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Sample records for categorical structure-activity relationship

  1. Structure-activity relationships of bumetanide derivatives

    DEFF Research Database (Denmark)

    Pedersen, Kasper Lykke; Töllner, Kathrin; Römermann, Kerstin;

    2015-01-01

    and its derivatives in dogs and their inhibition of hNKCC2A (r(2) = 0.817; P < 0.01). Replacement of the carboxylic group of bumetanide by a non-ionic residue, for example, an anilinomethyl group, decreased inhibition of hNKCC2A, indicating that an acidic group was required for transporter inhibition...... diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. EXPERIMENTAL APPROACH: In this study......, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 μM. There was good correlation between the diuretic potency of bumetanide...

  2. Structure-activity relationship of anthelmintic cyclooctadepsipeptides.

    Science.gov (United States)

    Ohyama, Makoto; Okada, Yumiko; Takahashi, Masaaki; Sakanaka, Osamu; Matsumoto, Maki; Atsumi, Kunio

    2011-01-01

    The relationship between cyclooctadepsipeptides and their anthelmintic efficacy was examined by converting the natural products, PF1022A, PF1022E and PF1022H. Some analogues substituted at the para position of the phenyllactate moiety showed higher or equivalent activity against the parasitic nematode, Ascaridia galli in chicken when compared with the parent compounds. It is suggested that lipophilicity and the polar surface area, in addition to structural requirements of the derivatives, influenced the anthelmintic efficacy in vivo. PMID:21737929

  3. Structure activity relationship of selective GABA uptake inhibitors

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Jørgensen, Lars; Madsen, Karsten K;

    2015-01-01

    A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the...

  4. Structure and Structure-activity Relationship of Functional Organic Molecules

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    @@ Research theme The group is made up of junior scientists from the State Key Laboratory of Elemento-organic Chemistry, Nankai University.The scientists focus their studis on the structure and structure-activity relationship of functional organic molecules not only because it has been the basis of their research, but also because the functional study of organic compounds is now a major scientific issue for organic chemists around the world.

  5. Structure-activity relationship of crustacean peptide hormones.

    Science.gov (United States)

    Katayama, Hidekazu

    2016-04-01

    In crustaceans, various physiological events, such as molting, vitellogenesis, and sex differentiation, are regulated by peptide hormones. To understanding the functional sites of these hormones, many structure-activity relationship (SAR) studies have been published. In this review, the author focuses the SAR of crustacean hyperglycemic hormone-family peptides and androgenic gland hormone and describes the detailed results of our and other research groups. The future perspectives will be also discussed. PMID:26624010

  6. Structure-activity relationship of indoloquinoline analogs anti-MRSA.

    Science.gov (United States)

    Zhao, Min; Kamada, Tomonori; Takeuchi, Aya; Nishioka, Hiromi; Kuroda, Teruo; Takeuchi, Yasuo

    2015-12-01

    Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity. PMID:26522949

  7. Structure-activity relationship of endomorphins and their analogs

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To study the structure-activity relationship of endomorphins (EMs), the action of opioid receptor binding (AORB), analgesic activity and vasodilator effects of EMs and their eight analogs were investigated, which were prepared by rationally replacing the 2-/3-amino acid (Aa) of EMs. The results showed: (ⅰ) The 2-Aa was comparatively more related to the selectivity of EMs while the 3-Aa to their affinity; (ⅱ) the analgesia and vasodilatation of EMs and their analogs were not completely dictated by their AORB (in vitro), the action of [D-Pro2]EM-2 was unusual; (ⅲ) EMs lost their analgesia in the central nervous system and their vasodilatation in the circulatory system with different mechanisms; the former was due to the degradation of some peptidase, and the latter possibly due to the feedback inhibi-tion.

  8. Structure-Activity Relationship of Fluoroquinolones Against K. pneumoniae

    Science.gov (United States)

    Li, Xiao-hong; Zhang, Rui-zhou; Cheng, Xin-lu; Yang, Xiang-dong

    2007-04-01

    The structure-activity relationship of fluoroquinolones, which show anti-K. pneumoniae activity, was studied by using principal component analysis (PCA) and hierarchical cluster analysis (HCA). The PCA results showed that the lowest unoccupied molecular orbital energy, energy difference between the highest occupied and the lowest unoccupied molecular orbital, dipole moment, net atomic charge on atom I, molecular polarizability, partition coefficient and molecular refractivity of these compounds are responsible for the separation between high-activity and low-activity groups. The HCA results were similar to those obtained with PCA. By using the chemometric results, four synthetic compounds were analyzed through PCA and HCA, and three of them are proposed as active molecules against K. pneumoniae which is consistent with the results of clinical experiments. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-K. pneumoniae activity.

