Energy Technology Data Exchange (ETDEWEB)

    Yasuda, H.; Kaiho, M.; Yamada, O.; Soneda, Y.; Kobayashi, M.; Makino, M. [National Institute for Resources and Environment, Tsukuba (Japan)

    1996-10-28

    Experiments were carried out to learn methanol sorption characteristics of heat-treated coal. When Taiheiyo coal is heat-treated at 125{degree}C, performed with a first methanol adsorption at 25{degree}C, and then desorption at 25{degree}C, a site with strong interaction with methanol and a site with relatively weak interaction are generated in test samples. A small amount of methanol remains in both sites. Then, when the methanol is desorbed at as low temperature as 70{degree}C, the methanol in the site with strong interaction remains as it has existed therein, but the methanol in the site with relatively weak interaction desorbs partially, hence the adsorption amount in a second adsorption at 25{degree}C increases. However, when desorption is performed at as high temperature as 125{degree}C, the methanol in the site with strong interaction also desorbs, resulting in increased adsorption heat in the second adsorption. The adsorption velocity drops, however. Existence of methanol in a site with strong interaction affects the adsorption velocity, but no effect is given by methanol in a site with weak interaction. 3 refs., 4 figs.

  13. Hydrogen Production from Methanol Using Corona Discharges

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Hydrogen production at room temperature from liquid methanol has been conductedusing corona discharge. The content of water in methanol solution has a significant effect on thisproduction. When water concentration increases from 1.0 % to 16.7 %, the methanol conversionrate changes from 0.196 to 0.284 mol/h. An important finding in this investigation is theformation of ethylene glycol as a major by-product. The yield of ethylene glycol is ranged from0.0045 to 0.0075 mol/h based on the water content.

  14. 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; and others

    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)

  15. The Catalysis of NAD+ on Methanol Anode Oxidation Electrode for Direct Methanol Fuel Cell

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ping; PAN Mu; YUAN Run-zhang

    2004-01-01

    A tentative idea of developing a liquid-catalytic system on methanol anode oxidation was proposed by analyzing the characteristics of methanol anode oxidation in direct methanol fuel cell. The kinetics of methanol oxidation at a glassy carbon electrode in the presence of nicotinamide adenine dinucleotide (NAD+) was investigated. It is found that the current density of methanol oxidation increases greatly and the electrochemical reaction impedance reduces obviously in the presence of NAD+ compared with those in the absence of NAD+. The catalytic activity of NAD+ is sensitive to temperature. When the temperature preponderates over 45℃, NAD+ is out of function of catalysis for methanol oxidation, which is probably due to the denaturation of NAD+ at a relatively high temperature.

  16. Methanol: A Versatile Fuel for Immediate Use

    Science.gov (United States)

    Reed, T. B.; Lerner, R. M.

    1973-01-01

    Advocates the large-scale production and use of methanol as a substitute for the diminishing reserves of low-cost petroleum resources. Describes the manufacturing process and advantages of the versatile fuel. (JR)

  17. Quiet Changes in the Methanol Supply Mode

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ The coal chemicals sector, the new coal chemicals sector in particular, has been emerging fast in China in recent years. The production scale of methanol as an important coal chemical product has expanded constantly.

  18. Investigations into low pressure methanol synthesis

    DEFF Research Database (Denmark)

    Sharafutdinov, Irek

    The central topic of this work has been synthesis, characterization and optimization of novel Ni-Ga based catalysts for hydrogenation of CO2 to methanol. The overall goal was to search for materials that could be used as a low temperature (and low pressure) methanol synthesis catalyst....... This is required for small scale delocalized methanol production sites, where installation of energy demanding compression units should be avoided. The work was triggered by DFT calculations, which showed that certain bimetallic systems are active towards methanol synthesis from CO2 and H2 at ambient pressure....... Among them, Ni-Ga has been chosen, primarily due to low price of constituent metals. After the preliminary optimization work, an optimal catalyst composition and preparation method has been suggested. Indeed, for an optimal catalyst, which is a SiO2 supported Ni-Ga prepared from a solution of nitrates...

  19. Production of methanol/DME from biomass

    DEFF Research Database (Denmark)

    Ahrenfeldt, Jesper; Henriksen, Ulrik Birk; Münster-Swendsen, Janus

    fraction of the biomass that is not converted to gas appears as soot. Thermodynamic computer models of DME and methanol plants based on using entrained flow gasification were created to show the potential of such plants. These models showed that the potential torrefied biomass to DME/methanol + net...... cleaning. This was proved by experiments. Thermodynamic computer models of DME and methanol plants based on using the Two-Stage Gasification concept were created to show the potential of such plants. The models showed that the potential biomass to DME/methanol + net electricity energy efficiency was 51......-58% (LHV). By using waste heat from the plants for district heating, the total energy efficiencies could reach 87-88% (LHV). • A lab-scale electrically heated entrained flow gasifier has been used to gasify wood and straw. Entrained flow gasifiers are today the preferred gasifier type for commercial coal...

  20. 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

  1. Application of Porous Nickel-Coated TiO2 for the Photocatalytic Degradation of Aqueous Quinoline in an Internal Airlift Loop Reactor

    Directory of Open Access Journals (Sweden)

    Mingxin Huo

    2012-02-01

    Full Text Available P25 film, prepared by a facile dip-coating method without any binder, was further developed in a recirculating reactor for quinoline removal from synthetic wastewater. Macroporous foam Ni, which has an open three-dimensional network structure, was utilized as a substrate to make good use of UV rays. Field emission scanning electron microscopy and X-ray diffraction analysis showed that the coated/calcinated P25 films consisted of two crystal phases, and had a number of uniform microcracks on the surface. The effects of initial quinoline concentration, light intensity, reaction temperature, aeration, and initial pH were studied. Increased reaction time, light intensity, environmental temperature, and gas aeration were found to significantly improve the quinoline removal efficiency. The aeration effect of oxygen dependency on the quinoline degradation had the trend pure oxygen > air > no gas > pure nitrogen with free O2. The solution pH crucially affected quinoline photodegradation; the high electrostatic adsorption of quinoline molecules on the TiO2 surface was strongly pH dependent. 2-Pyridine-carboxaldehyde, 3-pyridinecarboxaldehyde, and 2(1H-quinolinone were identified as the major intermediates of quinoline degradation. Based on these intermediates, a primary degradation mechanism was proposed. This reusable P25 film benefits the photodegradation of water contaminants and has potential in other various applications.

  2. Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist.

    Science.gov (United States)

    Stone, Trevor W; Behan, Wilhelmina M H

    2007-04-01

    Quinolinic acid is an agonist at glutamate receptors sensitive to N-methyl-D-aspartate (NMDA). It has been implicated in neural dysfunction associated with infections, trauma, and ischemia, although its neurotoxic potency is relatively low. This study was designed to examine the effects of a combination of quinolinic acid and the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Compounds were administered to the hippocampus of anesthetized male rats, animals being allowed to recover for 7 days before histological analysis of the hippocampus for neuronal damage estimated by counting of intact, healthy neurons. A low dose of quinolinic acid or IL-1beta produced no damage by itself, but the two together induced a significant loss of pyramidal neurons in the hippocampus. Higher doses produced almost total loss of pyramidal cells. Intrahippocampal TNF-alpha produced no effect alone but significantly reduced the neuronal loss produced by quinolinic acid. The adenosine A(2A) receptor antagonist ZM241385 reduced neuronal loss produced by the combinations of quinolinic acid and IL-1beta. The results suggest that simultaneous quinolinic acid and IL-1beta, both being induced by cerebral infection or injury, are synergistic in the production of neuronal damage and could together contribute substantially to traumatic, infective, or ischemic cerebral damage. Antagonism of adenosine A(2A) receptors protects neurons against the combination of quinolinic acid and IL-1beta.

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

    Directory of Open Access Journals (Sweden)

    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

  4. Striatal grafts provide sustained protection from kainic and quinolinic acid-induced damage.

    Science.gov (United States)

    Tulipan, N; Luo, S Q; Allen, G S; Whetsell, W O

    1988-12-01

    Grafts of neonatal striatal tissue were placed into the striata of adult rats. When challenged immediately with intrastriatal injections of either kainic or quinolinic acid, excitotoxic damage was prevented. Thirty days later these same graft recipients received another injection of excitotoxin. The intrastriatal grafts continued to mitigate toxin-induced damage. It is hypothesized that the grafted cells not only survive, but that they may continue to elaborate some substance or substances that prevent excitotoxin-induced injury for at least 30 days. Previous investigations indicated that grafts of neonatal striatal tissue can protect the recipient striatum from kainic acid toxicity. In the following study it is demonstrated that such grafts also protect the striatum from quinolinic acid, an endogenous excitotoxin which induces kainate-like neuronal degeneration and has been implicated in the pathogenesis of Huntington's disease. It is postulated that the salutary effect of striatal grafting may be sufficiently long lasting to mitigate a chronic toxic insult. Such grafting may therefore represent a therapy for Huntington's disease and other neurodegenerative disorders in which an endogenous or exogenous toxin has been implicated as the pathogenetic agent.

  5. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Susimaire P. Mantoani

    2016-02-01

    Full Text Available Alzheimer’s disease (AD is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

  6. Synthesis, characterization and emission properties of quinolin-8-olato chelated ruthenium organometallics

    Indian Academy of Sciences (India)

    Bikash Kumar Panda

    2004-08-01

    The reaction of Ru(RL1)(PPh3)2(CO)Cl, 1, with quinolin-8-ol (HQ) has afforded complexes of the type [Ru(RL2)(PPh3)2(CO)(Q)], 3, in excellent yield (RL1 is C6H2O-2-CHNHC6H4R()-3-Me-5, RL2 is C6H2OH-2-CHNC6H4R()-3-Me-5 and R is Me, OMe, Cl). In this process, quinolin-8-olato (Q) undergoes five-membered chelation, the iminium-phenolato function tautomerizing to the imine-phenol function. In dichloromethane solution, 3 displays a quasireversible 3+/3 couple near 0×50 V vs SCE (3+ is the ruthenium (III) analogue of 3). Coulometrically generated solutions of 3+ display a strong absorption near 395 nm associated with a shoulder near 475 nm and rhombic EPR spectra with values near 2.55, 2.13, 1.89. Solutions of 3 absorb near 415 nm and emit near 510 nm at 298 K and 585 nm at 77 K. The fluorescence is believed to originate from the 3MLCT state.

  7. Substituent influence on the spectra of some benzo[f]quinoline derivatives

    Science.gov (United States)

    Oanca, Gabriel; Stare, Jernej; Todirascu, Antonina Gritco; Creanga, Dorina; Dorohoi, Dana Ortansa

    2016-12-01

    The aim of this study was to investigate the relations between the properties of some organic compounds that are cycloaddition derivatives of benzo[f]quinoline, namely benzo[f]pyrrolo[1,2-a]quinolines (BQCDs) and the structure of variable substituent in the addition cycle. The work was focused on the differences in the molecular parameters like frontier orbitals and dipole moment as well as electronic absorption spectra of substituted BQCDs. The optimized molecular structures of BQCDs were calculated using Gaussian 09, with DFT method, the frontier orbitals and electronic absorption spectra being modeled with restricted Hartree Fock method also implemented in Gaussian 09. Influence of substituted radical on the dipole moments and frontier orbital energies of the BQCDs was evidenced from calculated values. Substituent effect on the BQCDs recorded electronic absorption spectra in diluted solution and protonated diluted solution was also emphasized: different types of the transitions underlying absorption bands in the visible range were presumed based on the quantum chemical and experimental investigation.

  8. A computational study on corrosion inhibition performances of novel quinoline derivatives against the corrosion of iron

    Science.gov (United States)

    Erdoğan, Şaban; Safi, Zaki S.; Kaya, Savaş; Işın, Dilara Özbakır; Guo, Lei; Kaya, Cemal

    2017-04-01

    In this computational study, the adsorption and corrosion inhibition properties of some novel quinoline derivatives namely, 2-amino-7-hydroxy-4-phenyl-1,4-dihydroquinoline-3-carbonitrile (Q1), 2-amino-7-hydroxy-4-(p-tolyl)-1,4-dihydroquinoline-3-carbonitrile (Q2), 2-amino-7-hydroxy-4-(4-methoxyphenyl)-1,4-dihydroquinoline-3-carbonitrile) (Q3) and 2-amino-4-(4-(dimethylamino)phenyl)-7-hydroxy-1,4-dihydroquinoline-3-carbonitrile (Q4) on the corrosion of iron were investigated using quantum chemical and molecular dynamics simulation approaches. Quantum chemical calculations section of the study provides enough calculation and discussion on the relationship between corrosion inhibition and global reactivity descriptors such as EHOMO, ELUMO, HOMO-LUMO energy gap (ΔE), chemical hardness (η), softness (σ), electronegativity (χ), chemical potential (μ), electrophilicity (ω), nucleophilicity (ɛ), electrons transferred from inhibitors to metal surface (ΔN), initial molecule-metal interaction energy (Δψ), total electronic energy (E), the energy change during electronic back-donation process (ΔEb-d). The adsorption behaviors of studied compounds on Fe (110) surface were investigated with the help of molecular dynamics simulation approach. The binding energies calculated on Fe (110) surface of mentioned quinoline derivatives followed the order: Q4 > Q3 > Q2 > Q1. It should be noted that the results obtained in the study are in good agreement with experimental inhibition efficiency results earlier reported.

  9. An environmentally benign one pot synthesis of substituted quinolines catalysed by fluoroboric acid based ionic liquid

    Indian Academy of Sciences (India)

    A Rajendran; C Karthikeyan; K Rajathi; D Ragupathy

    2012-07-01

    Organic synthesis generally required large amount of solvent, avoiding the use of organic solvents in synthesis is a paradigm shift directed at developing more benign chemistry, and with ionic liquids surprisingly can lead to access to new compounds. An elegant one-pot synthesis of quinoline derivatives has been achieved by reaction of substituted anilines with -ketoester at 60°C in ethanol using an ionic liquid [Et3NH]+[BF4]−as catalyst. All the reactions gave products with high degree of purity and excellent yield (78-93%) within the shorter span of time (20-65 min) than those reactions with conventional methods. The screening of solvents as well as the reuse of ionic liquid has been evaluated. The structure of the products has been elucidated by spectral and analytical data. The present scope and potential economic impact of the reaction are demonstrated by the synthesis of substituted quinolines. Remaining challenges and future perspectives of the new transformation are discussed.

  10. Experimental and theoretical studies on IR, Raman, and UV-Vis spectra of quinoline-7-carboxaldehyde.

    Science.gov (United States)

    Kumru, M; Küçük, V; Kocademir, M; Alfanda, H M; Altun, A; Sarı, L

    2015-01-05

    Spectroscopic properties of quinoline-7-carboxaldehyde (Q7C) have been studied in detail both experimentally and theoretically. The FT-IR (4000-50 cm(-1)), FT-Raman (4000-50 cm(-1)), dispersive-Raman (3500-50 cm(-1)), and UV-Vis (200-400 nm) spectra of Q7C were recorded at room temperature (25 °C). Geometry parameters, potential energy surface about CCH(O) bond, harmonic vibrational frequencies, IR and Raman intensities, UV-Vis spectrum, and thermodynamic characteristics (at 298.15K) of Q7C were computed at Hartree-Fock (HF) and density functional B3LYP levels employing the 6-311++G(d,p) basis set. Frontier molecular orbitals, molecular electrostatic potential, and Mulliken charge analyses of Q7C have also been performed. Q7C has two stable conformers that are energetically very close to each other with slight preference to the conformer that has oxygen atom of the aldehyde away from the nitrogen atom of the quinoline.

  11. Methanol-Tolerant Cathode Catalyst Composite For Direct Methanol Fuel Cells

    Science.gov (United States)

    Zhu, Yimin; Zelenay, Piotr

    2006-03-21

    A direct methanol fuel cell (DMFC) having a methanol fuel supply, oxidant supply, and its membrane electrode assembly (MEA) formed of an anode electrode and a cathode electrode with a membrane therebetween, a methanol oxidation catalyst adjacent the anode electrode and the membrane, an oxidant reduction catalyst adjacent the cathode electrode and the membrane, comprises an oxidant reduction catalyst layer of a platinum-chromium alloy so that oxidation at the cathode of methanol that crosses from the anode through the membrane to the cathode is reduced with a concomitant increase of net electrical potential at the cathode electrode.

  12. Vacuum-ultraviolet (VUV) photoionization of small methanol and methanol-water clusters

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Musahid; Ahmed, Musahid; Wilson, Kevin R.; Belau, Leonid; Kostko, Oleg

    2008-05-12

    In this work we report on thevacuum-ultraviolet (VUV) photoionization of small methanol and methanol-water clusters. Clusters of methanol with water are generated via co-expansion of the gas phase constituents in a continuous supersonic jet expansion of methanol and water seeded in Ar. The resulting clusters are investigated by single photon ionization with tunable vacuumultraviolet synchrotron radiation and mass analyzed using reflectron mass spectrometry. Protonated methanol clusters of the form (CH3OH)nH + (n=1-12) dominate the mass spectrum below the ionization energy of the methanol monomer. With an increase in water concentration, small amounts of mixed clusters of the form (CH3OH)n(H2O)H + (n=2-11) are detected. The only unprotonated species observed in this work are the methanol monomer and dimer. Appearance energies are obtained from the photoionization efficiency (PIE) curves for CH3OH +, (CH 3OH)2 +, (CH3OH)nH + (n=1-9), and (CH 3OH)n(H2O)H + (n=2-9 ) as a function of photon energy. With an increase in the water content in the molecular beam, there is an enhancement of photoionization intensity for methanol dimer and protonated methanol monomer at threshold. These results are compared and contrasted to previous experimental observations.

  13. Vacuum-Ultraviolet (VUV) Photoionization of Small Methanol and Methanol-Water Clusters

    Energy Technology Data Exchange (ETDEWEB)

    Kostko, Oleg; Belau, Leonid; Wilson, Kevin R.; Ahmed, Musahid

    2008-04-24

    In this work, we report on the vacuum-ultraviolet (VUV) photoionization of small methanol and methanol-water clusters. Clusters of methanol with water are generated via co-expansion of the gas phase constituents in a continuous supersonic jet expansion of methanol and water seeded in Ar. The resulting clusters are investigated by single photon ionization with tunable vacuum-ultraviolet synchrotron radiation and mass analyzed using reflectron mass spectrometry. Protonated methanol clusters of the form (CH3OH)nH+(n = 1-12) dominate the mass spectrum below the ionization energy of the methanol monomer. With an increase in water concentration, small amounts of mixed clusters of the form (CH3OH n(H2O)H+ (n = 2-11) are detected. The only unprotonated species observed in this work are the methanol monomer and dimer. Appearance energies are obtained from the photoionization efficiency (PIE) curves for CH3OH+, (CH3OH)2+, (CH3OH)nH+ (n = 1-9), and (CH3OH)n(H2O)H+ (n = 2-9) as a function of photon energy. With an increasein the water content in the molecular beam, there is an enhancement of photoionization intensity for the methanol dimer and protonated methanol monomer at threshold. These results are compared and contrasted to previous experimental observations.

  14. Transesterification of waste vegetable oil under pulse sonication using ethanol, methanol and ethanol–methanol mixtures

    Energy Technology Data Exchange (ETDEWEB)

    Martinez-Guerra, Edith; Gude, Veera Gnaneswar, E-mail: gude@cee.msstate.edu

    2014-12-15

    Highlights: • Pulse sonication effect on transesterification of waste vegetable oil was studied. • Effects of ethanol, methanol, and alcohol mixtures on FAMEs yield were evaluated. • Effect of ultrasonic intensity, power density, and its output rates were evaluated. • Alcohol mixtures resulted in higher biodiesel yields due to better solubility. - Abstract: This study reports on the effects of direct pulse sonication and the type of alcohol (methanol and ethanol) on the transesterification reaction of waste vegetable oil without any external heating or mechanical mixing. Biodiesel yields and optimum process conditions for the transesterification reaction involving ethanol, methanol, and ethanol–methanol mixtures were evaluated. The effects of ultrasonic power densities (by varying sample volumes), power output rates (in W), and ultrasonic intensities (by varying the reactor size) were studied for transesterification reaction with ethanol, methanol and ethanol–methanol (50%-50%) mixtures. The optimum process conditions for ethanol or methanol based transesterification reaction of waste vegetable oil were determined as: 9:1 alcohol to oil ratio, 1% wt. catalyst amount, 1–2 min reaction time at a power output rate between 75 and 150 W. It was shown that the transesterification reactions using ethanol–methanol mixtures resulted in biodiesel yields as high as >99% at lower power density and ultrasound intensity when compared to ethanol or methanol based transesterification reactions.

  15. Microfluidic distillation chip for methanol concentration detection.

    Science.gov (United States)

    Wang, Yao-Nan; Liu, Chan-Chiung; Yang, Ruey-Jen; Ju, Wei-Jhong; Fu, Lung-Ming

    2016-03-17

    An integrated microfluidic distillation system is proposed for separating a mixed ethanol-methanol-water solution into its constituent components. The microfluidic chip is fabricated using a CO2 laser system and comprises a serpentine channel, a boiling zone, a heating zone, and a cooled collection chamber filled with de-ionized (DI) water. In the proposed device, the ethanol-methanol-water solution is injected into the microfluidic chip and driven through the serpentine channel and into the collection chamber by means of a nitrogen carrier gas. Following the distillation process, the ethanol-methanol vapor flows into the collection chamber and condenses into the DI water. The resulting solution is removed from the collection tank and reacted with a mixed indicator. Finally, the methanol concentration is inversely derived from the absorbance measurements obtained using a spectrophotometer. The experimental results show the proposed microfluidic system achieves an average methanol distillation efficiency of 97%. The practicality of the proposed device is demonstrated by detecting the methanol concentrations of two commercial fruit wines. It is shown that the measured concentration values deviate by no more than 3% from those obtained using a conventional bench top system.

  16. Class I methanol masers: Masers with EGOs

    CERN Document Server

    Chen, Xi; Shen, Zhi-Qiang

    2009-01-01

    We have compared the results of a number of published class I methanol maser surveys with the catalogue of high-mass outflow candidates identified from the GLIMPSE survey (known as extended green objects or EGOs). We find class I methanol masers associated with approximately two-thirds of EGOs. Although the association between outflows and class I methanol masers has long been postulated on the basis of detailed studies of a small number of sources, this result demonstrates the relationship for the first time on a statistical basis. Despite the publication of a number of searches for class I methanol masers, a close physical association with another astrophysical object which could be targeted for the search is still lacking. The close association between class I methanol masers and EGOs therefore provides a large catalogue of candidate sources, most of which have not previously been searched for class I methanol masers. Interstellar masers and outflows have both been proposed to trace an evolutionary sequenc...

  17. B(HSO43: An efficient and recyclable catalyst for the preparation of substituted Friedländer quinoline synthesis

    Directory of Open Access Journals (Sweden)

    Saghanezhad Seyyed Jafar

    2013-01-01

    Full Text Available Substituted quinolines have been synthesized in the presence of catalytic amounts of boron sulfonic acid (BSA in solvent-free conditions. This methodology offers some advantages including high yield, short reaction time, low cost of the catalyst, green conditions by avoiding toxic solvents and recoverable catalyst.

  18. Hydrogen bonding in asphaltenes and coal. Progress report, July 1, 1976--December 31, 1976. [Between quinoline and o-phenylphenol

    Energy Technology Data Exchange (ETDEWEB)

    Li, N.C.

    1977-01-04

    Calorimetric studies of hydrogen bonding between quinoline and o-phenylphenol were carried out because they represent the nitrogenous heteronuclear aromatic bases and aromatic bases, respectively, found in the liquefaction products from coal. Further experiments are planned to try to resolve discrepancies observed between experimental and calculated values. (EJH)

  19. 10-hydroxybenzo[h]quinoline: Switching between single and double-well proton transfer through structural modifications

    DEFF Research Database (Denmark)

    Hristova, S; Dobrikov, G; Kamounah, F. S.;

    2015-01-01

    Proton transfer in 10-hydroxybenzo[h]quinoline (HBQ) and structurally modified compounds was investigated experimentally (steady state UV-Vis absorption and emission spectroscopy, NMR and advanced chemometric techniques) and theoretically (DFT and TD-DFT M06-2X/TZVP calculations) in the ground...

  20. Modelling and experimental studies on a direct methanol fuel cell working under low methanol crossover and high methanol concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, V.B.; Pinto, A.M.F.R. [Centro de Estudos de Fenomenos de Transporte, Departamento de Eng. Quimica, Faculdade de Engenharia da Universidade do Porto, Rua Dr. Roberto Frias, 4200-465 Porto (Portugal); Rangel, C.M. [Instituto Nacional de Energia e Geologia, Fuel Cells and Hydrogen, Estrada do Paco do Lumiar, 1649-038 Lisboa (Portugal)

    2009-08-15

    A number of issues need to be resolved before DMFC can be commercially viable such as the methanol crossover and water crossover which must be minimised in portable DMFCs. The main gain of this work is to systematically vary commercial MEA materials and check their influence on the cell performance of a direct methanol fuel cell operating at close to room temperature. A detailed experimental study on the performance of an <> developed DMFC with 25 cm{sup 2} of active membrane area, working near the ambient conditions is described. Tailored MEAs (membrane-electrode assemblies), with different structures and combinations of gas diffusion layers (GDLs), were designed and tested in order to select optimal working conditions at high methanol concentration levels without sacrificing performance. The experimental polarization and power density curves were successfully compared with the predictions of a steady state, one-dimensional model accounting for coupled heat and mass transfer, along with the electrochemical reactions occurring in the DMFC recently developed by the same authors. The influence of the anode gas diffusion layer media, the membrane thickness and the MEA properties on the cell performance are explained under the light of the predicted methanol crossover rate across the membrane. A tailored MEA build-up with the common available commercial materials was proposed to achieve relatively low methanol crossover, operating at high methanol concentrations. The use of adequate materials for the gas diffusion layers (carbon paper at the anode GDL and carbon cloth at the cathode GDL) enables the use of thinner membranes enhancing the water back diffusion which is essential to work at high methanol concentrations. (author)

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Production of methanol/DME from biomass

    Energy Technology Data Exchange (ETDEWEB)

    Ahrenfeldt, J.; Birk Henriksen, U.; Muenster-Swendsen, J.; Fink, A.; Roengaard Clausen, L.; Munkholt Christensen, J.; Qin, K.; Lin, W.; Arendt Jensen, P.; Degn Jensen, A.

    2011-07-01

    In this project the production of DME/methanol from biomass has been investigated. Production of DME/methanol from biomass requires the use of a gasifier to transform the solid fuel to a synthesis gas (syngas) - this syngas can then be catalytically converted to DME/methanol. Two different gasifier types have been investigated in this project: 1) The Two-Stage Gasifier (Viking Gasifier), designed to produce a very clean gas to be used in a gas engine, has been connected to a lab-scale methanol plant, to prove that the gas from the gasifier could be used for methanol production with a minimum of gas cleaning. This was proved by experiments. Thermodynamic computer models of DME and methanol plants based on using the Two-Stage Gasification concept were created to show the potential of such plants. The models showed that the potential biomass to DME/methanol + net electricity energy efficiency was 51-58% (LHV). By using waste heat from the plants for district heating, the total energy efficiencies could reach 87-88% (LHV). 2) A lab-scale electrically heated entrained flow gasifier has been used to gasify wood and straw. Entrained flow gasifiers are today the preferred gasifier type for commercial coal gasification, but little information exists on using these types of gasifiers for biomass gasification. The experiments performed provided quantitative data on product and gas composition as a function of operation conditions. Biomass can be gasified with less oxygen consumption compared to coal. The organic fraction of the biomass that is not converted to gas appears as soot. Thermodynamic computer models of DME and methanol plants based on using entrained flow gasification were created to show the potential of such plants. These models showed that the potential torrefied biomass to DME/methanol + net electricity energy efficiency was 65-71% (LHV). Different routes to produce liquid transport fuels from biomass are possible. They include production of RME (rapeseed oil

  3. Sterion membranes in Direct Methanol fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Linares, J. J.; Lobato, J.; Canizares, P.; Rodrigo, M. A.; Fernandez, A.

    2005-07-01

    Direct Methanol Fuel Cells (DMFCs) has been postulated as an alternative to traditional hydrogen fed Polymer Electrolyte Membrane Fuel Cells (H2-PEMFCs). Among their advantages, it can be pointed out the low cost of the fuel, simplicity of design, large availability, easy handling and distribution. However, there are still some challenges in this field, such as the development of electrocatalysts which can enhance the electrokinetics of methanol oxidation, the discovery of an electrolyte membrane with high conductivity and low methanol crossover at the same time and the production of methanol-tolerant electrocatalysts with high activity for oxygen reduction. So far, Nafion 117 has been the polymer membrane most widely used in DMFCs. Yet, it is well known that Nafion (Du Pont Inc.) membranes are not good barrier for methanol, so that the coulombic efficiency of Nafion-based DMFCs is significantly reduced by the chemical oxidation of methanol in the cathode. Recently, a new perfluorinated polymer with sulphonic acid groups (PFSA) has been developed, under the commercial name of Sterion (David Fuel Cell Components). As a difference as opposed to Nafion, this membrane is cast by the solution casting method, which provides a different sulphonic cluster configuration as compared to the extrusion cast Nafion membranes, which may give rise to different methanol crossover behaviour. In this work, it has been studied and analysed the suitability of Sterion in the DMFCs field. For that, it has been measured the methanol permeability of this membrane at different solute concentration and temperature, and its performance in an actual fuel cell at different operational conditions, such as methanol concentration, temperature and back pressure. Tests have been made using both oxygen and air in the cathode and half-cell potentials have been evaluated in some measurements in order to discriminate the contribution of both semi-reactions to the overall cell overvoltage. A lifetime

  4. Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

    Science.gov (United States)

    Santos, Sofia A; Lukens, Amanda K; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.

  5. 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

    prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results......: All surveyed drug shops illicitly sold SP and quinine (QN), and legally amodiaquine (AQ). Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%), QN (11%) and ACT (2%). Conclusions: In community...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

  6. Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials.

    Science.gov (United States)

    Anusha, Sebastian; Sinha, Ameya; Babu Rajeev, C P; Chu, Trang T T; Mathai, Jessin; Ximei, Huang; Fuchs, Julian E; Shivananju, NanjundaSwamy; Bender, Andreas; Preiser, Peter Rainer; Rangappa, Kanchugarakoppal S; Basappa; Chandramohanadas, Rajesh

    2015-11-21

    Malaria parasites are currently gaining drug-resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical scaffolds, with superior antimalarial activity remain an important priority, for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium falciparum parasites in vitro. The screening results showed potent inhibitory activity of a number of novel sulphonamides against P. falciparum at low micromolar concentrations, in particular in late-stage parasite development. Based on computational studies we hypothesize N-myristoyltransferase as the target of the compounds developed here. Our results demonstrate the value of novel bepotastine-based sulphonamide compounds for targeting the asexual developmental stages of P. falciparum.

  7. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    Directory of Open Access Journals (Sweden)

    Asrar Alam

    2014-01-01

    Full Text Available Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets.

  8. Validation of use of a traditional antimalarial remedy from French Guiana, Zanthoxylum rhoifolium Lam.

    Science.gov (United States)

    Jullian, V; Bourdy, G; Georges, S; Maurel, S; Sauvain, M

    2006-07-19

    Zanthoxylum rhoifolium bark (Rutaceae) is a medicinal plant, traditionally used in French Guiana to treat and prevent malaria. Bioassay-guided extractions of Zanthoxylum rhoifolium bark have shown that antiplasmodial activity is concentrated in the alkaloid fraction. Further fractionation of this extract has yielded seven benzophenanthridine alkaloids, dihydroavicine 1, dihydronitidine 2, oxyavicine 3, oxynitidine 4, fagaridine 5, avicine 6 and nitidine 7. Antimalarial activity of the last five compounds has been evaluated, and nitidine was the most potent, displaying an IC(50)<0.27microM against Plasmodium falciparum. Investigation of the traditional remedy, a trunk bark decoction in water, has shown that fagaridine 5, avicine 6 and nitidine 7 are also present in the decoction, therefore justifying the traditional use of Zanthoxylumrhoifolium bark as antimalarial.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. 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.

  11. On the molecular basis of the activity of the antimalarial drug chloroquine: EXAFS-assisted DFT evidence of a direct Fe-N bond with free heme in solution

    Science.gov (United States)

    Macetti, Giovanni; Rizzato, Silvia; Beghi, Fabio; Silvestrini, Lucia; Lo Presti, Leonardo

    2016-02-01

    4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking π···π interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0-5.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe-N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies.

  12. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

    Directory of Open Access Journals (Sweden)

    Tatyana Andreyevna Lisitsyna

    2010-01-01

    Full Text Available The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  13. Relative and Absolute Stereochemistry of Diacarperoxides: Antimalarial Norditerpene Endoperoxides from Marine Sponge Diacarnus megaspinorhabdosa

    Directory of Open Access Journals (Sweden)

    Fan Yang

    2014-08-01

    Full Text Available Five new norditerpene endoperoxides, named diacarperoxides H–L (1–5, and a new norditerpene diol, called diacardiol B (6, were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined by using spectroscopic analyses, computational approaches and chemical degradation. Diacarperoxides H–J (1–3 showed some interesting stereochemical issues, as well as antimalarial activity.

  14. Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds.

    Science.gov (United States)

    Guantai, Eric M; Ncokazi, Kanyile; Egan, Timothy J; Gut, Jiri; Rosenthal, Philip J; Smith, Peter J; Chibale, Kelly

    2010-12-01

    A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC(50) values against the D10, Dd2 and W2 strains of Plasmodium falciparum.

  15. Validation of use of a traditional antimalarial remedy from French Guiana, Zanthoxylum rhoifolium Lam

    OpenAIRE

    Jullian, Valérie; Bourdy, Geneviève; GEORGES, S.; Maurel, Séverine; Sauvain, Michel

    2006-01-01

    Zanthoxylum rhoifolium bark (Rutaceae) is a medicinal plant, traditionally used in French Guiana to treat and prevent malaria. Bioassay-guided extractions of Zanthoxylum rhoifolium bark have shown that antiplasmodial activity is concentrated in the alkaloid fraction. Further fractionation of this extract has yielded seven benzophenanthridine alkaloids, dihydroavicine 1, dihydronitidine 2, oxyavicine 3, oxynitidine 4, fagaridine 5, avicine 6 and nitidine 7. Antimalarial activity of the last fi...

  16. Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs

    OpenAIRE

    Movellan, Julie; Urbán, Patricia; Moles, Ernest; de la Fuente, Jesús M.; Sierra, Teresa; Serrano, José Luis; Fernàndez-Busquets, Xavier

    2014-01-01

    It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pl...

  17. 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.

  18. Molecular surveillance of antimalarial drug resistance related genes in Plasmodium falciparum isolates from Eritrea.

    Science.gov (United States)

    Menegon, Michela; Nurahmed, Abduselam M; Talha, Albadawi A; Nour, Bakri Y M; Severini, Carlo

    2016-05-01

    The introduction of artemisinin-based combination therapy has led to extraordinary results in malaria control, however the recent emergence of partial resistance to artemisinin therapy in Southeast Asia jeopardizes these successes. This study aimed at investigating resistance to the antimalarial drugs by evaluating the polymorphisms in the PfK13, Pfcrt and Pfmdr1 genes in Plasmodium falciparum isolates obtained from patients in Eritrea.

  19. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    OpenAIRE

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  20. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  1. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    Energy Technology Data Exchange (ETDEWEB)

    Phukon, Pinkee [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Radhapyari, Keisham [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India); Konwar, Bolin Kumar [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Nagaland University (Central), Lumami, Zunheboto, Nagaland 798627 (India); Khan, Raju, E-mail: khan.raju@gmail.com [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India)

    2014-04-01

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL{sup −1}) with sensitivity of 0.26 μA μg mL{sup −1}. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL{sup −1} and 0.0036 μg mL{sup −1} in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor.

  2. Glycosides as possible lead antimalarial in new drug discovery: future perspectives.

    Science.gov (United States)

    Marya; Khan, Haroon; Ahmad, Izhar

    2017-01-15

    Malaria remains one of the major public health problems worldwide and is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drug-resistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasizes how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycosides is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds.

  3. Synergistic in vitro antimalarial activity of plant extracts used as traditional herbal remedies in Mali.

    Science.gov (United States)

    Azas, N; Laurencin, N; Delmas, F; Di, Giorgio C; Gasquet, M; Laget, M; Timon-David, P

    2002-02-01

    In Mali, where malaria is endemic, plants are extensively used for treating periodic fevers and malaria. According to the advice of traditional medicine, plants are often mixed during the preparation of febrifugal decoctions. In previous studies, we demonstrated the potent in vitro antimalarial activity of extracts isolated from four plants commonly used in traditional remedies: Mitragyna inermis (Willd.) O. Kuntze, Rubiaceae, Nauclea latifolia (Sm.), Rubiaceae, Guiera senegalensis (Gmel.), Combretaceae, and Feretia apodanthera (Del.), Rubiaceae. In the present work, we evaluate the potent in vitro synergistic antimalarial interaction between these extracts, using standard isobologram analysis. Then, we evaluate their cytotoxicity on human monocytes and their mutagenic activity on an in vitro system of two beta-carboline alkaloids isolated from Guiera senegalensis (harman and tetrahydroharman). Three combinations demonstrate a strong, synergistic, inhibitory effect on in vitro plasmodial development and are devoid of cytotoxicity towards human cells. These results justify their use in association in traditional medicine. Moreover, tetrahydroharman, isolated from G. senegalensis, presents interesting antimalarial activity, no cytotoxicity and is not genotoxic in the Salmonella Ames test with and without metabolic activation.

  4. [Plasmodium falciparum susceptibility to antimalarial drugs: global data issued from the Pasteur Institutes international network].

    Science.gov (United States)

    Ménard, Didier; Ariey, Frédéric; Mercereau-Puijalon, Odile

    2013-01-01

    Malaria research units within the Institut Pasteur international network (RIIP-Palu) located in Africa, in South-East Asia and in South America, work for many years in close collaboration with the National malaria control programmes. Relying on technical platforms with well-equipped laboratories and scientific expertise, they are at the forefront of research on the antimalarial drug resistance by working together for training young scientists and developping similar protocols allowing comprehensive comparisons. Including fundamental and operational researches, they conduct regional and international projects which aim (1) to detect the emergence of antimalarial drugs resistant parasites and to evaluate their spatio-temporal distribution, (2) to develop in vitro and molecular tools, (3) to identify epidemiological factors involved in the emergence and the spread of antimalarial drugs resistant parasites and (4) to understand the molecular and cellular mechanisms implicated in resistance. In this review, will be presented methodological approaches and data obtained since 2000.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. A better resolution for integrating methods for monitoring Plasmodium falciparum resistance to antimalarial drugs.

    Science.gov (United States)

    Abdul-Ghani, Rashad; Al-Maktari, Mohamed T; Al-Shibani, Latifa A; Allam, Amal F

    2014-09-01

    Effective chemotherapy is the mainstay of malaria control. However, resistance of falciparum malaria to antimalarial drugs compromised the efforts to eliminate the disease and led to the resurgence of malaria epidemics. Three main approaches are used to monitor antimalarial drug efficacy and drug resistance; namely, in vivo trials, in vitro/ex vivo assays and molecular markers of drug resistance. Each approach has its implications of use as well as its advantages and drawbacks. Therefore, there is a need to use an integrated approach that would give the utmost effect to detect resistance as early as its emergence and to track it once spread. Such integration becomes increasingly needed in the era of artemisinin-based combination therapy as a forward action to deter resistance. The existence of regional and global networks for the standardization of methodology, provision of high quality reagents for the assessment of antimalarial drug resistance and dissemination of open-access data would help in approaching an integrated resistance surveillance system on a global scale.

  7. New developments in anti-malarial target candidate and product profiles.

    Science.gov (United States)

    Burrows, Jeremy N; Duparc, Stephan; Gutteridge, Winston E; Hooft van Huijsduijnen, Rob; Kaszubska, Wiweka; Macintyre, Fiona; Mazzuri, Sébastien; Möhrle, Jörg J; Wells, Timothy N C

    2017-01-13

    A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

  8. Transesterification of waste vegetable oil under pulse sonication using ethanol, methanol and ethanol-methanol mixtures.

    Science.gov (United States)

    Martinez-Guerra, Edith; Gude, Veera Gnaneswar

    2014-12-01

    This study reports on the effects of direct pulse sonication and the type of alcohol (methanol and ethanol) on the transesterification reaction of waste vegetable oil without any external heating or mechanical mixing. Biodiesel yields and optimum process conditions for the transesterification reaction involving ethanol, methanol, and ethanol-methanol mixtures were evaluated. The effects of ultrasonic power densities (by varying sample volumes), power output rates (in W), and ultrasonic intensities (by varying the reactor size) were studied for transesterification reaction with ethanol, methanol and ethanol-methanol (50%-50%) mixtures. The optimum process conditions for ethanol or methanol based transesterification reaction of waste vegetable oil were determined as: 9:1 alcohol to oil ratio, 1% wt. catalyst amount, 1-2 min reaction time at a power output rate between 75 and 150 W. It was shown that the transesterification reactions using ethanol-methanol mixtures resulted in biodiesel yields as high as >99% at lower power density and ultrasound intensity when compared to ethanol or methanol based transesterification reactions.

  9. Methanol utilizing Desulfotomaculum species utilizes hydrogen in a methanol-fed sulfate-reducing bioreactor

    NARCIS (Netherlands)

    Balk, M.; Weijma, J.; Goorissen, H.P.; Ronteltap, M.; Hansen, T.A.; Stams, A.J.M.

    2007-01-01

    A sulfate-reducing bacterium, strain WW1, was isolated from a thermophilic bioreactor operated at 65 degrees C with methanol as sole energy source in the presence of sulfate. Growth of strain WW1 on methanol or acetate was inhibited at a sulfide concentration of 200 mg l(-1), while on H-2/CO2, no ap

  10. Antimalarial Properties of Aqueous Crude Extracts of Gynostemma pentaphyllum and Moringa oleifera Leaves in Combination with Artesunate in Plasmodium berghei-Infected Mice.