  9. Structure-activity relationship studies of citalopram derivatives

    DEFF Research Database (Denmark)

    Larsen, M Andreas B; Plenge, Per; Andersen, Jacob;

    2016-01-01

    . The antidepressant drug citalopram displays high-affinity S1 binding and low-affinity S2 binding. To elucidate a possible therapeutic role of allosteric inhibition of SERT a drug that specifically targets the allosteric site is required. The purpose of this study was to find a compound bearing higher...... selectivity towards the S2 site. EXPERIMENTAL APPROACH: We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, that shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which...... distinguish citalopram from talopram in conferring selectivity towards the S1 and S2 site, respectively, was assessed by determining the binding of 14 citalopram/talopram analogous to the S1 and S2 binding sites in SERT using membranes of COS7 cells transiently expressing SERT. KEY RESULTS: The structure...

  10. Mereology of Quantitative Structure-Activity Relationships Models

    Directory of Open Access Journals (Sweden)

    Guillermo Restrepo

    2015-12-01

    Full Text Available In continuing with the research program initiated by Llored and Harré of exploring the part/whole (mereological discourses of chemistry, we analyse Quantitative Structure-Activity Relationships (QSAR studies, which are widespread approaches for modeling substances’ properties. The study is carried out by analyzing a particular QSAR model, and it is found that different mereologies are needed: from those regarding bulk substances as wholes and molecular entities as parts and to mereologies where the wholes are molecules whose parts are atoms, structured subsets of atoms, nuclei and electronic densities. We suggest a relationship between successful QSAR models and a deep understanding of the mereologies used and the ways they are intertwined. We note that QSAR modelers prefer the mereology of substance-molecule and then discuss how that is related to simplicity and computational capacity. Historical questions are opened, e.g. how the mereologies of substances have changed over time? and why they are mostly oriented toward organic chemistry?

  11. Structure activity relationships to assess new chemicals under TSCA

    Energy Technology Data Exchange (ETDEWEB)

    Auletta, A.E. [Environmental Protection Agency, Washington, DC (United States)

    1990-12-31

    Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the US Environmental Protection Agency (EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judgement of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of addition review of further testing. It should not be viewed as a replacement for testing. 4 tabs.

  12. Unbalance Quantitative Structure Activity Relationship Problem Reduction in Drug Design

    Directory of Open Access Journals (Sweden)

    D. Pugazhenthi

    2009-01-01

    Full Text Available Problem statement: Activities of drug molecules can be predicted by Quantitative Structure Activity Relationship (QSAR models, which overcome the disadvantage of high cost and long cycle by employing traditional experimental methods. With the fact that number of drug molecules with positive activity is rather fewer than that with negatives, it is important to predict molecular activities considering such an unbalanced situation. Approach: Asymmetric bagging and feature selection was introduced into the problem and Asymmetric Bagging of Support Vector Machines (AB-SVM was proposed on predicting drug activities to treat unbalanced problem. At the same time, features extracted from structures of drug molecules affected prediction accuracy of QSAR models. Hybrid algorithm named SPRAG was proposed, which applied an embedded feature selection method to remove redundant and irrelevant features for AB-SVM. Results: Numerical experimental results on a data set of molecular activities showed that AB-SVM improved AUC and sensitivity values of molecular activities and SPRAG with feature selection further helps to improve prediction ability. Conclusion: Asymmetric bagging can help to improve prediction accuracy of activities of drug molecules, which could be furthermore improved by performing feature selection to select relevant features from the drug.