    Science.gov (United States)

    Somsak, Voravuth; Borkaew, Preeyanuch; Klubsri, Chokdee; Dondee, Kittiyaporn; Bootprom, Panatda; Saiphet, Butsarat

    2016-01-01

    Due to the emergence and spread of malaria parasite with resistance to antimalarial drugs, discovery and development of new, safe, and affordable antimalarial are urgently needed. In this respect, medicinal plant extracts are targets to optimize antimalarial actions and restore efficacy of standard antimalarial drugs. The present study was aimed at determining the antimalarial activities of Gynostemma pentaphyllum and Moringa oleifera leaf extracts in combination with artesunate against Plasmodium berghei-infected mice. P. berghei ANKA maintained by serial passage in ICR mice were used based on intraperitoneal injection of 1 × 10(7) parasitized erythrocytes and subsequent development of parasitemia. These infected mice were used to investigate the antimalarial activity of artesunate (6 mg/kg) in combination with 500, 1,000, and 2,000 mg/kg of G. pentaphyllum and M. oleifera leaf extracts using 4-day suppressive test. It was found that these extracts showed significant (P leaf extract and 35, 40, and 50% for M. oleifera leaf extract. Additionally, artesunate combined with these extracts presented higher antimalarial activity, compared to extract treated alone with percentage of suppression of 78, 91, and 96% for G. pentaphyllum leaf extract and 73, 82, and 91% for M. oleifera leaf extract. The results indicated that combination treatment of G. pentaphyllum or M. oleifera leaf extracts with artesunate was able to increase the antimalarial activity by using low dose of artesunate. Hence, these results justified the combination of these extracts and artesunate in antimalarial herbal remedies.

  11. Methanol exchange between grassland and the atmosphere

    Directory of Open Access Journals (Sweden)

    A. Brunner

    2007-01-01

    Full Text Available Concentrations and fluxes of methanol were measured above two differently managed grassland fields (intensive and extensive in central Switzerland during summer 2004. The measurements were performed with a proton-transfer-reaction mass-spectrometer and fluxes were determined by the eddy covariance method. The observed methanol emission showed a distinct diurnal cycle and was strongly correlated with global radiation and water vapour flux. Mean and maximum daily emissions were found to depend on grassland species composition and, for the intensive field, also on the growing state. The extensive field with a more complex species composition had higher emissions than the graminoid-dominated intensive field, both on an area and on a biomass basis. A simple parameterisation depending on the water vapour flux and the leaf area index allowed a satisfying simulation of the temporal variation of methanol emissions over the growing phase. Accumulated carbon losses due to methanol emissions accounted for 0.024 and 0.048% of net primary productivity for the intensive and extensive field, respectively. The integral methanol emissions over the growing periods were more than one order of magnitude higher than the emissions related to cut and drying events.

  12. Molecular iodine catalyzed synthesis of tetrazolo[1,5-a]-quinoline based imidazoles as a new class of antimicrobial and antituberculosis agents

    Institute of Scientific and Technical Information of China (English)

    Divyesh C. Mungra; Harshad G. Kathrotiya; Niraj K. Ladani; Manish P. Patel; Ranjan G. Patel

    2012-01-01

    A series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 6a-I have been synthesized by a reaction of tetrazolo[1,5-a]quinoline-4-carbaldehyde 3a-d,benzil 4,aromatic amine 5a-c and ammonium acetate in the presence of iodine through one-pot multi-component reaction (MCR) approach.All the derivatives were screened for antimicrobial and antituberculosis activities and results worth further investigations.

  13. Methanol sensor operated in a passive mode

    Science.gov (United States)

    Ren, Xiaoming; Gottesfeld, Shimshon

    2002-01-01

    A sensor outputs a signal related to a concentration of methanol in an aqueous solution adjacent the sensor. A membrane electrode assembly (MEA) is included with an anode side and a cathode side. An anode current collector supports the anode side of the MEA and has a flow channel therethrough for flowing a stream of the aqueous solution and forms a physical barrier to control access of the methanol to the anode side of the MEA. A cathode current collector supports the cathode side of the MEA and is configured for air access to the cathode side of the MEA. A current sensor is connected to measure the current in a short circuit across the sensor electrodes to provide an output signal functionally related to the concentration of methanol in the aqueous solution.

  14. Efficient green methanol synthesis from glycerol

    Science.gov (United States)

    Haider, Muhammad H.; Dummer, Nicholas F.; Knight, David W.; Jenkins, Robert L.; Howard, Mark; Moulijn, Jacob; Taylor, Stuart H.; Hutchings, Graham J.

    2015-12-01

    The production of biodiesel from the transesterification of plant-derived triglycerides with methanol has been commercialized extensively. Impure glycerol is obtained as a by-product at roughly one-tenth the mass of the biodiesel. Utilization of this crude glycerol is important in improving the viability of the overall process. Here we show that crude glycerol can be reacted with water over very simple basic or redox oxide catalysts to produce methanol in high yields, together with other useful chemicals, in a one-step low-pressure process. Our discovery opens up the possibility of recycling the crude glycerol produced during biodiesel manufacture. Furthermore, we show that molecules containing at least two hydroxyl groups can be converted into methanol, which demonstrates some aspects of the generality of this new chemistry.

  15. Polarisation of Class II Methanol Masers

    CERN Document Server

    Stack, P D

    2011-01-01

    We have used the University of Tasmania Mt Pleasant 26m radio telescope to investigate the polarisation characteristics of a sample of strong 6.7 GHz methanol masers, the first spectral line polarisation observations to be undertaken with this instrument. As part of this process we have developed a new technique for calibrating linear polarisation spectral line observations. This calibration method gives results consistent with more traditional techniques, but requires much less observing time on the telescope. We have made the first polarisation measurements of a number of 6.7 GHz methanol masers and find linear polarisation at levels of a few - 10% in most of the sources we observed, consistent with previous results. We also investigated the circular polarisation produced by Zeeman splitting in the 6.7 GHz methanol maser G9.62+0.20 to get an estimate of the line of sight magnetic field strength of 35+/-7 mG.

  16. Radiolysis study of genistein in methanolic solution

    Science.gov (United States)

    Jung, Hee Jin; Park, Hae Ran; Jung, Uhee; Jo, Sung Kee

    2009-06-01

    The aim of the present work was to identify products obtained from genistein by ionizing radiation and to enhance the antioxidant properties of genistein through radiation-induced transformation. Genistein dissolved in methanol was irradiated γ-rays at a dose of 100 kGy. NMR and (HR) EI-MS spectroscopy were used to identify radiolysis products (GM1 and GM2). We proposed that rad CH 2OH may be implicated in the formation GM1 and GM2 during radiolysis of genistein in methanol. The genistein in methanol solution showed higher DPPH radical scavenging activity after γ-irradiation. Then, the antioxidant activities of radiolysis products were evaluated and compared to those of genistein.

  17. Excess Transport Properties of Binary Mixtures of Quinoline with Xylenes at Different Temperatures

    Directory of Open Access Journals (Sweden)

    Sk. Fakruddin

    2012-01-01

    Full Text Available The ultrasonic velocity and density of binary liquid mixtures of quinoline with o-xylene, m-xylene, and p-xylene have been measured over the entire range of composition at = 303.15, 308.15, 313.15, and 318.15 K. Using these data, various parameters like adiabatic compressibility (β, intermolecular free length (, and acoustic impedance ( and some excess parameters like excess adiabatic compressibility (, excess intermolecular free length (, excess acoustic impedance (, and excess ultrasonic velocity ( have been calculated for all the three mixtures. The calculated deviations and excess functions have been fitted to Redlich-Kister polynomial equation. The observed deviations have been explained on the basis of the intermolecular interactions present in these mixtures.

  18. Pyrazolo[3,4-h]quinolines promising photosensitizing agents in the treatment of cancer.

    Science.gov (United States)

    Spanò, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Salvador, Alessia; Brun, Paola; Vedaldi, Daniela; Diana, Patrizia; Cirrincione, Girolamo; Barraja, Paola

    2015-09-18

    A new series of pyrazolo[3,4-h]quinolines, heteroanalogues of angelicin was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI50 values reaching the nanomolar level (14.52-0.04 μM). Selected compounds were able to photoinduce a massive cell death with the involvement of mitochondria. Their photodamage cellular targets were proteins and lipids and they did not cause any kind of DNA photodamage. This latter event is of considerable importance in the modulation of long term side effects, generally associated with the use of classical furocoumarins.

  19. A fluorescence turn-on chemosensor for hydrogen sulfate anion based on quinoline and naphthalimide

    Science.gov (United States)

    Luo, Zaoli; Yin, Kai; Yu, Zhu; Chen, Mengxue; Li, Yan; Ren, Jun

    2016-12-01

    A new fluorescence turn-on chemosensor 1 based on quinoline and naphthalimide was prepared and its anion sensing toward various anions behavior was explored in this paper. Sensor 1 exhibited a highly selective fluorescent response toward HSO4- with an 8-fold fluorescence intensity enhancement in the presence of 10 equiv. of HSO4- in DMSO-H2O (1/1, v/v) solution. The sensor also displayed high sensitivity to hydrogen sulfate and the detection limit was calculated to be 7.79 × 10- 7 M. The sensing mechanism has been suggested to proceed via a hydrolysis process of the Schiff base group. The hydrolysis product has been isolated and further identified by 1H NMR and MS.

  20. Second-order optical effects in several pyrazolo-quinoline derivatives

    Science.gov (United States)

    Makowska-Janusik, M.; Gondek, E.; Kityk, I. V.; Wisła, J.; Sanetra, J.; Danel, A.

    2004-11-01

    Using optical poling of several pyazolo-quinoline (PAQ) derivatives we have found an existence of sufficiently high second order optical susceptibility at wavelength 1.76 μm varying in the range 0.9-2.8 pm/V. The performed quantum chemical simulations of the UV-absorption for isolated, solvated and incorporated into the polymethacrylate (PMMA) polymer films have shown that the PM3 method is the best among the semi-empirical ones to simulate the optical properties. The calculations of the hyperpolarizabilites have shown a good correlation with experimentally measured susceptibilities obtained from the optical poling. We have found that experimental susceptibility depends on linear molecular polarizability and photoinducing changes of the molecular dipole moment. It is clearly seen for the PAQ4-PAQ6 molecules possessing halogen atoms with relatively large polarizabilities.

  1. Second-order optical effects in several pyrazolo-quinoline derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Makowska-Janusik, M. [Solid State Department, Institute of Physics, WSP Czestochowa, Al. Armii Krajowej 13/15, Czestochowa PL42201 (Poland); Gondek, E. [Institute of Physics, Cracow University of Technology, ul. Podchorazych 1, 30-084 (Poland); Kityk, I.V. [Department of Biology and Biophysics, Technical University of Czestochowa, Al. Armii Krajowej 36, Czestochowa PL-42210 (Poland)]. E-mail: i.kityk@wsp.czest.pl; WisIa, J. [Departament of Chemistry, Hugon Kollataj Agricultural University, Al. Mickiewicza 24/28, 30-059 Cracow (Poland); Sanetra, J. [Institute of Physics, Cracow University of Technology, ul. Podchorazych 1, 30-084 (Poland); Danel, A. [Department of Chemistry, Hugon Kollataj Agricultural University, Al. Mickiewicza 24/28, 30-059 Cracow (Poland)

    2004-11-15

    Using optical poling of several pyazolo-quinoline (PAQ) derivatives we have found an existence of sufficiently high second order optical susceptibility at wavelength 1.76 {mu}m varying in the range 0.9-2.8 pm/V. The performed quantum chemical simulations of the UV-absorption for isolated, solvated and incorporated into the polymethacrylate (PMMA) polymer films have shown that the PM3 method is the best among the semi-empirical ones to simulate the optical properties. The calculations of the hyperpolarizabilites have shown a good correlation with experimentally measured susceptibilities obtained from the optical poling. We have found that experimental susceptibility depends on linear molecular polarizability and photoinducing changes of the molecular dipole moment. It is clearly seen for the PAQ4-PAQ6 molecules possessing halogen atoms with relatively large polarizabilities.

  2. Photocatalytic conversion of methane to methanol

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, C.E.; Noceti, R.P.; D`Este, J.R. [Pittsburgh Energy Technology Center, PA (United States)

    1995-12-31

    A long-term goal of our research group is the exploration of novel pathways for the direct oxidation of methane to liquid fuels, chemicals, and intermediates. The use of three relatively abundant and inexpensive reactants, light, water, and methane, to produce methanol is attractive. The products of reaction, methanol and hydrogen, are both commercially desirable, methanol being used as is or converted to a variety of other chemicals, and the hydrogen could be utilized in petroleum and/or chemical manufacturing. Methane is produced as a by-product of coal gasification. Depending upon reactor design and operating conditions, up to 18% of total gasifier product may be methane. In addition, there are vast proven reserves of geologic methane in the world. Unfortunately, a large fraction of these reserves are in regions where there is little local demand for methane and it is not economically feasible to transport it to a market. There is a global research effort under way in academia, industry, and government to find methods to convert methane to useful, more readily transportable and storable materials. Methanol, the initial product of methane oxidation, is a desirable product of conversion because it retains much of the original energy of the methane while satisfying transportation and storage requirements. Investigation of direct conversion of methane to transportation fuels has been an ongoing effort at PETC for over 10 years. One of the current areas of research is the conversion of methane to methanol, under mild conditions, using light, water, and a semiconductor photocatalyst. The use of three relatively abundant and inexpensive reactants, light, water, and methane, to produce methanol, is attractive. Research in the laboratory is directed toward applying the techniques developed for the photocatalytic splitting of the water and the photochemical conversion of methane.

  3. Photocytotoxicity of a 5-nitrofuran-ethenyl-quinoline antiseptic (Quinifuryl to P388 mouse leukemia cells

    Directory of Open Access Journals (Sweden)

    Daghastanli N.A.

    2004-01-01

    Full Text Available Quinifuryl (MW 449.52, 2-(5'-nitro-2'-furanylethenyl-4-{N-[4'-(N,N-diethylamino-1'-methylbutyl]carbamoyl} quinoline, is a water soluble representative of a family of 5-nitrofuran-ethenyl-quinoline drugs which has been shown to be highly toxic to various lines of transformed cells in the dark. In the present study, the toxicity of Quinifuryl to P388 mouse leukemia cells was compared in the dark and under illumination with visible light (390-500 nm. Illumination of water solutions of Quinifuryl (at concentrations ranging from 0.09 to 9.0 µg/ml in the presence of P388 cells resulted in its photodecomposition and was accompanied by elevated cytotoxicity. A significant capacity to kill P388 cells was detected at a drug concentration as low as 0.09 µg/ml. The toxic effect detected at this drug concentration under illumination exceeded the effect observed in the dark by more than three times. Moreover, the general toxic effect of Quinifuryl, which included cell proliferation arrest, was nearly 100%. Both dose- and time-dependent toxic effects were measured under illumination. The LC50 value of Quinifuryl during incubation with P388 cells was ~0.45 µg/ml under illumination for 60 min and >12 µg/ml in the dark. We have demonstrated that the final products of the Quinifuryl photolysis are not toxic, which means that the short-lived intermediates of Quinifuryl photodecomposition are responsible for the phototoxicity of this compound. The data obtained in the present study are the first to indicate photocytotoxicity of a nitroheterocyclic compound and demonstrate the possibility of its application as a photosensitizer drug for photochemotherapy.

  4. Synthesis and Optimization of a Methanol Process

    DEFF Research Database (Denmark)

    Grue, J.; Bendtsen, Jan Dimon

    2003-01-01

    In the present paper, a simulation model for a methanol process is proposed. The objective is to develop a model for flowsheet optimization, which requires simple thermodynamic and unit operation models. Simplified thermodynamic models are combined with a more advanced model for the rate of react......In the present paper, a simulation model for a methanol process is proposed. The objective is to develop a model for flowsheet optimization, which requires simple thermodynamic and unit operation models. Simplified thermodynamic models are combined with a more advanced model for the rate...

  5. Synthesis and Optimization of a Methanol Proces

    DEFF Research Database (Denmark)

    Grue, J.; Bendtsen, Jan Dimon

    2003-01-01

    In the present paper, a simulation model for a methanol process is proposed. The objective is to develop a model for flowsheet optimization, which requires simple thermodynamic and unit operation models. Simplified thermodynamic models are combined with a more advanced model for the rate of react......In the present paper, a simulation model for a methanol process is proposed. The objective is to develop a model for flowsheet optimization, which requires simple thermodynamic and unit operation models. Simplified thermodynamic models are combined with a more advanced model for the rate...

  6. Silicon Based Direct Methanol Fuel Cells

    DEFF Research Database (Denmark)

    Larsen, Jackie Vincent

    The purpose of this project has been to investigate and fabricate small scale Micro Direct Methanol Fuel Cells (μDMFC). They are investigated as a possible alternative for Zinc-air batteries in small size consumer devices such as hearing aids. In such devices the conventional rechargeable batteries...... such as lithium-ion batteries have insufficiently low energy density. Methanol is a promising fuel for such devices due to the high energy density and ease of refueling compared to charging batteries, making μDMFC a suitable replacement energy source. In this Ph.D. dissertation, silicon micro fabrication...

  7. Abacavir methanol 2.5-solvate

    Directory of Open Access Journals (Sweden)

    Phuong-Truc T. Pham

    2009-08-01

    Full Text Available The structure of abacavir (systematic name: {(1S,4R-4-[2-amino-6-(cyclopropylamino-9H-purin-9-yl]cyclopent-2-en-1-yl}methanol, C14H18N6O·2.5CH3OH, consists of hydrogen-bonded ribbons which are further held together by additional hydrogen bonds involving the hydroxyl group and two N atoms on an adjacent purine. The asymmetric unit also contains 2.5 molecules of methanol solvate which were grossly disordered and were excluded using SQUEEZE subroutine in PLATON [Spek, (2009. Acta Cryst. D65, 148–155].

  8. Effect of 8-hydroxy-, 8-mercapto- and 5-chloro-7-iodo-8-hydroxy-quinoline on the uptake and distribution of nickel in mice

    Energy Technology Data Exchange (ETDEWEB)

    Borg-Neczak, K.; Tjaelve, H. (Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala Biomedical Centre, Uppsala (Sweden))

    1994-01-01

    Oral administration of Ni[sup 2+] together with 8-hydroxyquinoline (8-OH-quinoline), 8-mercaptoquinoline (8-SH-quinoline) or 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) resulted in increased tissue levels of the metal in several tissues of mice in comparison with animals given the Ni[sup 2+] alone. Ni[sup 2+] forms lipophilic complexes with these compounds and it can be assumed that this will facilitate the uptake of Ni[sup 2+] over the walls of the gastrointestinal tract. Our results showed that 8-SH-quinoline, in contrast to 8-OH-quinoline and clioquinol, induces a markedly changed distribution pattern of the Ni[sup 2+] in the body, with uptake of the metal in tissues such as the central nervous system, pigmented tissues, the pancreatic islets and the thyroid. It is probable that the Ni[sup 2+] -complex with 8-SH-quinoline is stable enough to persist for a time period in the tissues and that the obtained pattern partly reflects the distribution of the complexed metal. In contrast, following the absorption from the gastrointestinal tract there may be a dissociation of the complexes between Ni[sup 2+] and 8-OH-quinoline or clioquinol, resulting in increased metal levels in various tissues, but with similar distribution as when the Ni[sup 2+] is given alone. (au) (21 refs.).

  9. 37 GHz methanol masers : Horsemen of the Apocalypse for the class II methanol maser phase?

    CERN Document Server

    Ellingsen, S P; Sobolev, A M; Voronkov, M A; Caswell, J L; Lo, N

    2011-01-01

    We report the results of a search for class II methanol masers at 37.7, 38.3 and 38.5 GHz towards a sample of 70 high-mass star formation regions. We primarily searched towards regions known to show emission either from the 107 GHz class II methanol maser transition, or from the 6.035 GHz excited OH transition. We detected maser emission from 13 sources in the 37.7 GHz transition, eight of these being new detections. We detected maser emission from three sources in the 38 GHz transitions, one of which is a new detection. We find that 37.7 GHz methanol masers are only associated with the most luminous 6.7 and 12.2 GHz methanol maser sources, which in turn are hypothesised to be the oldest class II methanol sources. We suggest that the 37.7 GHz methanol masers are associated with a brief evolutionary phase (of 1000-4000 years) prior to the cessation of class II methanol maser activity in the associated high-mass star formation region.

  10. METHANOL REMOVAL FROM METHANOL-WATER MIXTURE USING ACTIVATED SLUDGE, AIR STRIPPING AND ADSORPTION PROCESS: COMPARATIVE STUDY

    Directory of Open Access Journals (Sweden)

    SALAM K. AL-DAWERY

    2015-12-01

    Full Text Available An experimental research has been carried out in order to examine the removal of methanol from methanol-water mixtures using three different methods; activated sludge; activated carbon and air stripping. The results showed that the methanol was totally consumed by the bacteria as quickly as the feed entered the activated sludge vessel. Air stripping process has a limited ability for removing of methanol due to strong intermolecular forces between methanol and water; however, the results showed that the percentage of methanol removed using air pressure at 0.5 bar was higher than that of using air pressure of 0.25 bar. Removal of methanol from the mixture with a methanol content of 5% using activated carbon was not successful due to the limited capacity of the of the activated carbon. Thus, the activated sludge process can be considered as the most suitable process for the treatment of methanol-water mixtures.

  11. Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.

    Science.gov (United States)

    Chugh, Monika; Scheurer, Christian; Sax, Sibylle; Bilsland, Elizabeth; van Schalkwyk, Donelly A; Wicht, Kathryn J; Hofmann, Natalie; Sharma, Anil; Bashyam, Sridevi; Singh, Shivendra; Oliver, Stephen G; Egan, Timothy J; Malhotra, Pawan; Sutherland, Colin J; Beck, Hans-Peter; Wittlin, Sergio; Spangenberg, Thomas; Ding, Xavier C

    2015-02-01

    Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.

  12. Effect of Methanol Crossover in a Liquid-FeedPolymer-Electrolyte Direct Methanol Fuel Cell

    OpenAIRE

    Ravikumar, MK; Shukla, AK

    1996-01-01

    The performance of a liquid-feed direct methanol fuel cell employing a proton-exchange membrane electrolyte with Pt-Ru/C as anode and Pt/C as cathode is reported. The fuel cell can deliver a power density of ca. 0.2 $W/cm^2$ at 95°C, sufficient to suggest that the stack construction is well worthwhile.Methanol crossover across the polymer electrolyte at concentrations beyond 2 M methanol affects the performance of the cell which appreciates with increasing operating temperature.

  13. Metacridamide B methanol-d4 monosolvate

    Science.gov (United States)

    The title compound was extracted from conidia of the fungus Metarhizium acridum. Crystals were obtained as a methanol-d4 solvate. The tail part of the 4-methylhexan-2-yl group exhibits disorder over two positions, with an occupancy ratio of 0.682 (9):0.318 (9). The crystal structure confirms the abs...

  14. Parameters affecting methanol utilization by yeasts

    Energy Technology Data Exchange (ETDEWEB)

    Foda, M.S.; El-Masry, H.G.

    1981-01-01

    Screening of 28 yeast cultures, representing 22 species of various yeasts, with respect to their capabilities to assimilate methanol, has shown that this property was mostly found in certain species of the two genera Hansenula and Candida. When methanol was used as a sole carbon source for a methanol-adapted strain of Hansenula polymorpha, a linear yield response could be obtained with increasing alcohol up to 2% concentration. The amount of inoculum proved to be the decisive factor in determining a priori the ability of the organism to grow at 6% methanol as final concentration. The optimum pH values for growth ranged between 4.5-5.5 with no growth at pH 6.5 or higher. A marked growth stimulation was obtained when the medium was supplied with phosphate up to 0.08 M as final concentration. Within the nitrogen sources tested, corn steep liquor concentrate gave the highest yield of cells. The significance of the obtained results are discussed with reference to feasibilities of application.

  15. Engineering Escherichia coli for methanol conversion

    NARCIS (Netherlands)

    Müller, Jonas E N; Meyer, Fabian; Litsanov, Boris; Kiefer, Patrick; Potthoff, Eva; Heux, Stéphanie; Quax, Wim J; Wendisch, Volker F; Brautaset, Trygve; Portais, Jean-Charles; Vorholt, Julia A

    2015-01-01

    Methylotrophic bacteria utilize methanol and other reduced one-carbon compounds as their sole source of carbon and energy. For this purpose, these bacteria evolved a number of specialized enzymes and pathways. Here, we used a synthetic biology approach to select and introduce a set of "methylotrophy

  16. Methanol and acetaldehyde fluxes over ryegrass

    Science.gov (United States)

    Custer, Thomas; Schade, Gunnar

    2007-09-01

    Oxygenated volatile organic compounds (OVOCs) play an active role in tropospheric chemistry but our knowledge concerning their release and ultimate fate is limited. However, the recent introduction of Proton Transfer Reaction Mass Spectrometry (PTRMS) has improved our capability to make direct field observations of OVOC mixing ratios and fluxes. We used PTRMS in an eddy covariance setup to measure selected OVOC exchange rates above a well-characterized agricultural plot in Northern Germany. In fall 2003, mixing ratios of methanol and acetaldehyde 2 m above the field ranged from 1 to 10 and 0.4 to 2.1 ppb, respectively, well correlated with one another. Fluxes of both gases were followed for growing Italian ryegrass (Lolium multiflorum) over a significant portion of its life cycle. Diurnally fluctuating emissions of methanol and very small acetaldehyde fluxes were observed up to the cutting and removal of the grass. Methanol emissions were exponentially related to ambient temperatures and appeared to be higher during the grass' rapid leaf area expansion and after a rain event. Acetaldehyde exchanges averaged over the whole period indicated very slow deposition. Our measurements confirm previous, similar results, as well as presumptions that grasses are comparatively low methanol emitters compared to non-grass species.

  17. Methanol emission from low mass protostars

    CERN Document Server

    Maret, S; Tielens, A G G M; Caux, E; Le Floc'h, B; Faure, A; Castets, A; Flower, D R

    2005-01-01

    We present observations of methanol lines in a sample of Class 0 low mass protostars. Using a 1-D radiative transfer model, we derive the abundances in the envelopes. In two sources of the sample, the observations can only be reproduced by the model if the methanol abundance is enhanced by about two order of magnitude in the inner hot region of the envelope. Two other sources show similar jumps, although at a lower confidence level. The observations for the other three sources are well reproduced with a constant abundance, but the presence of a jump cannot be ruled out. The observed methanol abundances in the warm gas around low mass protostars are orders of magnitude higher than gas phase chemistry models predict. Hence, in agreement with other evidences, this suggest that the high methanol abundance reflects recent evaporation of ices due to the heating by the newly formed star. The observed abundance ratios of CH3 OH, H2 CO, and CO are in good agreement with grain surface chemistry models. However, the abs...

  18. Optimized fuel cell grade hydrogen from methanol

    Science.gov (United States)

    Choi, Yongtaek

    2003-10-01

    To evaluate reaction rates liar making hydrogen from methanol, kinetic studies of methanol decomposition, methanol steam reforming, water gas shift reaction, and CO selective oxidation have been performed. These reactions were studied in a micro reactor testing unit using a commercial Cu-ZnO/Al2O3 catalyst for the first three reactions and Pt-Fe/gamma-alumina catalyst for the last reaction. The activity tests were performed between 120˜325°C and atmospheric pressure with a range of feed rates and compositions. For methanol decomposition, water addition to the feed increased the yield of hydrogen and reduced the formation of by-products. XPS analysis of used catalyst samples and time on-stream data showed that the Cu2+ oxidation state of copper favors methanol decomposition. A simplified reaction network of 5 elementary reactions was proposed and all five rate expressions were obtained using non-linear least squares optimization, numerical integration of a one-dimensional PFR model, and extensive experimental data. Similar numerical analysis was carried out to obtain the rate expressions for methanol steam reaction, the water gas shift reaction, and CO selective oxidation. For the kinetics of the water gas shift reaction, an empirical rate expression was obtained from the experimental data. Based on a review of published work on the WGS reaction mechanism, our study found that a rate expression derived from a regenerative mechanism and another rate expression derived from adsorptive mechanism fit the experimental data equally well. For the kinetics of CO preferential oxidation, a reaction model in which three reactions (CO oxidation, H2 oxidation and the WGS reaction) occur simultaneously was chosen to predict the reactor performance. In particular the reverse water gas shift reaction had an important role when fitting the experimental data precisely and explained the selectivity decrease at higher reaction temperatures. Combining the three reactors and several

  19. CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity.

    Science.gov (United States)

    Roy, Kuldeep K; Bhunia, Shome S; Saxena, Anil K

    2011-09-01

    The integrated ligand- and structure-based drug design techniques have been applied on a homogeneous dataset of thiolactone-class of potent anti-malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q(2) = 0.716) and CoMSIA (q(2) = 0.632) models well explained structure-activity variation in both the training (CoMFA R(2) = 0.948 & CoMSIA R(2) = 0.849) and test set (CoMFA R(2) (pred) = 0.789 & CoMSIA R(2) (pred) = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high-resolution (2.35 Å) structure of FabB-TLM binary complex (PDB-ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H-bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein-ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone-class of compounds that could furnish improved anti-malarial activity.

  20. Ruthenium-catalysed synthesis of 2- and 3-substituted quinolines from anilines and 1,3-diols

    DEFF Research Database (Denmark)

    Monrad, Rune Nygaard; Madsen, Robert

    2011-01-01

    A straightforward synthesis of substituted quinolines is described by cyclocondensation of anilines with 1,3-diols. The reaction proceeds in mesitylene solution with catalytic amounts of RuCl3·xH 2O, PBu3 and MgBr2·OEt2. The transformation does not require any stoichiometric additives and only...... produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy and chloro substituents as well as naphthylamines were shown to participate in the heterocyclisation. In the 1,3-diol a substituent was allowed in the 1- or the 2-position giving rise to 2- and 3-substituted quinolines......, respectively. The best results were obtained with 2-alkyl substituted 1,3-diols to afford 3-alkylquinolines. The mechanism is believed to involve dehydrogenation of the 1,3-diol to the 3-hydroxyaldehyde which eliminates water to the corresponding α,β-unsaturated aldehyde. The latter then reacts with anilines...

  1. CsxH3-xPW12O40 heteropoly salts catalyzed quinoline synthesis via Friedlander reaction

    Institute of Scientific and Technical Information of China (English)

    Ezzat Rafiee; Fereshte Khajooei Nejad; Mohammad Joshaghani

    2011-01-01

    Various type of cesium partially substituted phosphotungstate, CsxH3-xPW12O40 (x = 1.0, 2.0 and 2.5), were synthesized and their catalytic activities were investigated in the synthesis of quinoline. It was shown that catalytic activities of these catalysts correlated to surface acidity and total number of acidic sites. Finally, a series of quinoline derivatives were synthesized with Cs2.5H0.5PW12O40 via the Friedlander reaction in high to excellent yields and the plausible mechanism was proposed. Simple experiment, catalyst reusability, short reaction time and preclusion of toxic solvent are the advantages of this method.

  2. Regioselective Synthesis of C-3-Functionalized Quinolines via Hetero-Diels-Alder Cycloaddition of Azadienes with Terminal Alkynes.

    Science.gov (United States)

    Saunthwal, Rakesh K; Patel, Monika; Verma, Akhilesh K

    2016-08-05

    A highly efficient metal and protection-free approach for the regioselective synthesis of C-3-functionalized quinolines from azadienes (in situ generated from 2-aminobenzyl alcohol) and terminal alkynes through [4 + 2] cycloaddition has been developed. An unprecedented reaction of 2-aminobenzyl alcohol with 1,3- and 1,4-diethynylbenzene provided the C-3 tolylquinolines via [4 + 2] HDA and oxidative decarboxylation. The -NH2 group directed mechanistic approach was well supported by the control experiments and deuterium-labeling studies and by isolating the azadiene intermediate. The reactivity and selectivity of unprotected azadiene in metal-free base-assisted hetero-Diels-Alder reaction is exploited to quickly assemble an important class of C-3-functionalized quinolines, which are difficult to access.

  3. Selectivity of Direct Methanol Fuel Cell Membranes

    Science.gov (United States)

    Aricò, Antonino S.; Sebastian, David; Schuster, Michael; Bauer, Bernd; D’Urso, Claudia; Lufrano, Francesco; Baglio, Vincenzo

    2015-01-01

    Sulfonic acid-functionalized polymer electrolyte membranes alternative to Nafion® were developed. These were hydrocarbon systems, such as blend sulfonated polyetheretherketone (s-PEEK), new generation perfluorosulfonic acid (PFSA) systems, and composite zirconium phosphate–PFSA polymers. The membranes varied in terms of composition, equivalent weight, thickness, and filler and were investigated with regard to their methanol permeation characteristics and proton conductivity for application in direct methanol fuel cells. The behavior of the membrane electrode assemblies (MEA) was investigated in fuel cell with the aim to individuate a correlation between membrane characteristics and their performance in a direct methanol fuel cell (DMFC). The power density of the DMFC at 60 °C increased according to a square root-like function of the membrane selectivity. This was defined as the reciprocal of the product between area specific resistance and crossover. The power density achieved at 60 °C for the most promising s-PEEK-based membrane-electrode assembly (MEA) was higher than the benchmark Nafion® 115-based MEA (77 mW·cm−2 vs. 64 mW·cm−2). This result was due to a lower methanol crossover (47 mA·cm−2 equivalent current density for s-PEEK vs. 120 mA·cm−2 for Nafion® 115 at 60 °C as recorded at OCV with 2 M methanol) and a suitable area specific resistance (0.15 Ohm cm2 for s-PEEK vs. 0.22 Ohm cm2 for Nafion® 115). PMID:26610582

  4. Selectivity of Direct Methanol Fuel Cell Membranes

    Directory of Open Access Journals (Sweden)

    Antonino S. Aricò

    2015-11-01

    Full Text Available Sulfonic acid-functionalized polymer electrolyte membranes alternative to Nafion® were developed. These were hydrocarbon systems, such as blend sulfonated polyetheretherketone (s-PEEK, new generation perfluorosulfonic acid (PFSA systems, and composite zirconium phosphate–PFSA polymers. The membranes varied in terms of composition, equivalent weight, thickness, and filler and were investigated with regard to their methanol permeation characteristics and proton conductivity for application in direct methanol fuel cells. The behavior of the membrane electrode assemblies (MEA was investigated in fuel cell with the aim to individuate a correlation between membrane characteristics and their performance in a direct methanol fuel cell (DMFC. The power density of the DMFC at 60 °C increased according to a square root-like function of the membrane selectivity. This was defined as the reciprocal of the product between area specific resistance and crossover. The power density achieved at 60 °C for the most promising s-PEEK-based membrane-electrode assembly (MEA was higher than the benchmark Nafion® 115-based MEA (77 mW·cm−2 vs. 64 mW·cm−2. This result was due to a lower methanol crossover (47 mA·cm−2 equivalent current density for s-PEEK vs. 120 mA·cm−2 for Nafion® 115 at 60 °C as recorded at OCV with 2 M methanol and a suitable area specific resistance (0.15 Ohm cm2 for s-PEEK vs. 0.22 Ohm cm2 for Nafion® 115.

  5. Synthesis of spiro[benzo[ℎ]quinoline-7,3'- indolines] via a three-component condensation reaction

    Indian Academy of Sciences (India)

    Abbas Rahmati; Miranda Eskandari-Vashareh

    2014-01-01

    An efficient one-pot synthesis of a new series of spiro[benzo[ℎ]quinoline-7,3'-indoline] was accomplished simply by the reaction of an isatin, naphthalen-1-amine and a CH-acid (,-dimethylbarbituric acid, barbituric acid, dimedone or 1,3-indandion) in acetic acid. During this process, the effects of solvent and temperature have been investigated on the yield of reactions.

  6. 磷钼酸喹啉重量法测磷%Determination of Phosphorus Content Using Quinoline Phosphomolybdate

    Institute of Scientific and Technical Information of China (English)

    周校书

    2012-01-01

    Quinoline phosphomolybdate gravimetric determination of phosphorus ore and phosphorus pentoxide content in the concentrate,the method was accurate,reliable,and was the phosphate arbitration analysis,which corresponded with national standards GB/T 1871-80 and GB/T 1871.1-1995.International standard ISO 6598(Fertilizers-Determination of Phosphorus Content-Quinoline Phosphomolybdate Gravimetric Method) and the national standard GB 10512-89(Nitrate Fertilizer in the Determination of Phosphorus Quinoline Phosphomolybdate Gravimetric Method) were basically the same test procedure.It was used that quinoline molybdenum lemon ketone reagents,the glass filter of crucible type,and maintaining(180±2) ℃ constant temperature oven.Glass crucible-type filter was a special vessel.The feasibility of analysis of phosphorus pentoxide content was discussed by using ordinary filter paper instead of glass crucible filter.Tests showed that the method with an ordinary filter paper for analysis instead of glass crucible-type filter was practical,and its precision and accuracy met the requirements of GB/T 1871.1-1995.%磷钼酸喹啉重量法测定磷矿石和磷精矿中五氧化二磷含量,方法准确可靠,是磷矿的仲裁分析法。本文探讨了用普通滤纸代替玻璃坩埚式滤器分析五氧化二磷含量的可行性。试验表明,用普通滤纸代替玻璃坩埚式滤器切实可行,方法精密度和准确度能满足常规分析要求。

  7. Copper-catalyzed direct amination of quinoline N-oxides via C-H bond activation under mild conditions.

    Science.gov (United States)

    Zhu, Chongwei; Yi, Meiling; Wei, Donghui; Chen, Xuan; Wu, Yangjie; Cui, Xiuling

    2014-04-04

    A highly efficient and concise one-pot strategy for the direct amination of quinoline N-oxides via copper-catalyzed dehydrogenative C-N coupling has been developed. The desired products were obtained in good to excellent yields for 22 examples starting from the parent aliphatic amines. This methodology provides a practical pathway to 2-aminoquinolines and features a simple system, high efficiency, environmental friendliness, low reaction temperature, and ligand, additives, base, and external oxidant free conditions.

  8. Microwave-assisted Synthesis of Pyrazolo[4,3-f]quinolin-7-one Derivatives via Multi-component Reactions

    Institute of Scientific and Technical Information of China (English)

    PENG Juhua; HAO Wenjuan; WANG Xiang; TU Shujiang; MA Ning; ZHANG Ge

    2009-01-01

    A series of new pyrazolo[4,3-f]quinolin-7-one derivatives were synthesized by multi-component reactions of equimolar amount of aromatic aldehydes with 2,2-dimethyl-1,3-dioxane-4,6-dione and 1H-indazol-5-amine in ethylene glycol without catalyst under microwave irradiation.This one-pot protocol has the advantage of good yields,simple workup procedure and shorter reaction time.

  9. Conformational isomerization of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    A series of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives were designed and synthesized as anti-Mycobacterium tuberculosis drugs. NMR spectra showed that two conformational isomers of these compounds exist in solution,which is not due to cis-trans isomerization of amide bond. We proposed that the spatial interactions between three large aromatic groups caused the conformational isomerization,which was supported by molecular modeling and X-ray diffraction.

  10. Microwave-assisted synthesis of novel nonperipherally substituted metallophthalocyanines bearing (7-(trifluoromethyl)quinolin-4-yl)oxy groups

    OpenAIRE

    EVREN, Didem; YENİLMEZ, Hacer Yasemin; BURAT, Ayfer KALKAN

    2014-01-01

    The synthesis, characterization, and spectroscopic properties of novel nonperipherally tetrasubstituted metallophthalocyanines (zinc, cobalt, copper, manganese, and indium) bearing 4 (7-(trifluoromethyl)quinolin-4-yl)oxy units has been reported. The new compounds have been characterized using UV-Vis, IR, 1H NMR, 13C NMR, 19F NMR, and mass spectroscopic data. The absorption properties of these new complexes were compared to those of peripherally substituted phthalocyanine derivatives. Based on...

  11. Methanol poisoning. VI. Role of folic acid in the production of methanol poisoning in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Makar, A.B. (Alexandria Univ., Egypt); Tephly, T.R.

    1977-05-01

    Methanol poisoning is well known to occur in humans but does not develop in common laboratory animals such as the rat. Rodents display neither metabolic acidosis nor ocular toxicity after methanol treatment, findings that commonly result in humans and that have recently been described in the monkey. Since methanol administration in the monkey leads to marked accumulation of formic acid and metabolic acidosis, experiments were devised to reduce formate metabolism in the rat and thereby study whether methanol administration would lead to the accumulation of formic acid and acidosis in that species. Several methods were employed to induce a state of folate deficiency in the rat, a prerequisite to producing a decrease in formate oxidation to CO/sub 2/ in that species. Rats placed on a folate-deficient diet for 10-12 wk showed a marked decrease in formate oxidation and a marked sensitivity to methanol poisoning, as evidenced by high blood formate levels and marked decreases in blood pH. Treatment of rats with methotrexate was relatively ineffective in inducing decreases in formate oxidation, but in rats fed a folate-deficient diet for 9 days and injected once daily for 9 days with 1 mg/kg methotrexate, a significant elevation of blood formate and decrease in blood pH was observed. In rats that were acidotic following methanol administration no accumulation of formaldehyde was observed. These results indicate that it is possible to sensitize the rat to methanol poisoning by reducing its capacity to oxidize formate. They also show that once the rat is susceptible to methanol poisoning, metabolic acidosis and formate accumulation occur without the accumulation of formaldehyde.

  12. Design, synthesis and evaluation of antimalarial potential of polyphosphazene linked combination therapy of primaquine and dihydroartemisinin.