  13. Review of Quantitative Structure - Activity Relationships for Acute Mammalian Toxicity

    Directory of Open Access Journals (Sweden)

    Iglika Lessigiarska

    2006-12-01

    Full Text Available This paper reviews Quantitative Structure-Activity Relationship (QSAR models for acute mammalian toxicity published in the last decade. A number of QSAR models based on cytotoxicity data from mammalian cell lines are also included because of their possible use as a surrogate system for predicting acute toxicity to mammals. On the basis of the review, the following conclusions can be made: i a relatively small number of models for in vivo toxicity are published in the literature. This is due to the nature of the endpoint - acute systemic toxicity is usually related to whole body phenomena and therefore is very complex. The complexity of the mechanisms involved leads to difficulties in the QSAR modelling; ii most QSAR models identify hydrophobicity as a parameter of high importance for the modelled toxicity. In addition, many models indicate the role of the electronic and steric effects; iii most of the literature-based models are restricted to single chemical classes. Models based on more heterogeneous data sets are those incorporated in expert systems. In general, the QSAR models for mammalian toxicity identified in this review are considered useful for investigating the mechanisms of toxicity of defined chemical classes. However, for predictive purposes in the regulatory assessment of chemicals most of the models require additional information to satisfy internationally agreed validation principles. In addition, the development of new models covering larger chemical domains would be useful for the regulatory assessment of chemicals.

  14. Development of structure-activity relationship for metal oxide nanoparticles

    Science.gov (United States)

    Liu, Rong; Zhang, Hai Yuan; Ji, Zhao Xia; Rallo, Robert; Xia, Tian; Chang, Chong Hyun; Nel, Andre; Cohen, Yoram

    2013-05-01

    Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were evaluated, based on an initial pool of thirty NP descriptors. The conduction band energy and ionic index (often correlated with the hydration enthalpy) were identified as suitable NP descriptors that are consistent with suggested toxicity mechanisms for metal oxide NPs and metal ions. The best performing nano-SAR with the above two descriptors, built with support vector machine (SVM) model and of validated robustness, had a balanced classification accuracy of ~94%. An applicability domain for the present data was established with a reasonable confidence level of 80%. Given the potential role of nano-SARs in decision making, regarding the environmental impact of NPs, the class probabilities provided by the SVM nano-SAR enabled the construction of decision boundaries with respect to toxicity classification under different acceptance levels of false negative relative to false positive predictions.Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were

  15. Structure-activity relationship of CART peptide fragments

    Czech Academy of Sciences Publication Activity Database

    Maletínská, Lenka; Maixnerová, Jana; Hlaváček, Jan; Blokešová, Darja; Elbert, Tomáš; Šanda, Miloslav; Slaninová, Jiřina; Železná, Blanka

    2007-01-01

    Roč. 88, č. 4 (2007), s. 565. ISSN 0006-3525. [American Peptide Society Symposium /20./. 26.06.2007-30.06.2007, Montreal] Institutional research plan: CEZ:AV0Z40550506 Keywords : cocaine and amphetamine regulated transcript peptide * structure * activity Subject RIV: CE - Biochemistry

  16. Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

    2012-01-01

    calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

  17. Total Synthesis and Structure-Activity Relationship of Glycoglycerolipids from Marine Organisms

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2014-06-01

    Full Text Available Glycoglycerolipids occur widely in natural products, especially in the marine species. Glycoglycerolipids have been shown to possess a variety of bioactivities. This paper will review the different methodologies and strategies for the synthesis of biological glycoglycerolipids and their analogs for bioactivity assay. In addition, the bioactivities and structure-activity relationship of the glycoglycerolipids are also briefly outlined.

  18. Structure-activity relationship study between baicalein and wogonin by spectrometry, molecular docking and microcalorimetry.

    Science.gov (United States)

    Tu, Bao; Li, Rong-Rong; Liu, Zhi-Juan; Chen, Zhi-Feng; Ouyang, Yu; Hu, Yan-Jun

    2016-10-01

    Flavones (e.g. baicalein and wogonin) extensively used worldwide in food preparation and traditional medicine. In this study, a systematically comparative study of their structure-activity relationships (SAR) on their interaction with BSA, antioxidant activity and antibacterial activity has been carried out by spectrometry, molecular docking and microcalorimetry. Our results show that the skeleton structure of flavones, the number of hydroxyl groups, the type of functional group, conjugated system and the steric hindrance may be responsible for their different biological activity. These findings not only would lay a scientific foundation for discovering and designing flavones-based food and drug, may also help us to understanding the structure-activity relationship between flavones at the molecular level. PMID:27132840

  19. Inhibitors of bacterial and mammalian hyaluronidase - Synthesis and structure-activity relationships

    OpenAIRE

    Salmen, Sunnhild

    2004-01-01

    The role and the importance of hyaluronic acid and hyaluronidases in physiological and pathophysiological processes are largely misunderstood, so that selective and potent hyaluronidase inhibitors are required. As such compounds are not known so far, the goal of this project was to identify and to synthesise lead-like compounds, to optimise the structures and to study the structure-activity relationships. Therefore, we applied the following strategies: structurally dif...