    Science.gov (United States)

    Kumar, Sahil; Singh, Rajesh K; Sharma, Rajiv; Murthy, R S R; Bhardwaj, T R

    2015-01-23

    Various polymer drug conjugates (13-16) such as primaquine and dihydroartemisinin conjugated 2-propoxy substituted polyphosphazenes (13), primaquine and dihydroartemisinin conjugated 4-acetamidophenoxy substituted polyphosphazenes (14), primaquine and dihydroartemisinin conjugated 4-formyl substituted polyphosphazenes (15) and primaquine and dihydroartemisinin conjugated 4-aminoethylbenzoate substituted polyphosphazenes (16) were synthesized using substituted polyphosphazenes as polymer and primaquine and dihydroartemisinin as combination antimalarial pharmacophores and formulated to nanoparticles to achieve novel controlled combined drug delivery approach for radical cure of malaria. The polymeric backbone was suitably substituted to impart different physicochemical properties. The polymer-drug conjugates were characterized by IR, (1)H NMR, (31)P NMR and their molecular weights were determined by Gel Permeation Chromatography. The thermal properties of the conjugates (13-16) were studied by DSC and TGA. The conjugates (13-16) were then formulated to nanoparticles formulations to increase their uptake by hepatocytes and to achieve targeted drug delivery. The nanoparticle formulations were characterized by Zeta Sizer and their morphology were studied by TEM (Transmission Electron Microscopy) imaging. The nanoparticles formulations exhibited biphasic in vitro drug release profile, the initial burst release followed by a sustained release owing to the non-fickian diffusion during first step release and fickian diffusion during second step release. In vivo antimalarial efficacy was tested using Plasmodium berghei (NK65 resistant strain) infected swiss albino mice at different doses. The combination therapy exhibited promising antimalarial efficacy at lower doses in comparison to the standard drug combination. Further, this combination therapy provided protection over 35days without any recrudescence, thus proving to be effective against resistant malaria. The study

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Synthesis and anticonvulsant activity of 7-benzylamino-4, 5-dihydro- [ 1, 2, 4] triazolo[ 4, 3-a] quinolines

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A series of 7-substituted-benzylamino-4, 5-dihydro-[ 1,2, 4]triazolo[4, 3-a] quinoline derivatives was synthesized and evaluated for their anticonvulsant activity. The subcutaneous pentylenetetrazole test (sc-PTZ) demonstrated that the most effective compound in controlling the sc-PTZ induced seizure was 7-(3-bromine-benzylamino)-4, 5-dihydro-[ 1,2, 4]triazolo[4, 3-a]quinoline (4j) with an ED50 of 5.0 mg/kg and the PI of 20.7, which was also safer than the reference drugs. And the maximal electroshock test (MES)demonstrated that among these derivatives, 7-(3-fluorobenzylamino) -4, 5-dihydro-[ 1,2, 4]trizolo[4, 3-a]quinoline (4i), with an ED50 of 15.3 mg/kg and the PI of 7.2, was the safest in MES test. Furthermore, their neurotoxicities were measured by the rotarod neurotoxicity test, and the results showed that all derivatives possessed lower neurotoxicity.

  16. Methanol production from Eucalyptus wood chips. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Fishkind, H.H.

    1982-06-01

    This feasibility study includes all phases of methanol production from seedling to delivery of finished methanol. The study examines: production of 55 million, high quality, Eucalyptus seedlings through tissue culture; establishment of a Eucalyptus energy plantation on approximately 70,000 acres; engineering for a 100 million gallon-per-day methanol production facility; potential environmental impacts of the whole project; safety and health aspects of producing and using methanol; and development of site specific cost estimates.

  17. 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

    Background 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). Methods and Findings 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

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

    Directory of Open Access Journals (Sweden)

    Benjamin Palafox

    Full Text Available BACKGROUND: 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. METHODS AND FINDINGS: 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

  19. Simultaneous observation of water and class I methanol masers toward class II methanol maser sources

    CERN Document Server

    Kang, Hyunwoo; Byun, Do-Young; Lee, Seokho; Park, Yong-Sun

    2015-01-01

    We present a simultaneous single-dish survey of 22 GHz water maser and 44 GHz and 95 GHz class I methanol masers toward 77 6.7 GHz class II methanol maser sources, which were selected from the Arecibo methanol maser Galactic plane survey (AMGPS) catalog.Water maser emission is detected in 39 (51%) sources, of which 15 are new detections. Methanol maser emission at 44 GHz and 95 GHz is found in 25 (32%) and 19 (25%) sources, of which 21 and 13 sources are newly detected, respectively. We find 4 high-velocity (> 30 km/s) water maser sources, including 3 dominant blue- or redshifted outflows.The 95 GHz masers always appear with the 44 GHz maser emission. They are strongly correlated with 44 GHz masers in velocity, flux density, and luminosity, while they are not correlated with either water or 6.7 GHz class II methanol masers. The average peak flux density ratio of 95 GHz to 44 GHz masers is close to unity, which is two times higher than previous estimates. The flux densities of class I methanol masers are more ...

  20. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development.

    Science.gov (United States)

    Deniskin, Roman; Frame, I J; Sosa, Yvett; Akabas, Myles H

    2016-04-01

    Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs). Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1). Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1) homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([(3)H]adenosine) and pyrimidines ([(3)H]uridine), whereas wild type (fui1Δ) yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM), compared to guanosine (14.9 μM) and adenosine (142 μM). For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range). IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR) had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1). The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel antimalarial drugs

  1. Molecular Farming in Artemisia annua, a sustainable approach to improve anti-malarial drug production

    Directory of Open Access Journals (Sweden)

    Giuseppe ePulice

    2016-03-01

    Full Text Available Malaria is a parasite infection affecting millions of people worldwide. Even though progresses in prevention and treatment have been developed, 198 million cases of malaria occurred in 2013, resulting in 584000 estimated deaths. 90% of all malaria deaths occurred in Africa, mostly among children under the age of five. This article aims to review malaria’s history, epidemiology and current treatments, with a particular focus on the potential of molecular farming that use metabolic engineering in plants as effective anti-malarial solution. Malaria indeed represents an example of how a health problem on one hand, may eventually influence the proper development of a country due to the burden of the disease, and on the other hand, constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is here proposed as a sustainable alternative for the production not only of natural herbal repellents used for malaria prevention but also for the production of sustainable anti-malarial drugs like artemisinin used for primary parasite infection treatments.Artemisinin, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua plant. However, the low concentration of artemisinin in plant makes this molecule relatively expensive and difficult to meet the worldwide demand of Artemisinin Combination Therapies, especially for economically disadvantaged people in developing countries. The biosynthetic pathway of artemisinin, a process that only takes place in glandular secretory trichomes of A. annua, is relatively well elucidated, and significant efforts using plant genetic engineering have been made to increase the production of this compound. These include studies on diverse transcription factors, which all have been shown to regulate artemisinin genetic pathway and other biological processes. Therefore, genetic manipulation of these genes may be used as a cost-effective potential

  2. In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

    Directory of Open Access Journals (Sweden)

    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

  3. Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials.

    Science.gov (United States)

    Yeates, Clive L; Batchelor, John F; Capon, Edward C; Cheesman, Neil J; Fry, Mitch; Hudson, Alan T; Pudney, Mary; Trimming, Helen; Woolven, James; Bueno, José M; Chicharro, Jesús; Fernández, Esther; Fiandor, José M; Gargallo-Viola, Domingo; Gómez de las Heras, Federico; Herreros, Esperanza; León, María L

    2008-05-08

    A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.

  4. Synthesis and antimalarial activity of new 3-arylquinoxaline-2-carbonitrile derivatives.

    Science.gov (United States)

    Zarranz, Belén; Jaso, Andrés; Aldana, Ignacio; Monge, Antonio; Maurel, Séverine; Deharo, Eric; Jullian, Valérie; Sauvain, Michel

    2005-01-01

    New series of 3-arylquinoxaline-carbonitrile derivatives have been synthesized from various 5-substituted or 5,6-disubstituted benzofuroxanes and tested for their in vitro and in vivo activity against the erythrocytic development of Plasmodium falciparum strain with different chloroquine-resistance status. Quinoxaline 1,4-dioxide derivatives showed superior antimalarial activity in respect to reduced quinoxaline analogues. The best activity was observed with nonsubstituted quinoxaline 1,4-dioxides in positions 6 and 7 of the aromatic ring and with a hydrogen or chloro substituent in para position of the phenyl group.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1 for antimalarial drug development

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    Roman Deniskin

    2016-04-01

    Full Text Available Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs. Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1. Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1 homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([3H]adenosine and pyrimidines ([3H]uridine, whereas wild type (fui1Δ yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM, compared to guanosine (14.9 μM and adenosine (142 μM. For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range. IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1. The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel

  8. Antimalarial drug resistance of Plasmodium falciparum in India: changes over time and space

    OpenAIRE

    Shah, Naman K.; Dhillon, Gajender P S; Dash, Adtiya P; Arora, Usha; Meshnick, Steven R.; Valecha, Neena

    2011-01-01

    After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that India’s large geographical...

  9. Antimalarial Properties of Aqueous Crude Extracts of Gynostemma pentaphyllum and Moringa oleifera Leaves in Combination with Artesunate in Plasmodium berghei-Infected Mice

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    Voravuth Somsak

    2016-01-01

    Full Text Available Due to the emergence and spread of malaria parasite with resistance to antimalarial drugs, discovery and development of new, safe, and affordable antimalarial are urgently needed. In this respect, medicinal plant extracts are targets to optimize antimalarial actions and restore efficacy of standard antimalarial drugs. The present study was aimed at determining the antimalarial activities of Gynostemma pentaphyllum and Moringa oleifera leaf extracts in combination with artesunate against Plasmodium berghei-infected mice. P. berghei ANKA maintained by serial passage in ICR mice were used based on intraperitoneal injection of 1 × 107 parasitized erythrocytes and subsequent development of parasitemia. These infected mice were used to investigate the antimalarial activity of artesunate (6 mg/kg in combination with 500, 1,000, and 2,000 mg/kg of G. pentaphyllum and M. oleifera leaf extracts using 4-day suppressive test. It was found that these extracts showed significant (P<0.05 antimalarial activity in dose-dependent manner with percentage of suppression of 45, 50, and 55% for G. pentaphyllum leaf extract and 35, 40, and 50% for M. oleifera leaf extract. Additionally, artesunate combined with these extracts presented higher antimalarial activity, compared to extract treated alone with percentage of suppression of 78, 91, and 96% for G. pentaphyllum leaf extract and 73, 82, and 91% for M. oleifera leaf extract. The results indicated that combination treatment of G. pentaphyllum or M. oleifera leaf extracts with artesunate was able to increase the antimalarial activity by using low dose of artesunate. Hence, these results justified the combination of these extracts and artesunate in antimalarial herbal remedies.

  10. Antimalarial Properties of Aqueous Crude Extracts of Gynostemma pentaphyllum and Moringa oleifera Leaves in Combination with Artesunate in Plasmodium berghei-Infected Mice

    Science.gov (United States)

    Borkaew, Preeyanuch; Klubsri, Chokdee; Dondee, Kittiyaporn; Bootprom, Panatda; Saiphet, Butsarat

    2016-01-01

    Due to the emergence and spread of malaria parasite with resistance to antimalarial drugs, discovery and development of new, safe, and affordable antimalarial are urgently needed. In this respect, medicinal plant extracts are targets to optimize antimalarial actions and restore efficacy of standard antimalarial drugs. The present study was aimed at determining the antimalarial activities of Gynostemma pentaphyllum and Moringa oleifera leaf extracts in combination with artesunate against Plasmodium berghei-infected mice. P. berghei ANKA maintained by serial passage in ICR mice were used based on intraperitoneal injection of 1 × 107 parasitized erythrocytes and subsequent development of parasitemia. These infected mice were used to investigate the antimalarial activity of artesunate (6 mg/kg) in combination with 500, 1,000, and 2,000 mg/kg of G. pentaphyllum and M. oleifera leaf extracts using 4-day suppressive test. It was found that these extracts showed significant (P < 0.05) antimalarial activity in dose-dependent manner with percentage of suppression of 45, 50, and 55% for G. pentaphyllum leaf extract and 35, 40, and 50% for M. oleifera leaf extract. Additionally, artesunate combined with these extracts presented higher antimalarial activity, compared to extract treated alone with percentage of suppression of 78, 91, and 96% for G. pentaphyllum leaf extract and 73, 82, and 91% for M. oleifera leaf extract. The results indicated that combination treatment of G. pentaphyllum or M. oleifera leaf extracts with artesunate was able to increase the antimalarial activity by using low dose of artesunate. Hence, these results justified the combination of these extracts and artesunate in antimalarial herbal remedies. PMID:27872647

  11. Acidities of Water and Methanol in Aqueous Solution and DMSO

    Science.gov (United States)

    Gao, Daqing

    2009-01-01

    The relative acidities of water and methanol have been a nagging issue. In gas phase, methanol is more acidic than water by 36.0 kJ/mol; however, in aqueous solution, the acidities of methanol and water are almost identical. The acidity of an acid in solution is determined by both the intrinsic gas-phase ionization Gibbs energy and the solvent…

  12. A Methanol Intoxication Outbreak From Recreational Ingestion of Fracking Fluid.

    Science.gov (United States)

    Collister, David; Duff, Graham; Palatnick, Wesley; Komenda, Paul; Tangri, Navdeep; Hingwala, Jay

    2017-01-19

    Single-patient methanol intoxications are a common clinical presentation, but outbreaks are rare and usually occur in settings in which there is limited access to ethanol and methanol is consumed as a substitute. In this case report, we describe an outbreak of methanol intoxications that was challenging from a public health perspective and discuss strategies for managing such an outbreak.

  13. Prediction of potential antimalarial targets of artemisinin based on protein information from whole genome of Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    HAN LiPing; HUANG Qiang; NAN Peng; ZHONG Yang

    2009-01-01

    On the basis of the genomic data and protein pathway information about Plasmodium falciparum clone 3D7 from the NCBI taxonomy database and the KEGG database,eight key protein enzymes in the signal pathways were selected to perform molecular docking with artemisinin.The binding modes obtained from the molecular docking suggested that purine nucleoside phosphorylase (pfPNP),peptide deformylase (pfPDF),and ribose 5-phosphate isomerase (pfRpiA) may be involved in the antimalarial mode of action of artemisinin.Artemisinin exhibited its antimalarial activity probably by interfering with the metabolic pathways of purine,pyrimidine,methionine,glyoxylate and dicarboxylate,or pentose phosphate.

  14. 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.

  15. 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. PMID:23133522

  16. The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

    Energy Technology Data Exchange (ETDEWEB)

    Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil); Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya [Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP (Brazil); Pessoa-Pureur, Regina, E-mail: rpureur@ufrgs.br [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil)

    2014-04-01

    Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to {sup 32}P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca{sup 2+}/calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca{sup 2+} quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca{sup 2+} influx through voltage-dependent Ca{sup 2+} channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative

  17. Biodegradation of methanol vapor in a biofilter

    Institute of Scientific and Technical Information of China (English)

    Durai Arulneyam; T. Swaminathan

    2003-01-01

    Volatile organic compounds (VOCs) are a new class of air pollutants posing threat to the environment. Newer technologies are being developed for their control among which biofiltration seem to be most attractive. Biofiltration of methanol vapor from air stream was evaluated in this study. Experimental investigations were conducted on a laboratory scale biofilter, containing mixture of compost and polystyrene inert particles as the filter materials. Mixed consortium of activated sludge was used as an inoculum. The continuous performance of biofilter for methanol removal was monitored for different concentrations and flow rates. The removal efficiencies decreased at higher concentrations and higher gas flow rates. A maximum elimination capacity of 85 g/(m3.h) was achieved. The response of biofilter to upset loading operation showed that the biofilm in the biofilters was quite stable and quickly adapted to adverse operational conditions.

  18. Depolymerization of polyethylene terephthalate in supercritical methanol

    Science.gov (United States)

    Goto, Motonobu; Koyamoto, Hiroshi; Kodama, Akio; Hirose, Tsutomu; Nagaoka, Shoji

    2002-11-01

    The degradation of polyethylene terephthalate (PET) in supercritical methanol was investigated with the aim of developing a process for chemical recycling of waste plastics. A batch reactor was used at temperatures of 573-623 K under an estimated pressure of 20 MPa for a reaction time of 2-120 min. PET was decomposed to its monomers, dimethyl terephthalate and ethylene glycol, by methanolysis in supercritical methanol. The reaction products were analysed using size-exclusion chromatography, gas chromatography-mass spectrometry, and reversed-phase liquid chromatography. The molecular weight distribution of the products was obtained as a function of reaction time. The yields of monomer components of the decomposition products including by-products were measured. Continuous kinetics analysis was performed on the experimental data.

  19. Stevioside methanol tetra­solvate

    Science.gov (United States)

    Wu, Yunshan; Rodenburg, Douglas L.; Ibrahim, Mohamed A.; McChesney, James D.; Avery, Mitchell A.

    2013-01-01

    Stevioside is a naturally occurring diterpenoid glycoside in Stevia rebaudiana Bertoni. The title compound, C38H60O18·4CH3OH, crystallized as its methanol tetrasolvate. Stevioside consists of an aglycone steviol (a tetra­cyclic diterpene in which the four-fused-ring system consists of three six-membered rings and one five-membered ring) and a sugar part (three glucose units). A weak intra­molecular O—H⋯O hydrogen bond occurs. In the crystal, the methanol mol­ecules participate in a two-dimensional hydrogen-bonded network parallel to b axis with the sugars and together they form a hydrophilic tunnel which encloses the lipophilic part of the molecule. PMID:23476589

  20. Investigation of indolglyoxamide and indolacetamide analogues of polyamines as antimalarial and antitrypanosomal agents.

    Science.gov (United States)

    Wang, Jiayi; Kaiser, Marcel; Copp, Brent R

    2014-05-28

    Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 μM, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively). To expand the structure-activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic "capping acids", and polyamines including spermine (PA3-4-3) and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10-92 nM) but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM). There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.

  1. 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.

  2. Antimalarial activity of Ageratum conyzoides in combination with chloroquine and artesunate

    Institute of Scientific and Technical Information of China (English)

    Ukwe Chinwe V; Ekwunife Obinna I; Epueke Ebele A; Ubaka Chukwuemeka M

    2010-01-01

    Objective: To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides (A. conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice. Methods: Using malaria (Plasmodium berghei) infected albino mice of both sexes, aqueous extracts of A. conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity, respectively. Four-day suppressive test and Rane's curative test were carried out. Results: Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations. Suppressive activities of both extract-drug combinations were greater than the individual drugs alone. Extract-chloroquine (100:5) produced the highest suppressive effect (98% suppression). Curative tests showed absolute survival in two extract-drug combinations. Two extract-drug combinations produced higher curative effects than the individual drugs alone. The highest dose combinations of extract-chloroquine (100:5) and extract-artesunate (100:5) produced absolute parasitemia clearance (cure) in the infected mice. Conclusions: The study indicated that aqueous extract of A. conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice. It contributes a lot in the malaria endemic and poverty stricken tropics.

  3. In silico analysis reveals the anti-malarial potential of quinolinyl chalcone derivatives.

    Science.gov (United States)

    Thillainayagam, Mahalakshmi; Pandian, Lavanya; Murugan, Kumar Kalavathy; Vijayaparthasarathi, Vijayakumar; Sundaramoorthy, Sarveswari; Anbarasu, Anand; Ramaiah, Sudha

    2015-01-01

    In this study, the correlation between chemical structures and various parameters such as steric effects and electrostatic interactions to the inhibitory activities of quinolinyl chalcone derivatives is derived to identify the key structural elements required in the rational design of potent and novel anti-malarial compounds. The molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are carried out on 38 chalcones derivatives using Plasmodium falciparum lactate dehydrogenase (PfLDH) as potential target. Surflex-dock is used to determine the probable binding conformations of all the compounds at the active site of pfLDH and to identify the hydrogen bonding interactions which could be used to alter the inhibitory activities. The CoMFA model has provided statistically significant results with the cross-validated correlation coefficient (q(2)) of .850 and the non-cross-validated correlation coefficient (r(2)) of .912. Standard error of estimation (SEE) is .280 and the optimum number of component is five. The predictive ability of the resultant model is evaluated using a test set comprising of 13 molecules and the predicted r(2) value is .885. The results provide valuable insight for optimization of quinolinyl chalcone derivatives for better anti-malarial therapy.

  4. Phycocyanin Extraction from Spirulina platensis and Its Antimalarial Activity In-Vitro

    Directory of Open Access Journals (Sweden)

    Diah Anggraini Wulandari

    2016-04-01

    Full Text Available Phycocyanin is a pigment-protein complex from the light-harvesting phycobiliprotein family which isoften found in cyanobacteria. The product phycocyanin produced by phanizomenon flos-aquae and Spirulinasp. The aim of this study were to determine the best solvents purification phycocanin from Spirulina platensisin three solvents, phosphate buffer, water and aceton ammonium sulphate and to evaluate the antimalarialactivity in vitro of phycocyanin in the best solvent extraction from S. platensis. The method of this study wasusing in-vitro antimalarial method. The result showed C- phycocyanin (C-PC, yield, and protein contentsof phycocyanin were 8 mg/mL, 20.22%, 1.88% extracted and purified by phosphate buffer, 6.63 mg/mL,16.58 %, 3.51% extracted and purified by water, 2.86 mg/mL, 7.15%, 8.4% extracted and purified by acetoneammonium sulphate respectively. Phosphate buffer was the best solvent of phycocyanin extraction from S.platensis. Antimalarial activity in vitro of phycocyanin in hosphate buffer against Plasmodium falciparumstrains 3D7 with IC50 was 158,489 μg/mL. The possible mechanism might be relied on the destruction ofpolymerization of Haemozoin by binding of C-PC with ferriprotoporphyrin-IX at the water surface of theplasma membrane.

  5. Gas chromatographic method for the determination of lumefantrine in antimalarial finished pharmaceutical products

    Directory of Open Access Journals (Sweden)

    Sultan Suleman

    2015-09-01

    Full Text Available A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O–bis(trimethyl-silyltrifluoro-acetamide at 70°C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length × 0.32 mm i.d., 0.25 μm film thickness column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett–Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD = 1.0%], linearity (=0.9986, precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%, and high sensitivity with detection limits of 0.01 μg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products.

  6. A framework for assessing the risk of resistance for anti-malarials in development

    Directory of Open Access Journals (Sweden)

    Ding Xavier C

    2012-08-01

    Full Text Available Abstract Resistance is a constant challenge for anti-infective drug development. Since they kill sensitive organisms, anti-infective agents are bound to exert an evolutionary pressure toward the emergence and spread of resistance mechanisms, if such resistance can arise by stochastic mutation events. New classes of medicines under development must be designed or selected to stay ahead in this vicious circle of resistance control. This involves both circumventing existing resistance mechanisms and selecting molecules which are resilient against the development and spread of resistance. Cell-based screening methods have led to a renaissance of new classes of anti-malarial medicines, offering us the potential to select and modify molecules based on their resistance potential. To that end, a standardized in vitro methodology to assess quantitatively these characteristics in Plasmodium falciparum during the early phases of the drug development process has been developed and is presented here. It allows the identification of anti-malarial compounds with overt resistance risks and the prioritization of the most robust ones. The integration of this strategy in later stages of development, registration, and deployment is also discussed.

  7. Antimalarial properties of Artemisia vulgaris L. ethanolic leaf extract in a Plasmodium berghei murine malaria model

    Directory of Open Access Journals (Sweden)

    Gayan S. Bamunuarachchi

    2013-12-01

    Full Text Available Background & objectives: Artemisinin isolated from Artemisia annua is the most potent antimalarial drug against chloroquine-resistant Plasmodium falciparum malaria. Artemisia vulgaris, an invasive weed, is the only Artemisia species available in Sri Lanka. A pilot study was undertaken to investigate the antiparasitic activity of an A. vulgaris ethanolic leaf extract (AVELE in a P. berghei ANKA murine malaria model that elicits pathogenesis similar to falciparum malaria. Methods: A 4-day suppressive and the curative assays determined the antiparasitic activity of AVELE using four doses (250, 500, 750 and 1000 mg/kg, Coartem® as the positive control and 5% ethanol as the negative control in male ICR mice infected with P. berghei. Results: The 500, 750 and 1000 mg/kg doses of AVELE significantly (p ≤0.01 inhibited parasitaemia by 79.3, 79.6 and 87.3% respectively, in the 4-day suppressive assay, but not in the curative assay. Chronic administration of the high dose of AVELE ruled out overt signs of toxicity and stress as well as hepatotoxicity, renotoxicity and haematotoxicity. Interpretation & conclusion: The oral administration of a crude ethonolic leaf extract of A. vulgaris is non-toxic and possesses potent antimalarial properties in terms of antiparasitic activity.

  8. Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs.

    Science.gov (United States)

    Hromadkova, L; Soukup, T; Vlcek, J

    2012-08-01

    Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex ® database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed ®, MEDLINE ®, InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents.

  9. Phytochemical Analysis and Antimalarial Activity Aqueous Extract of Lecaniodiscus cupanioides Root.

    Science.gov (United States)

    Nafiu, Mikhail Olugbemiro; Abdulsalam, Taoheed Adedeji; Akanji, Musbau Adewumi

    2013-01-01

    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.

  10. 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.

  11. Formulation and particle size reduction improve bioavailability of poorly water-soluble compounds with antimalarial activity.

    Science.gov (United States)

    Wang, Hongxing; Li, Qigui; Reyes, Sean; Zhang, Jing; Xie, Lisa; Melendez, Victor; Hickman, Mark; Kozar, Michael P

    2013-01-01

    Decoquinate (DQ) is highly effective at killing malaria parasites in vitro; however, it is extremely insoluble in water. In this study, solid dispersion method was used for DQ formulation which created a suitable physical form of DQ in aqueous phase for particle manipulation. Among many polymers and surfactants tested, polyvinylpyrrolidone 10, a polymer, and L- α -phosphatidylcholine or polysorbate, two surfactants, were chosen as DQ formulation components. The formulation particles were reduced to a mean size between 200 to 400 nm, which was stable in aqueous medium for at least three weeks. Pharmacokinetic (PK) studies showed that compared to DQ microparticle suspension, a nanoparticle formulation orally dosed to mice showed a 14.47-fold increase in area under the curve (AUC) of DQ plasma concentration and a 4.53-fold increase in AUC of DQ liver distribution. WR 299666, a poorly water-soluble compound with antimalarial activity, was also tested and successfully made into nanoparticle formulation without undergoing solid dispersion procedure. We concluded that nanoparticles generated by using appropriate formulation components and sufficient particle size reduction significantly increased the bioavailability of DQ and could potentially turn this antimalarial agent to a therapeutic drug.

  12. QSAR modeling of antimalarial activity of urea derivatives using genetic algorithm–multiple linear regressions

    Directory of Open Access Journals (Sweden)

    Abolghasem Beheshti

    2016-05-01

    Full Text Available A quantitative structure–activity relationship (QSAR was performed to analyze antimalarial activities of 68 urea derivatives using multiple linear regressions (MLR. QSAR analyses were performed on the available 68 IC50 oral data based on theoretical molecular descriptors. A suitable set of molecular descriptors were calculated to represent the molecular structures of compounds, such as constitutional, topological, geometrical, electrostatic and quantum-chemical descriptors. The important descriptors were selected with the aid of the genetic algorithm (GA method. The obtained model was validated using leave-one-out (LOO cross-validation; external test set and Y-randomization test. The root mean square errors (RMSE of the training set, and the test set for GA–MLR model were calculated to be 0.314 and 0.486, the square of correlation coefficients (R2 were obtained 0.801 and 0.803, respectively. Results showed that the predictive ability of the model was satisfactory, and it can be used for designing similar group of antimalarial compounds.

  13. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    Directory of Open Access Journals (Sweden)

    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.

  14. Phytochemical screening, antimalarial and histopathological studies of Allophylus africanus and Tragia benthamii

    Institute of Scientific and Technical Information of China (English)

    Oladosu I.A.; Balogun S.O.; Ademowo G.O.

    2013-01-01

    The anti-malarial potential of different parts ofAllophylus africanus P.Beauv and Tragia benthamii Baker were determined in vivo for suppressive,curative and cytotoxic activities in mice receiving 0.2 mL of a standard inoculum size of 1 × 107 infected erythrocytes of Plasmodium berghei (NK-65) intraperitoneally.The A.africanus extracts suppressed parasitaemia following administration to infected mice by 92.82%-97.81% on day 7 post-infection against 96.81% for chloroquine.The infected extract-treated animals had significantly moderate (P < 0.05) packed cell volume (PCV) compared with the infected,untreated animals.Phytochemical screening revealed a predominance of tannins,saponins,flavonoids and carbohydrates in all parts of A.africanus,and alkaloids instead of flavonoids in the extract of T.benthamii.The results suggest that the extract possesses considerable antimalarial activity.These results support further studies on A.africanus.

  15. 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.

  16. Understanding the biology of the Plasmodium falciparum apicoplast; an excellent target for antimalarial drug development.

    Science.gov (United States)

    Chakraborty, Arnish

    2016-08-01

    Malaria is a life-threatening tropical disease, caused by the intracellular parasite Plasmodium falciparum. The World Health Organization counts malaria as one of the top ten causes of worldwide death. The unavailability of a successful malaria vaccine and the ever-increasing instances of drug resistance in the malaria parasite demand the discovery of new targets within P. falciparum for the development of next generation antimalarials. Fortunately, all apicomplexan parasites, including P. falciparum harbor a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is a semi-autonomous organelle within P. falciparum containing a 35kb circular genome. Despite a genome of its own, majority of the apicoplast proteins are encoded by the parasite nucleus and imported into the apicoplast. The organelle has been shown to be essential to P. falciparum survival and the loss the apicoplast manifests as a 'delayed death' response in the parasite. The apicoplast has evolved out of cyanobacteria in a complex, two step endosymbiotic event. As a result the architecture and the gene expression machinery of the apicoplast is quite bacteria-like and is susceptible to a wide range of antibiotics such as fosmidomycin, tetracycline, azithromycin, clindamycin and triclosan. The biosynthetic pathways for isoprenoids, fatty acids and heme operate within the malaria apicoplast, making the organelle an excellent target for drug development. The review focuses on the evolution, biology and the essentiality of the apicoplast within the malaria parasite and discusses some of the recent achievements towards the design and discovery of apicoplast targeted antimalarial compounds.

  17. Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    Science.gov (United States)

    Wright, Megan H.; Clough, Barbara; Rackham, Mark D.; Rangachari, Kaveri; Brannigan, James A.; Grainger, Munira; Moss, David K.; Bottrill, Andrew R.; Heal, William P.; Broncel, Malgorzata; Serwa, Remigiusz A.; Brady, Declan; Mann, David J.; Leatherbarrow, Robin J.; Tewari, Rita; Wilkinson, Anthony J.; Holder, Anthony A.; Tate, Edward W.

    2014-02-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  18. Liquid methanol under a static electric field

    Energy Technology Data Exchange (ETDEWEB)

    Cassone, Giuseppe, E-mail: giuseppe.cassone@impmc.upmc.fr [Sorbonne Universités, UPMC Univ Paris 06, UMR 7590, IMPMC, F-75005 Paris (France); CNRS, UMR 7590, IMPMC, F-75005 Paris (France); Università degli Studi di Messina, Dipartimento di Fisica e di Scienze della Terra, Contrada Papardo, 98166 Messina (Italy); CNR-IPCF, Viale Ferdinando Stagno d’Alcontres 37, 98158 Messina (Italy); Giaquinta, Paolo V., E-mail: paolo.giaquinta@unime.it [Università degli Studi di Messina, Dipartimento di Fisica e di Scienze della Terra, Contrada Papardo, 98166 Messina (Italy); Saija, Franz, E-mail: saija@ipcf.cnr.it [CNR-IPCF, Viale Ferdinando Stagno d’Alcontres 37, 98158 Messina (Italy); Saitta, A. Marco, E-mail: marco.saitta@impmc.upmc.fr [Sorbonne Universités, UPMC Univ Paris 06, UMR 7590, IMPMC, F-75005 Paris (France); CNRS, UMR 7590, IMPMC, F-75005 Paris (France)

    2015-02-07

    We report on an ab initio molecular dynamics study of liquid methanol under the effect of a static electric field. We found that the hydrogen-bond structure of methanol is more robust and persistent for field intensities below the molecular dissociation threshold whose value (≈0.31 V/Å) turns out to be moderately larger than the corresponding estimate obtained for liquid water. A sustained ionic current, with ohmic current-voltage behavior, flows in this material for field intensities above 0.36 V/Å, as is also the case of water, but the resulting ionic conductivity (≈0.40 S cm{sup −1}) is at least one order of magnitude lower than that of water, a circumstance that evidences a lower efficiency of proton transfer processes. We surmise that this study may be relevant for the understanding of the properties and functioning of technological materials which exploit ionic conduction, such as direct-methanol fuel cells and Nafion membranes.

  19. 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

  20. Neurological Complications Resulting from Non-Oral Occupational Methanol Poisoning

    Science.gov (United States)

    Lee, Seung Keun; Gil, Young-Eun; Kim, Hyunjoo; Choi, Jun Young

    2017-01-01

    Methanol poisoning results in neurological complications including visual disturbances, bilateral putaminal hemorrhagic necrosis, parkinsonism, cerebral edema, coma, or seizures. Almost all reported cases of methanol poisoning are caused by oral ingestion of methanol. However, recently there was an outbreak of methanol poisoning via non-oral exposure that resulted in severe neurological complications to a few workers at industrial sites in Korea. We present 3 patients who had severe neurological complications resulting from non-oral occupational methanol poisoning. Even though initial metabolic acidosis and mental changes were improved with hemodialysis, all of the 3 patients presented optic atrophy and ataxia or parkinsonism as neurological complications resulting from methanol poisoning. In order to manage it adequately, as well as to prevent it, physicians should recognize that methanol poisoning by non-oral exposure can cause neurologic complications. PMID:28049252

  1. Kinetics of methanol steam reforming over COPZr-2 catalyst

    Institute of Scientific and Technical Information of China (English)

    Yongfeng Li; Weiming Lin; Lin Yu; Zhifeng Hao; Rongjian Mai

    2008-01-01

    The COPZr-2 catalyst, which was prepared in our prophase research, showed good catalytic performance in methanol steam reforming reaction. In this article, the best one was chosen as an example to study the reaction kinetics of methanol steam reforming over this type of catalyst. First, the effects of methanol conversion to outlet CO2 and methanol conversion to outlet CO on methanol pseudo contact time W/FMeOH were investigated. Then by applying the reaction route that methanol direct reforming (DR) and methanol decomposition (DE) were carried out in parallel, the reaction kinetic model with power function type was established. And the parameters for the model were estimated using a non-linear regression program which computed weighted least squares of the defined objects function. Finally, the kinetic model passed the correlation test and the F-test.

  2. Alternative energies for road traffic - methanol. Alternative Energien fuer den Strassenverkehr - Methanol

    Energy Technology Data Exchange (ETDEWEB)

    1983-01-01

    Methanol motor fuels are alternative fuels which can supplement to the supply with petrol and diesel fuel from mineral oil to a greater extent. Since 1979, a fleet comprising more than 1,000 vehicles is being tested by customers in a practical large-scale test involving the motor fuels M15 and M100. The study on hand was produced by means of forecasts and facts based on today's technology and state of experience. The part concerning demand development and availability demonstrates in what quantities methanol could be available till the year 2000 (demand tendencies, future methanol production capacity in the world). The part concerning technology examines how the methanol quantities mentioned before could be used in road traffic (Otto engine, diesel engine, state of testing and trial, fuel technology) introduction phase, cost). The part concerning framework conditions notes that, in principle, there are no unsurmountable obstacles with setting up or amending methanol-specific technical and legal regulations.

  3. Effects of the methanolic seeds extract of Carica Papaya on plasmodium Berghei infected mice

    Institute of Scientific and Technical Information of China (English)

    Amazu LU; Ebong OO; Azikiwe CCA; Unekwe PC; Siminialayi MI; Nwosu PJC; Ezeani MC; Obidiya OS; Ajugwo AO

    2009-01-01

    Objective:The leaves extract of Carica Papaya(C.Papaya)papaya has been shown to possess antimalarial ac-tivity,thus this work aims at finding out if the plants antimalarial activity is present in or extended to the seeds.Methods:The seeds of C.papaya were collected from its fruit,air dried for 5 days and ground into fine powder.80.65 g of the powder was then soaked for 48hours in 300 mL of methanol.Filtration was carried out using Whatman No.1 filter paper.The filtrate was evaporated to dryness by a three-day continuous heating on a hot plate of 30℃.The dry extract yield was scraped out of the Petri dish weighed and refrigerated until re-quired.The percentage extract yield was calculated out from the initial powder weight.A preliminary phyto-chemical study was done by re-dissolving the appropriate amount of the dry extract in distilled water and appro-priate test reagent added.The LD50 of the seeds of C.papaya was carried out using arithmetic method.Swiss albino Mice of both sexes and of average weight of 1 8-25 g were used as animals for antimalarial activity.They were housed in standard animal house,fed on Rats/Mice pellets and had non restricted excess to both feed and water throughout the 60day study period.While the non pregnant female Mice were used as test animals,the male animals were used as malaria parasite donors.Precautions were taken to ensure that all animals in the study groups were free from infection with Eperythrozoon coocoides.The female animals were then divided into three main groups (A-C)of 25 animals per group.Group A was used for malaria suppressive study (early in-fection-day 0-3)and was further subdivided to 5subgroups (a-e)of 5animals per group.Group B was used for malaria curative study (established malaria infection-day 3-7)and was further subdivided to 5subgroups (a-e) of 5animals per group.Group C was used for malaria prophylactic study (repository-4days treatment prior to malaria parasite infection)and was also further subdivided

  4. Studies on laser flash photolysis and pulse radiolysis of quinoline and some of its derivatives%喹啉及其衍生物的脉冲辐解和激光光解研究

    Institute of Scientific and Technical Information of China (English)

    ZHU Dazhang; WANG Shilong; SUN Xiaoyu; LI Wenzhe; ZENG Kailing; NI Yaming; WANG Wenfeng; YAO Side

    2005-01-01

    Quinoline and some of its derivatives were reported to be carcinogenic, toxic and mutagenic[1-3]. The widespread use of quinoline and its derivatives entails that these compounds are distributed in the environment, polluting soil and water together with many other environmental chemicals.Time-resolved laser flash photolysis and pulse radiolysis have been used to study the reaction of quinoline (Q), 2, 6-dimethyl-quinoline (DMQ) and isoquinoline (IQ) with hydrated electrons, hydroxyl radicals and hydrogen radicals. Transient absorption spectra were obtained and reaction rate constants to the reactions were determined, as showed in Table 1. Rossible mechanisms of the reactions were suggested.In addition, oxidization reactions of SO4·-, Br2·- and N3·- with isoquinoline, quinoline and its derivatives were studied. It showed that SO4- could oxidize quinoline, 2, 6-dimethylquinoline and isoquinoline; Br2·-could oxidize isoquinoline to its cation radicals, but it could not oxidize quinoline or 2, 6-diemethylquinoline; N3·- could oxidize none of them.With a better understandings on photolysis and radiolysis of isoquinoline, quinoline and its derivates, the study is of help for degradation of the chemicals and for environment protection.

  5. Establishment of true niacin deficiency in quinolinic acid phosphoribosyltransferase knockout mice.

    Science.gov (United States)

    Terakata, Miki; Fukuwatari, Tsutomu; Sano, Mitsue; Nakao, Natsuki; Sasaki, Ryuzo; Fukuoka, Shin-Ichi; Shibata, Katsumi

    2012-12-01

    Pyridine nucleotide coenzymes are involved in >500 enzyme reactions and are biosynthesized from the amino acid L-tryptophan (L-Trp) as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid (QA) phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-), or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and qprt(+/-) mice. On the contrary, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (P niacin, such as blood and liver NAD concentrations, were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of QA was greater in the qprt(-/-) mice than in the qprt(+/+) and qprt(+/-) mice (P niacin-deficient mice.

  6. Hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity.

    Science.gov (United States)

    Mantu, Dorina; Antoci, Vasilichia; Moldoveanu, Costel; Zbancioc, Gheorghita; Mangalagiu, Ionel I

    2016-01-01

    The design, synthesis, structure, and in vitro anticancer and antimycobacterial activity of new hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives are described. The strategy adopted for synthesis is straight and efficient, involving a three-step setup procedure: N-acylation, N-alkylation, and quaternization of nitrogen heterocycle. The solubility in microbiological medium and anticancer and antimycobacterial activity of a selection of new synthesized compounds were evaluated. The hybrid derivatives have an excellent solubility in microbiological medium, which make them promising from the pharmacological properties point of view. One of the hybrid compounds, 9 (with a benzimidazole and 8-aminoquinoline skeleton), exhibits a very good and selective antitumor activity against Renal Cancer A498 and Breast Cancer MDA-MB-468. Moreover, the anticancer assay suggests that the hybrid Imz (Bimz)/2-AP (8-AQ) compounds present a specific affinity to Renal Cancer A498. Concerning the antimycobacterial activity, only the hybrid compound, 9, has a significant activity. SAR correlations have been performed.