  20. Pearson versus Spearman, Kendall's Tau Correlation Analysis on Structure-Activity Relationships of Biologic Active Compounds

    OpenAIRE

    Jäntschi, Lorentz; Sorana-Daniela BOLBOACĂ

    2006-01-01

    A sample of sixty-seven pyrimidine derivatives with inhibitory activity on E. coli dihydrofolate reductase (DHFR) was studied by the use of molecular descriptors family on structure-activity relationships. Starting from the results obtained by applying of MDF-SAR methodology on pyrimidine derivatives and from the assumption that the measured activity (compounds’ inhibitory activity) of a biologically active compounds is a semi-quantitative outcome (can be related with the type of equipment us...

  1. α-N-heterocyclic thiosemicarbazone derivatives as potential antitumor agents: A structure-activity relationships approach

    OpenAIRE

    Matesanz, Ana I.; Souza, Pilar

    2009-01-01

    α-N-Heterocyclic thiosemicarbazones, (N)-TSCs, are potent inhibitors of ribonucleotide reductase (RR). This enzyme plays a critical role in DNA synthesis and repair, and is a well-recognized target for cancer chemotherapeutic agents. In this review the structural features of (N)-TSCs, required for maximum antitumour activity have been explored. Special attention is given to the mechanisms of action and structure-activity relationships

  2. Quantum Chemical Study on Structure-activity Relationship of Several Kinds of Drugs

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; CHENG Xin-Lu; ZHANG Rui-Zhou; YANG Xiang-Dong

    2005-01-01

    The structure-activity relationship of several drugs with similar structure has been investigated by using ab initio method.The relation between the dipole moments and biological activities of these drugs was judged after comparing their geometric structures, dipole moments and inhibitory concentrations.In principle, new drug molecule could be reasonably designed by altering the place of groups and ultimately, the potential drug could be screened by comparing the dipole moments of obtained molecules.

  3. Quantitative Structure activity relationship and risk analysis of some pesticides in the cattle milk

    OpenAIRE

    Faqir Muhammad*, Ijaz Javed, Masood Akhtar1, Zia-ur-Rahman, Mian Muhammad Awais1, Muhammad Kashif Saleemi2 and Muhammad Irfan Anwar3

    2012-01-01

    Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR) models were used to predict the residues...

  4. Structure-activity relationship of surfactant for preparing DMFC anodic catalyst

    International Nuclear Information System (INIS)

    Three kinds of surfactants as stabilizer were applied to the preparation of electrocatalysts for direct methanol fuel cell (DMFC). The catalysts have been characterized by examining their catalytic activities, morphologies and particle sizes by means of cyclic voltammetry, chronoamperometry, X-ray diffraction and transmission electron microscopy (TEM). It is found that the surfactants with different structures have a significantly influence on the catalyst shape and activity. The catalysts prepared with non-ionic surfactants as the stabilizer show higher activity for direct oxidation of methanol. The structure-activity relationship (SAR) analysis has been explored and the effect of hydrophile-lipophile balance (HLB value) has also been discussed

  5. Structure-activity relationship in high-performance iron-based electrocatalysts for oxygen reduction reaction

    Science.gov (United States)

    Song, Ping; Wang, Ying; Pan, Jing; Xu, Weilin; Zhuang, Lin

    2015-12-01

    A sustainable Iron (Fe), Nitrogen (N) co-doped high performance Fe-Nx/C electrocatalyst for oxygen reduction reaction (ORR) is synthesized simply based on nitric acid oxidation of cheap carbon black. The obtained optimal nonprecious metal electrocatalyst shows high ORR performance in both alkaline and acidic conditions and possesses appreciable performance/price ratio due to its low cost. Furthermore, the structure-activity relationship of different active sites on Fe-Nx/C is revealed systematically: Fe-N4/2-C > Fe4-N-C > N-C >> Fe4-C ≥ C, from both experimental and theoretical points of view.