  7. Effects of impregnation methods and drying conditions on quinoline hydrodenitrogenation over Ni-W based catalysts

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Fang; Qiu, Zegang; Zhao, Liangfu; Xiang, Hongwei [Institute of Coal Chemistry, Chinese Academy of Sciences (China); Guo, Shaoqing [Taiyuan University of Science and Technology (China)

    2014-04-15

    The effects of impregnation methods (co-impregnation and sequential impregnation) and drying conditions (air and vacuum) on the structure and catalytic behavior of MCM-41 supported Ni-W catalysts were investigated. The catalysts were characterized by powder X-ray diffraction (XRD) analysis, Fourier-transform infrared spectroscopy (FT-IR), diffuse reflectance UV-Vis absorbance spectroscopy (DRS), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and pyridine adsorbed infrared spectroscopy (Py-IR) techniques. They were tested for hydrodenitrogenation (HDN) of quinoline at temperatures of 300-400 deg C. The HDN results showed that the catalysts prepared by co-impregnation were more active than the catalysts prepared by sequential impregnation and the catalysts prepared by drying under vacuum were more active than the catalysts dried in air. Characterization revealed that the co-impregnation method and drying under vacuum promoted the dispersion of W, the formation of the active phases, and the formation of acidic sites on the catalysts. (author)

  8. Determination of three physical properties of quinoline ionic liquids with hexafluorophosphate

    Directory of Open Access Journals (Sweden)

    Tang Dan

    2016-01-01

    Full Text Available Densities of one acidic ionic liquid (IL Quinolinum hexafluorophosphate ([HBpy][PF6], and four neutral dicationic ionic liquids (ILs based on quinoline and hexafluoro-phosphate and linked with poly(ethylene glycol (PEG: ([PEG200-DIL][PF6]2, [PEG400-DIL][PF6]2, [PEG800-DIL][PF6]2 and [PEG1000-DIL][PF6]2 were determined. In addition, the solubilities of six ILs in six lower alcohols, water, acetonitrile and diethyl ether were measured at 288.15 K; and the hydroscopicity of above five ILs were measured at the temperature of 298.15 K and relative humidity of 79% for 24 h. Densities of five ionic liquids were determined between 283.15 and 333.15 K. Then the densities of five binary system (ILs/acetonitrile were explored between 283.15 and 333.15 K, the type of the ionic liquid, the concentration of five ILs in CH3CN, and the effect of temperature on the binary systems, were correlated with the measured data.

  9. Quinoline based polymeric drug for biological applications: synthesis, characterization, antimicrobial, and drug releasing studies.

    Science.gov (United States)

    Uma, P; Suresh, J; Selvaraj, Revathy; Karthik, S; Arun, A

    2015-01-01

    Novel acrylate monomer of quinoline-based chalcone 1-(4-(7-chloroquinolin-4-ylamino)phenyl) acrylate (CPA) was synthesized using (4-(2-chloroquinolin-5-ylamino)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (CPE) and acryloyl chloride. CPA is characterized by different techniques like IR, (1)H NMR and UV-visible spectrometry techniques. Poly(CPA), poly(CPA-co-AA) and poly(CPA-co-HEA) are prepared by solution polymerization technique using CPA, acrylic acid (AA) and hydroxyethylacrylate (HEA), respectively. The antimicrobial activities of the compounds are tested using four different micro-organisms. In vitro cumulative drug release studies are done using UV visible spectroscopic technique. The molecular weights of these polymers are found to be around 5000 g/mol. The synthesized polymers showed two stages of thermal decomposition temperature centred around 220 and 350 °C, respectively. The antimicrobial activity of the polymer sample is found to be very high and especially for gram-negative bacteria with a minimum value of 3.91 μg/mL. The in vitro drug-releasing rate is dependent on the comonomer, pH and temperature of the medium.

  10. Spectral investigation and theoretical study of zwitterionic and neutral forms of quinolinic acid

    Science.gov (United States)

    Karabacak, M.; Sinha, L.; Prasad, O.; Bilgili, S.; Sachan, Alok K.; Asiri, A. M.; Atac, A.

    2015-09-01

    In this study, molecular structure and vibrational analysis of quinolinic acid (2,3-pyridinedicarboxylic acid), in zwitterionic and neutral forms, were presented using FT-IR, FT-Raman, NMR, UV experimental techniques and quantum chemical calculations. FT-IR and FT-Raman spectra of 2,3-pyridinedicarboxylic acid (2,3-PDCA) in the solid phase were recorded in the region 4000-400 cm-1 and 3500-0 cm-1, respectively. The geometrical parameters and energies were obtained for zwitter and neutral forms by using density functional theory (DFT) at B3LYP/6-311++G(d,p) level of theory. 3D potential energy scan was performed by varying the selected dihedral angles using M06-2X and B3LYP functionals at 6-31G(d) level of theory and thus the most stable conformer of the title compound was determined. The most stable conformer was further optimized at higher level and vibrational wavenumbers were calculated. Theoretical vibrational assignment of 2,3-PDCA, using percentage potential energy distribution (PED) was done with MOLVIB program. 13C and 1H NMR spectra were recorded in DMSO. Chemical shifts were calculated at the same level of theory. The UV absorption spectra of the studied compound in ethanol and water were recorded in the range of 200-400 nm. The optimized geometric parameters were compared with experimental data.

  11. Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease.

    Science.gov (United States)

    Schwarcz, Robert; Guidetti, Paolo; Sathyasaikumar, Korrapati V; Muchowski, Paul J

    2010-02-09

    The neurodegenerative disease Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in early stages of the disease.

  12. Investigating the Spectrum of Biological Activity of Substituted Quinoline-2-Carboxamides and Their Isosteres

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    Ales Imramovsky

    2012-01-01

    Full Text Available In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethylquinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonylquinoline and 1-(2-naphthoylpyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds, the structure-activity relationships are discussed.

  13. Green synthesis of novel quinoline based imidazole derivatives and evaluation of their antimicrobial activity

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    N.C. Desai

    2014-12-01

    Full Text Available We have described the conventional and microwave method for the synthesis of N-(4-((2-chloroquinolin-3-ylmethylene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl(arylamides 3a–l. It is observed that the solvent-free microwave thermolysis is a convenient, rapid, high-yielding, and environmental friendly protocol for the synthesis of quinoline based imidazole derivatives when compared with conventional reaction in a solution phase. Antimicrobial activity of the newly synthesized compounds is screened in vitro on the following microbial cultures: Escherichia coli (MTCC 443, Pseudomonas aeruginosa (MTCC 1688, Staphylococcus aureus (MTCC 96, Streptococcus pyogenes (MTCC 442, Candida albicans (MTCC 227, Aspergillus niger (MTCC 282, Aspergillus clavatus (MTCC 1323. All the synthesized bio-active molecules are tested for their in vitro antimicrobial activity by bioassay namely serial broth dilution. Among these compounds 3c, 3d, 3f, 3h and 3j show significant potency against different microbial strains. All the compounds have been characterized by IR, 1H NMR, 13C NMR and mass spectral data. On the basis of statistical analysis, it is observed that these compounds give significant co-relation.

  14. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease

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    Brew Bruce J

    2009-12-01

    Full Text Available Abstract The excitotoxin quinolinic acid (QUIN is synthesized through the kynurenine pathway (KP by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD. The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-γ and TNF-α on primary human astrocytes. We found that QUIN induces IL-1β expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls; features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

  15. Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex

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    Wang Lily

    2005-07-01

    Full Text Available Abstract There is evidence that the kynurenine pathway (KP and particularly one of its end products, quinolinic acid (QUIN play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC. We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1 apoptotic astrocytes have been observed in the brains of ADC patients, 2 ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3 QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking and biochemical changes (nucleus condensation and over-expression of active caspase 3 of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC.

  16. Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches.

    Science.gov (United States)

    Shah, Priyanka; Tiwari, Sunita; Siddiqi, Mohammad Imran

    2015-01-01

    Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti-malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects.

  17. Why hospital pharmacists have failed to manage antimalarial drugs stock-outs in pakistan? A qualitative insight.

    Science.gov (United States)

    Malik, Madeeha; Hassali, Mohamed Azmi Ahmad; Shafie, Asrul Akmal; Hussain, Azhar

    2013-01-01

    Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital) and Rawalpindi (twin city). Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors' analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  18. Why Hospital Pharmacists Have Failed to Manage Antimalarial Drugs Stock-Outs in Pakistan? A Qualitative Insight

    Directory of Open Access Journals (Sweden)

    Madeeha Malik

    2013-01-01

    Full Text Available Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital and Rawalpindi (twin city. Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors’ analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  19. Design, synthesis and in vitro evaluation of tetrahydropyrimidine-isatin hybrids as potential antitubercular and antimalarial agents

    Institute of Scientific and Technical Information of China (English)

    Tarunkumar Nanjibhai Akhaja; Jignesh Priyakant Raval

    2012-01-01

    A series of 5-substituted-3-[{5-(6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl}-imino]-1,3-dihydro-2H-indol-2-one were synthesized,characterized and screened for their anti-tubercular and antimalarial activity.

  20. Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

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    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.

  1. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery.

    Science.gov (United States)

    McCarty, Sara E; Schellenberger, Amanda; Goodwin, Douglas C; Fuanta, Ngolui Rene; Tekwani, Babu L; Calderón, Angela I

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial.

  2. Plants as Sources of Antimalarial Drugs Part. 1. In vitro Test Method for the Evaluation of Crude Extracts from Plants.

    Science.gov (United States)

    O'neill, M J; Bray, D H; Boardman, P; Phillipson, J D; Warhurst, D C

    1985-10-01

    An IN VITRO antimalarial test, utilising the inhibition of uptake of [G- (3)H]-hypoxanthine into PLASMODIUM FALCIPARUM cultured in human blood, has been used to assess the activity of crude extracts of ARTEMISIA ANNUA and A. VULGARIS (Compositae) and of BRUCEA JAVANICA, AILANTHUS ALTISSIMA, and SIMABA CEDRON (Simaroubaceae).

  3. Synthesis in aqueous medium and organic praseodymium complexes with ligands derived from Schiff base quinolinic. Characterization and physicochemical study; Sintesis en medio acuoso y organico de complejos de praseodimio con ligantes derivados de base de Schiff quinolicos. Caracterizacion y estudio fisicoquimico

    Energy Technology Data Exchange (ETDEWEB)

    Garcia G, A.

    2015-07-01

    It was investigated the coordination ability of the quinolinic Schiff base organic tetradentate quinolinic ligand (Q Schiff-(OH){sub 2}) towards the trivalent praseodymium by UV/Vis spectrophotometric titration (St). By St, was studied the formed species between the Q Schiff-(OH){sub 2} ligand and the praseodymium nitrate salt in equimolar concentrations (5.86 x 10{sup -4} M: 5.22 x 10{sup -4} M) in methanol. The statistical analysis of the experimental results suggested three complexed species with 1Pr:3L, 1Pr:2L y 1Pr:1L stoichiometries. The predominant stoichiometries were the second and the latter. Based on these results and data from the scientific literature, the methodology for the syntheses of the complexes Q Schiff-(OH){sub 2}-Pr in aqueous-organic and organic media was established and a molar ratio M:L= 1:2 of praseodymium nitrate and the ligand was used. The new complexes were characterized by UV/Vis, Infrared, X-ray Photoelectron Spectroscopy (XP S), Diffuse Reflectance (Dr) and Thermogravimetric Analysis/Differential Scanning Calorimetry (TGA/DSC). Elemental analysis of C, N, O and Pr by XP S suggested 1Pr:2L:1Na (PrC{sub 32}H{sub 20}N{sub 4}O{sub 4}Na) stoichiometry of the complex synthesized by the aqueous-organic medium while for the complex synthesized by the organic medium it was 1Pr:3L (PrC{sub 48}H{sub 33}N{sub 6}O{sub 6}). In the first case, the praseodymium ion charge was neutralized by the anionic ligands whose remaining charge was compensated by the sodium ion. In the second case, the ion charge was neutralized by the ligands. The minimum formula was Pr(Q Schiff){sub 2}Na for the pure coordination compound from the aqueous-organic medium and the minimum formula Pr(Q Schiff){sub 3} for that from the organic medium. XP S also indicated that the oxidation state of praseodymium ion was maintained. Both complexes were stable in methanol, ethanol and acetonitrile at least for 5 days. The photophysical properties of the studied complexes were

  4. Biogenic methanol and its impacts on tropospheric oxidants

    Science.gov (United States)

    Tie, Xuexi; Guenther, Alex; Holland, Elisabeth

    2003-09-01

    We use a global chemical transport model (MOZART-2) to estimate the effects of surface emissions of methanol on tropospheric oxidants. The importance of methanol in tropospheric chemistry is two fold. First, methanol has a relatively large surface emission with an estimated global emission of 70 to 350 Tg methanol/year. The estimated methanol flux is comparable to other major hydrocarbon surface emissions such as isoprene and total monoterpenes, but the chemical lifetime of methanol is several days (in the boundary layer) to a few weeks (in the upper troposphere), which is much longer than the chemical lifetime of isoprene or monoterpenes (For example, the chemical lifetime of isoprene is about 2 hours). With a surface emission of 104 to 312 Tg methanol/year (encompasses estimated uncertainty in methanol emissions), the calculation shows that on average, the inclusion of methanol emission produces approximately 1-2% increase in O3, 1-3% decrease in OH, 3-5% increase in HO2, and 3-9% increase in CH2O globally. The maximum perturbation to the oxidants occurs in the tropical upper troposphere. However, the uncertainty associated with current methanol emission estimates produces significantly different model predictions of tropospheric oxidant distributions.

  5. Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

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    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

  6. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

    Science.gov (United States)

    Shah, Syed Muhammad Hassan; Ullah, Farhat; Khan, Shahzeb; Shah, Syed Muhammad Mukarram; de Matas, Marcel; Hussain, Zahid; Minhas, Muhammad Usman; AbdEl-Salam, Naser M; Assi, Khaled Hafez; Isreb, Mohammad

    2016-01-01

    Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities. PMID:27920499

  7. Chemical composition of essential oils of Piper jacquemontianum and Piper variabile from Guatemala and bioactivity of the dichloromethane and methanol extracts

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    Sully M. Cruz

    2011-08-01

    Full Text Available The essential oils from two native species from Guatemala were studied for their chemical composition and the dichloromethane and methanol extracts for their biological activity. A GC-MS analysis of the essential oil from Piper jacquemontianum Kunth, Piperaceae, showed 34 constituents, consisting mainly of linalool (69.4%, while Piper variabile C. DC. essential oil had 36 constituents, camphor (28.4%, camphene (16.6% and limonene (13.9% being the major components. Dichloromethane extracts of both species were cytotoxic against MCF-7, H-460 and SF-268 cell lines (<7 µg/mL. Dichloromethane extract of P. jacquemontianum was slightly active against bacteria (0.5 mg/mL, was active against promastigotes of Leishmania (20.4-61.0 µg/mL, and epimastigotes of Trypanosoma cruzi (51.9 µg/mL. The methanol extract of P. variabile showed antimalarial activity against Plasmodium falciparum F32 (4.5 µg/mL, and the dichloromethane extract against Leishmania (55.8-76.3 µg/mL and T. cruzi (45.8 µg/mL. None of the extracts from the two species was active against Aedes aegypti larvae and Artemia salina nauplii.

  8. Methanol may function as a cross-kingdom signal.

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    Yuri L Dorokhov

    Full Text Available Recently, we demonstrated that leaf wounding results in the synthesis of pectin methylesterase (PME, which causes the plant to release methanol into the air. Methanol emitted by a wounded plant increases the accumulation of methanol-inducible gene mRNA and enhances antibacterial resistance as well as cell-to-cell communication, which facilitates virus spreading in neighboring plants. We concluded that methanol is a signaling molecule involved in within-plant and plant-to-plant communication. Methanol is considered to be a poison in humans because of the alcohol dehydrogenase (ADH-mediated conversion of methanol into toxic formaldehyde. However, recent data showed that methanol is a natural compound in normal, healthy humans. These data call into question whether human methanol is a metabolic waste product or whether methanol has specific function in humans. Here, to reveal human methanol-responsive genes (MRGs, we used suppression subtractive hybridization cDNA libraries of HeLa cells lacking ADH and exposed to methanol. This design allowed us to exclude genes involved in formaldehyde and formic acid detoxification from our analysis. We identified MRGs and revealed a correlation between increases in methanol content in the plasma and changes in human leukocyte MRG mRNA levels after fresh salad consumption by volunteers. Subsequently, we showed that the methanol generated by the pectin/PME complex in the gastrointestinal tract of mice induces the up- and downregulation of brain MRG mRNA. We used an adapted Y-maze to measure the locomotor behavior of the mice while breathing wounded plant vapors in two-choice assays. We showed that mice prefer the odor of methanol to other plant volatiles and that methanol changed MRG mRNA accumulation in the mouse brain.We hypothesize that the methanol emitted by wounded plants may have a role in plant-animal signaling. The known positive effect of plant food intake on human health suggests a role for

  9. Direct methanol feed fuel cell and system

    Science.gov (United States)

    Surampudi, Subbarao (Inventor); Frank, Harvey A. (Inventor); Narayanan, Sekharipuram R. (Inventor); Chun, William (Inventor); Jeffries-Nakamura, Barbara (Inventor); Kindler, Andrew (Inventor); Halpert, Gerald (Inventor)

    2009-01-01

    Improvements to non acid methanol fuel cells include new formulations for materials. The platinum and ruthenium are more exactly mixed together. Different materials are substituted for these materials. The backing material for the fuel cell electrode is specially treated to improve its characteristics. A special sputtered electrode is formed which is extremely porous. The fuel cell system also comprises a fuel supplying part including a meter which meters an amount of fuel which is used by the fuel cell, and controls the supply of fuel based on said metering.

  10. Thermodynamic properties of direct methanol polymer electrolyte fuel cell

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Ji Yun; Bae, Young Chan [Division of Chemical Engineering and Molecular Thermodynamics Laboratory, Hanyang University, Sungdonggu Haengdangdong 17, Seoul 133-791 (Korea, Republic of); Sun, Yang Kook [Division of Chemical Engineering and Center for Information and Communication, Materials, Hanyang University, Seoul 133-791 (Korea, Republic of)

    2005-08-18

    A new semi-empirical model is established to describe the cell voltage of a direct methanol fuel cell (DMFC) as a function of current density. The model equation is validated experimental data over a wide range of a methanol concentration and temperatures. A number of existing models are semi-empirical. They, however, have a serious mathematical defect. When the current density, j, becomes zero, the equation should reduce to the open circuit voltage, E{sub 0}. These models, however, do not meet the mathematical boundary condition. The proposed model focuses on very unfavorable conditions for the cell operation, i.e. low methanol solution concentrations and relatively low cell temperatures. A newly developed semi-empirical equation with reasonable boundary conditions includes the methanol crossover effect that plays a major role in determining the cell voltage of DMFC. Also, it contains methanol activity based on thermodynamic functions to represent methanol crossover effect. (author)

  11. Rh-Catalyzed, Regioselective, C-H Bond Functionalization: Access to Quinoline-Branched Amines and Dimers.

    Science.gov (United States)

    Reddy, M Damoder; Fronczek, Frank R; Watkins, E Blake

    2016-11-04

    Rh-catalyzed, chelation-induced, C-5 regioselective C-H functionalization of 8-amidoquinolines with a range of N-Boc aminals is reported for the first time. The addition of in situ generated imines to C(sp(2))-H bonds afforded branched amines in good to excellent yields. Moreover, this transformation features good functional group compatibility, broad substrate scope, and mild reaction conditions and is suitable for gram-scale synthesis. In addition, an unprecedented, chelation-induced, site-selective, remote dimerization of quinolines led to the formation of dimer frameworks in moderate yields under Rh-catalyzed conditions.

  12. 4-(2-aminooxyethoxy)-2-(ethylureido)quinoline-oligonucleotide conjugates: synthesis, binding interactions, and derivatization with peptides.

    Science.gov (United States)

    Hamma, Tomoko; Miller, Paul S

    2003-01-01

    Oligo-2'-O-methylribonucleotides conjugated with 4-(2-aminooxyethoxy)-2-(ethylureido)quinoline (AOQ) and 4-ethoxy-2-(ethylureido)quinoline (EOQ) were prepared by reaction of the AOQ or EOQ phosphoramidite with the protected oligonucleotide on a controlled pore glass support. Deprotection with ethylenediamine enabled successful isolation and purification of the highly reactive AOQ-conjugated oligomer. Polyacrylamide gel electrophoresis mobility shift experiments showed that the dissociation constants of complexes formed between an AOQ- or EOQ-conjugated 8-mer and complementary RNA or 2'-O-methyl-RNA targets (9- and 10-mers) were in the low nM concentration range at 37 degrees C, whereas no binding was observed for the corresponding nonconjugated oligomer, even at a concentration of 500 nM. Fluorescence studies suggested that this enhanced affinity is most likely due to the ability of the quinoline ring of the AOQ or EOQ group to stack on the last base pair formed between the oligomer and target, thus stabilizing the duplex. The binding affinity of a 2'-O-methyl RNA 15-mer, which contained an alternating methylphosphonate/phosphodiester backbone, for a 59-nucleotide stem-loop HIV TAR RNA target, increased 2.3 times as a consequence of conjugation with EOQ. The aminooxy group of AOQ-conjugated oligomers is a highly reactive nucleophile, which reacts readily with aldehydes and ketones to form stable oxime derivatives. This feature was used to couple an AOQ-oligomer with leupeptin, a tripeptide that contains a C-terminus aldehyde group. A simple method was developed to introduce a ketone functionality into peptides that contain a cysteine residue by reacting the peptide with bromoacetone. The resulting keto-peptide was then coupled to the AOQ-oligomer. This procedure was used to prepare oligonucleotide conjugates of a tetrapeptide, RGDC, and a derivative of HIV tat peptide having a C-terminus cysteine. The combination of the unique reactivity of the aminooxy group and

  13. Crystal structure of chlorido(piperidine-κN(quinoline-2-carboxylato-κ2N,Oplatinum(II

    Directory of Open Access Journals (Sweden)

    Chi Nguyen Thi Thanh

    2014-07-01

    Full Text Available The title compound, [Pt(C10H6NO2Cl(C5H11N], crystallizes with one molecule in the asymmetric unit. The PtII cation has a slightly distorted square-planar coordination environment defined by a chloride anion, the quinoline N atom and a carboxylate O atom of the bidentate quinaldate ligand and a piperidine N atom. An intramolecular C—H...Cl hydrogen bond occurs. In the crystal, molecules are stacked into columns along the c axis by the formation of N—H...Cl and C—H...O hydrogen bonds.

  14. Dichlorido[methyl 2-(quinolin-8-yloxy-κ2N,Oacetate-κO]mercury(II

    Directory of Open Access Journals (Sweden)

    Yu-Hong Wang

    2012-07-01

    Full Text Available In the neutral title complex, [HgCl2(C12H11NO3], the HgII ion is pentacoordinated by two Cl atoms, one N atom and two weakly coordinating O atoms from the methyl 2-(quinolin-8-yloxyacetate ligand. The coordination around the HgII ion may be described as highly distorted trigonal–bipyramidal. Centrosymmetric dimers are formed by an additional weak Hg...Cl interaction, leading to a distorted octahedral coordination geometry around the HgII ion.

  15. 3-Ethyl-4-hy-droxy-8-meth-oxy-quinolin-2(1H)-one.

    Science.gov (United States)

    Kafka, Stanislav; Pevec, Andrej; Proisl, Karel; Kimmel, Roman; Košmrlj, Janez

    2012-11-01

    In the title compound, C(12)H(13)NO(3), the quinoline ring system is approximately planar with a maximum deviation from the least-squares plane of 0.058 (2) Å. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules into chains running along the b-axis direction. The chains also feature π-π inter-actions between pyridine and benzene rings of inversion-related mol-ecules [centroid-centroid distance = 3.609 (2) Å].

  16. Discovery of new antimalarial chemotypes through chemical methodology and library development.

    Science.gov (United States)

    Brown, Lauren E; Chih-Chien Cheng, Ken; Wei, Wan-Guo; Yuan, Pingwei; Dai, Peng; Trilles, Richard; Ni, Feng; Yuan, Jing; MacArthur, Ryan; Guha, Rajarshi; Johnson, Ronald L; Su, Xin-zhuan; Dominguez, Melissa M; Snyder, John K; Beeler, Aaron B; Schaus, Scott E; Inglese, James; Porco, John A

    2011-04-26

    In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC(50)'s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.

  17. 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.

  18. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil.

    Directory of Open Access Journals (Sweden)

    Valtcho D Zheljazkov

    Full Text Available 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

  19. 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

  20. 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.

  1. 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

  2. The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine

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    Giovanny Garavito

    2012-09-01

    Full Text Available The effectiveness of methylene blue (MB combined with pyrimethamine (PYR, chloroquine (CQ or quinine (Q was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day or Q (25 mg/kg/day. No synergy was found between MB (15 mg/Kg and CQ (0.75 mg/Kg. Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

  3. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

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    Shah SMH

    2016-11-01

    Full Text Available Syed Muhammad Hassan Shah,1 Farhat Ullah,2 Shahzeb Khan,2,3 Syed Muhammad Mukarram Shah,4 Marcel de Matas,5 Zahid Hussain,6 Muhammad Usman Minhas,7 Naser M AbdEl-Salam,8 Khaled Hafez Assi,3 Mohammad Isreb3 1Department of Pharmacy, Sarhad University of Science & Information Technology, Peshawar, 2Department of Pharmacy, University of Malakand, Chakdara, Pakistan; 3Institute of Life Sciences Research, School of Pharmacy, University of Bradford, West Yorkshire, 4Department of Pharmacy, University of Swabi, KPK, Pakistan; 5SEDA Pharmaceutical Development Services, The BioHub at Alderley Park, Cheshire, UK; 6Faculty of Pharmacy, Department of Pharmaceutics, Universiti Teknologi MARA, Selangor, Malaysia; 7Faculty of Pharmacy & Alternative Medicine, The Islamia University of Bahawalpur Pakistan, Bahawalpur, Pakistan; 8Riyadh Community College, King Saud University, Riyadh, Saudi Arabia Abstract: Artemether (ARTM is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL and stabilizer solution (300.0±2.0 µg/mL. The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0. The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05 compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0

  4. Methanol Observation of IRAS 19312+1950: A Possible New Type of Class I Methanol Masers

    CERN Document Server

    Nakashima, Jun-ichi; Salii, Svetlana V; Zhang, Yong; Yung, Bosco H K; Deguchi, Shuji

    2015-01-01

    We report the result of a systematic methanol observation toward IRAS 19312+1950. The properties of the SiO, H2O and OH masers of this object are consistent with those of mass-losing evolved stars, but some other properties are difficult to explain in the standard scheme of stellar evolution in its late stage. Interestingly, a tentative detection of radio methanol lines was suggested toward this object by a previous observation. To date, there are no confirmed detections of methanol emission towards evolved stars, so investigation of this possible detection is important to better understand the circumstellar physical/chemical environment of IRAS 19312+1950. In this study, we systematically observed multiple methanol lines of IRAS 19312+1950 in the lambda=3mm, 7mm, and 13mm bands, and detected 6 lines including 4 thermal lines and 2 class I maser lines. We derived basic physical parameters including kinetic temperature and relative abundances by fitting a radiative transfer model. According to the derived exci...

  5. Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials

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    Peter K. Ngure , Lorraine Nyaoke & David Minja

    2012-03-01

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

  6. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

    Science.gov (United States)

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  7. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    Directory of Open Access Journals (Sweden)

    S M D K Ganga Senarathna

    Full Text Available The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10(-6 cm/sec, followed by amodiaquine around 20 x 10(-6 cm/sec; both mefloquine and artesunate were around 10 x 10(-6 cm/sec. Methylene blue was between 2 and 6 x 10(-6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine.

  8. The Stapled AKAP Disruptor Peptide STAD-2 Displays Antimalarial Activity through a PKA-Independent Mechanism.

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    Briana R Flaherty

    Full Text Available Drug resistance poses a significant threat to ongoing malaria control efforts. Coupled with lack of a malaria vaccine, there is an urgent need for the development of new antimalarials with novel mechanisms of action and low susceptibility to parasite drug resistance. Protein Kinase A (PKA has been implicated as a critical regulator of pathogenesis in malaria. Therefore, we sought to investigate the effects of disrupted PKA signaling as a possible strategy for inhibition of parasite replication. Host PKA activity is partly regulated by a class of proteins called A Kinase Anchoring Proteins (AKAPs, and interaction between HsPKA and AKAP can be inhibited by the stapled peptide Stapled AKAP Disruptor 2 (STAD-2. STAD-2 was tested for permeability to and activity against Plasmodium falciparum blood stage parasites in vitro. The compound was selectively permeable only to infected red blood cells (iRBC and demonstrated rapid antiplasmodial activity, possibly via iRBC lysis (IC50 ≈ 1 μM. STAD-2 localized within the parasite almost immediately post-treatment but showed no evidence of direct association with PKA, indicating that STAD-2 acts via a PKA-independent mechanism. Furosemide-insensitive parasite permeability pathways in the iRBC were largely responsible for uptake of STAD-2. Further, peptide import was highly specific to STAD-2 as evidenced by low permeability of control stapled peptides. Selective uptake and antiplasmodial activity of STAD-2 provides important groundwork for the development of stapled peptides as potential antimalarials. Such peptides may also offer an alternative strategy for studying protein-protein interactions critical to parasite development and pathogenesis.

  9. In Vivo Antimalarial Activity of Annona muricata Leaf Extract in Mice Infected with Plasmodium berghei.

    Science.gov (United States)

    Somsak, Voravuth; Polwiang, Natsuda; Chachiyo, Sukanya

    2016-01-01

    Malaria is one of the most important infectious diseases in the world. The choice for the treatment is highly limited due to drug resistance. Hence, finding the new compounds to treat malaria is urgently needed. The present study was attempted to evaluate the antimalarial activity of the Annona muricata aqueous leaf extract in Plasmodium berghei infected mice. Aqueous leaf extract of A. muricata was prepared and tested for acute toxicity in mice. For efficacy test in vivo, standard 4-day suppressive test was carried out. ICR mice were inoculated with 10(7) parasitized erythrocytes of P. berghei ANKA by intraperitoneal injection. The extracts (100, 500, and 1000 mg/kg) were then given orally by gavage once a day for 4 consecutive days. Parasitemia, percentage of inhibition, and packed cell volume were subsequently calculated. Chloroquine (10 mg/kg) was given to infected mice as positive control while untreated control was given only distilled water. It was found that A. muricata aqueous leaf extract at doses of 100, 500, and 1000 mg/kg resulted in dose dependent parasitemia inhibition of 38.03%, 75.25%, and 85.61%, respectively. Survival time was prolonged in infected mice treated with the extract. Moreover, no mortality to mice was observed with this extract up to a dose of 4000 mg/kg. In conclusion, the A. muricata aqueous leaf extract exerted significant antimalarial activity with no toxicity and prolonged survival time. Therefore, this extract might contain potential lead molecule for the development of a new drug for malaria treatment.

  10. Present development concerning antimalarial activity of phospholipid metabolism inhibitors with special reference to in vivo activity

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    Marie L. Ancelin

    1994-01-01

    Full Text Available The systematic screening of more than 250 molecules against Plasmodium falciparum in vitro has previously shown that interfering with phospholipid metabolism is lethal to the malaria parasite. These compounds act by impairing choline transport in infected erythrocytes, resulting in phosphatidylcholine de novo biosynthesis inhibition. A thorough study was carried out with the leader compound G25, whose in vitro IC50 is 0.6 nM. It was very specific to mature parasites (trophozoïtes as determined in vitro with P. falciparum and in vivo with P. chabaudi -infected mice. This specificity corresponds to the most intense phase of phospholipid biosynthesis activity during the parasite cycle, thus corroborating the mechanism of action. The in vivo antimalarial activity (ED50 against P. chabaudi was 0.03 mg/kg, and a similar sensitivity was obtained with P. vinckei petteri, when the drug was intraperitoneally administered in a 4 day suppressive test. In contrast, P. berghei was revealed as less sensitive (3- to 20-fold, depending on the P. berghei-strain. This difference in activity could result either from the degree of synchronism of every strain, their invasion preference for mature or immature red blood cells or from an intrinsically lower sensitivity of the P. berghei strain to G25. Irrespective of the mode of administration, G25 had the same therapeutic index (lethal dose 50 (LD50/ED50 but the dose to obtain antimalarial activity after oral treatment was 100-fold higher than after intraperitoneal (or subcutaneous administration. This must be related to the low intestinal absorption of these kind of compounds. G25 succeeded to completely inhibiting parasitemia as high as 11.2% without any decrease in its therapeutic index when administered subcutaneously twice a day for at least 8 consecutive days to P. chabaudi -infected-rodent model. Transition to human preclinical investigations now requires a synthesis of molecules which would permit oral

  11. 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

  12. Evaluation of antimalarial resistance marker polymorphism in returned migrant workers in China.

    Science.gov (United States)

    Feng, Jun; Li, Jun; Yan, He; Feng, Xinyu; Xia, Zhigui

    2015-01-01

    Imported malaria has been a great challenge for public health in China due to decreased locally transmitted cases and frequent exchange worldwide. Plasmodium falciparum has been mainly responsible for the increasing impact. Currently, artesunate plus amodiaquine, one of the artemisinin combination therapies recommended by the World Health Organization, has been mainly used against uncomplicated P. falciparum malaria in China. However, drug resistance marker polymorphism in returning migrant workers has not been demonstrated. Here, we have evaluated the prevalence of pfmdr1 and pfcrt polymorphisms, as well as the K13 propeller gene, a molecular marker of artemisinin resistance, in migrant workers returned from Ghana to Shanglin County, Guangxi Province, China, in 2013. A total of 118 blood samples were randomly selected and used for the assay. Mutations of the pfmdr1 gene that covered codons 86, 184, 1034, and 1246 were found in 11 isolates. Mutations at codon N86Y (9.7%) were more frequent than at others, and Y(86)Y(184)S(1034)D(1246) was the most prevalent (63.6%) of the four haplotypes. Mutations of the pfcrt gene that covered codons 74, 75, and 76 were observed in 17 isolates, and M(74)N(75)T(76) was common (70.6%) in three haplotypes. Eight different genotypes of the K13 propeller were first observed in 10 samples in China, 2 synonymous mutations (V487V and A627A) and 6 nonsynonymous mutations. C580Y was the most prevalent (2.7%) in all the samples. The data presented might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance in China.

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

    Directory of Open Access Journals (Sweden)

    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

  14. Anti-malarial activity of leaf-extract of hydrangea macrophylla, a common Japanese plant.

    Directory of Open Access Journals (Sweden)

    Kamei K

    2000-10-01

    Full Text Available To find a new anti-malarial medicine derived from natural resources, we examined the leaves of 13 common Japanese plants in vitro. Among them, a leaf-extract of Hydrangea macrophylla, a common Japanese flower, inhibited the parasitic growth of Plasmodium falciparum. The IC50 of Hydrangea macrophylla leaf extract to Plasmodium falciparum was 0.18 microg/ml. The IC50 to NIH 3T3-3 cells, from a normal mouse cell line, was 7.2 microg/ml. Thus, selective toxicity was 40. For the in vivo test, we inoculated Plasmodium berghei, a rodent malaria parasite, to ddY mice and administered the leaf-extract of Hydrangea macrophylla (3.6 mg/0.2 ml orally 3 times a day for 3 days. Malaria parasites did not appear in the blood of in the treated mice, but they did appear in the control group on day 3 or 4 after inoculation with the parasites. When leaf extract was administered to 5 mice 2 times a day for 3 days, malaria parasites did not appear in 4 of the mice but did appear in 1 mouse. In addition, the leaf-extract was administered orally 3 times a day for 3 days to Plasmodium berghei infected mice with a parasitemia of 2.7%. In the latter group, malaria parasites disappeared on day 3 after initiating the treatment, but they appeared again after day 5 or 6. Although we could not cure the mice entirely, we confirmed that the Hydrangea macrophylla leaf extract did contain an anti-malarial substance that can be administered orally.

  15. Methanol Oxidation on Model Elemental and Bimetallic Transition Metal Surfaces

    DEFF Research Database (Denmark)

    Tritsaris, G. A.; Rossmeisl, J.

    2012-01-01

    Direct methanol fuel cells are a key enabling technology for clean energy conversion. Using density functional theory calculations, we study the methanol oxidation reaction on model electrodes. We discuss trends in reactivity for a set of monometallic and bimetallic transition metal surfaces, flat...... sites on the surface and to screen for novel bimetallic surfaces of enhanced activity. We suggest platinum copper surfaces as promising anode catalysts for direct methanol fuel cells....

  16. Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation

    Directory of Open Access Journals (Sweden)

    Sukhbir Lal Khokra

    2016-11-01

    Full Text Available A small library of twenty-four quinoline based butenolides also known as furanones and their nitrogen analogues was prepared by using two different aroylpropionic acids, viz. 3-(2-naphthoylpropionic acid (3 and 3-(biphenyl-4-ylpropionic acid (4, as starting materials. The 3-aroylpropionic acids were reacted with different 6-substituted-2-chloroquinolin-3-carbaldehydes (2a–d to obtain the corresponding furan-2(3H-ones (5a–h. The purified and characterized furanones were then converted into their corresponding 2(3H-pyrrolones (6a–h and N-benzyl-pyrrol-2(3H-ones (7a–h. The antimicrobial activities of the title compounds were evaluated against two strains of each Gram +ve (Staphylococcus aureus and Bacillus subtilis, Gram −ve bacteria (Escherichia coli and Pseudomonas aeruginosa and against fungal strains of Aspergillus niger and Aspergillus flavus. In vivo anti-inflammatory potential of the title compounds was investigated by standard method. Majority of the compounds showed significant antibacterial activity against both the Gram +ve strains. Eight most potent anti-inflammatory compounds (5b, 5d, 5h, 6b, 7b, 7d, 7f, 7h which exhibited >53% inhibition in edema, were also screened for their in vivo analgesic activity. All the tested compounds were found to have significant reduction in ulcerogenic action but only three compounds (5d, 5h and 7h showed comparable analgesic activity to standard drug, diclofenac. The results were also validated using in silico approach and maximum mol doc score was obtained for compounds 7a–h. On comparing the in vivo and in silico anti-inflammatory results of synthesized compounds, N-benzyl pyrrolones (7a–h emerged as the potent anti-inflammatory agents. It was also observed that compounds that possess electron withdrawing group such as Cl or NO2 are more biologically active.

  17. Antiperoxidative and antiinflammatory effect of Sida cordifolia Linn. on quinolinic acid induced neurotoxicity.

    Science.gov (United States)

    Swathy, S S; Panicker, Seema; Nithya, R S; Anuja, M M; Rejitha, S; Indira, M

    2010-09-01

    Sida cordifolia is a plant belonging to the Malvaceae family used in many ayurvedic preparations. This study aimed at assessing the effects of ethanolic extract of Sida cordifolia root on quinolinic acid (QUIN) induced neurotoxicity and to compare its effect with the standard drug deprenyl in rat brain. Rats were divided into six groups: (1) control group (2) QUIN (55 microg/100 g bwt/day) (3) 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (4) Deprenyl (100 microg/100 g bwt/day) (5) QUIN (55 microg/100 g bwt/day) + 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (6) QUIN (55 microg/100 g bwt/day) + Deprenyl (100 microg/100 g bwt/day). At the end of the experimental period a status of lipid peroxidation products, protein peroxidation product, activities of the scavenging enzymes and the activities of the inflammatory markers were analyzed. Results revealed that the lipid peroxidation products decreased and the activities of the scavenging enzymes increased significantly in the brain of the plant extract treated group, deprenyl treated group and also in the coadminstered groups. The activities of markers of inflammatory responses such as cyclooxygenase and lipoxygenase were found to be significantly increased in the QUIN treated rats and this was decreased upon the administration of plant extract and deprenyl. In short, the study revealed that 50% ethanolic extract of Sida cordifolia has got potent antioxidant and antiinflammatory activity and the activity is comparable with the standard drug deprenyl.

  18. Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

    Science.gov (United States)

    Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

    2015-02-01

    Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection.

  19. Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives.

    Science.gov (United States)

    El-Gamal, Mohammed I; Khan, Mohammad Ashrafuddin; Tarazi, Hamadeh; Abdel-Maksoud, Mohammed S; Gamal El-Din, Mahmoud M; Yoo, Kyung Ho; Oh, Chang-Hyun

    2017-02-15

    This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines. Compounds 1e and 1g were the most promising analogues. Both compounds showed strong potency and broad-spectrum antiproliferative activity against the different tested cancer types. Their IC50 and TGI values were less than those of the reference drug, sorafenib, against most of the tested cell lines of the nine different cancer types. Furthermore, the most potent compounds 1d-g were tested against C-RAF kinase as a potential molecular target of this series of compounds. All of them showed high potency, and the most potent derivative was compound 1e (IC50 = 0.10 μM). It was further tested against a panel of another twelve kinases, and it showed selectivity against C-RAF kinase. This could be, at least in part, the possible mechanism of antiproliferative action of this series of compounds at molecular level. The binding modes of compounds 1e and 1g were studied by docking studies, which highlighted the importance of the urea linker compared with the amide linker.

  20. Studies on cluster, salt and molecular complex of zinc-quinolinate

    Indian Academy of Sciences (India)

    Prithiviraj Khakhlary; Jubaraj B Baruah

    2015-02-01

    Reactions of zinc halides with 8-hydroxyquinoline (hydroxQ) in equimolar ratio were carried out in different solvents. Respective solvates of tetranuclear clusters, namely [Zn4(oxyQ)6X2].(solvent)2, (when X=Cl, Solvent=dimethylformamide (1), dimethylacetamide (2) and dimethysulphoxide (3); X = Br, solvent = dimethylformamide (4), oxyQ=quinolinate anion) were obtained. Bond parameters of these isostructural clusteres 1–4 are compared from their single crystal structures. Anhydrous form of the cluster have porous packing and is thermally stable below 250° C. Surface area of the clusters 1 and 4 are 8.933 and 6.172 m2/g, respectively. Complexes 1 and 4 can be reversibly hydrated, which is reflected in colour changes. The reaction of zinc chloride with 8-hydroxyquinoline in equimolar ratio followed by crystallization from water gave salt (HhydroxQ)2 [ZnCl4] (5) and a similar reaction followed by crystallization from 3-methylpyridine (3mepy) resulted in the molecular complex [Zn(oxyQ)2(3mepy)]. [Zn(oxyQ)2(3mepy)2].3H2O (6). Complex 5 is formed from a hydrolytic equilibrium of water with zinc chloride yielding tetrachloro zinc anion and zinc hydroxide. Taking advantage of this reaction, a composite material of ZnO@complex 5 exhibiting dual fluorescence at 450 and 575 nm on excitation at 390 nm was prepared. Fluorescence emission properties of all the complexes in solid state are compared with fluorescence emission of the ligand