  6. Study of the structure-activity relationships of parabens: a practical class

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Joao Paulo dos Santos; Savino, Giovanna; Amarante, Andre Cortinas Goncalves, E-mail: joao.fernandes@mackenzie.br [Centro de Ciencias Biologicas e da Saude, Universidade Presbiteriana Mackenzie, Sao Paulo, SP (Brazil); Sousa, Milena Rodrigues de; Silva, Geane Ramos da [Universidade Camilo Castelo Branco, Sao Paulo, SP (Brazil); Cianciulli, Maria Eliza [Universidade do Grande ABC, Santo Andre, SP (Brazil); Correa, Michelle Fidelis; Ferrarini, Marcio [Centro Universitario Sao Camilo, Sao Paulo, SP (Brazil)

    2013-09-01

    Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

  7. Substrate structure-activity relationships guide rational engineering of modular polyketide synthase ketoreductases.

    Science.gov (United States)

    Bailey, Constance B; Pasman, Marjolein E; Keatinge-Clay, Adrian T

    2016-01-14

    Modular polyketide synthase ketoreductases can set two chiral centers through a single reduction. To probe the basis of stereocontrol, a structure-activity relationship study was performed with three α-methyl, β-ketothioester substrates and four ketoreductases. Since interactions with the β-ketoacyl moiety were found to be most critical, residues implicated in contacting this moiety were mutated. Two mutations were sufficient to completely reverse the stereoselectivity of the model ketoreductase EryKR1, converting it from an enzyme that generates (2S,3R)-products into one that yields (2S,3S)-products. PMID:26568113

  8. Structure-Activity Relationships of Synthetic Coumarins as HIV-1 Inhibitors

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available HIV/AIDS pandemics is a serious threat to health and development of mankind, and searching for effective anti-HIV agents remains actual. Considerable progress has been made in recent years in the field of drug development against HIV. A lot of structurally different coumarins were found to display potent anti-HIV activity. The current review demonstrates the variety of synthetic coumarins having unique mechanism of action referring to the different stages of HIV replication. Recent studies based on the account of various synthetic coumarins seem to indicate that some of them serve as potent non-nucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed.The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against resistant mutants. The investigation on chemical anti-HIV agents gives hope and optimism about it. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives.

  9. Quantitative structure-activity relationships for the Toxicity of Substituted Benzenes to Cyprinus carpio

    Institute of Scientific and Technical Information of China (English)

    GUANG-HUA LU; CHAO WANG; XING YUAN; PEI-ZHEN LAN

    2005-01-01

    Objective To measure the 96h-LC50 values of 32 substituted benzenes to the carp and to study the relationship between quantitative structure-activity and structural parameters of chemicals. Methods The acute toxicity values of 32 substituted benzenes to the carp were determined in a semistatic test. The energy of the lowest unoccupied molecular orbital, and the highest occupied molecular orbital, the dipole moment and the molecular weight of substituted benzenes were calculated by the quantum chemical method MOPAC6.0. Results The range of the toxicity of studied compounds was broad, and the most toxic compound was pentachlorophenol, while the least toxic compound was 4-methylaniline. By the stepwise regression analyses, a series of Quantitative structure-activity relationships (QSAR) equations were derived from all compounds and subclasses. The equation log1/LC50=0.759logP +2.222 (R2 (adj)=0.818) was found to fit well and the average predicted percentage error was 6.16%. Conclusion The toxicity of anilines and phenols to the carp could be modeled well by logP alone, whereas the toxicity of the halogenated benzenes and nitrobenznes not containing hydroxyl or amino group can be controlled by hydrophobic and electronic factors.

  10. Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus

    Institute of Scientific and Technical Information of China (English)

    Hui ZHANG; Lu ZHANG; Li-juan PENG; Xiao-wu DONG; Di WU; Vivian Chi-Hua WU; Feng-qin FENG

    2012-01-01

    Fatty acids and derivatives (FADs) are resources for natural antimicrobials.In order to screen for additional potent antimicrobial agents,the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay.Monoglycerides of fatty acids were the most potent class of fatty acids,among which monotridecanoin possessed the most potent antimicrobial activity.The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR:R2=0.942,Q2LOO=0.910; CoMFA:R2=0.979,Q2=0.588,respectively).Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structureactivity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents.

  11. Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models

    Science.gov (United States)

    The present study explores the merit of utilizing available pharmaceutical data to construct a quantitative structure-activity relationship (QSAR) for prediction of the fraction of a chemical unbound to plasma protein (Fub) in environmentally relevant compounds. Independent model...

  12. Molecular Descriptors Family on Structure Activity Relationships 3. Antituberculotic Activity of some Polyhydroxyxanthones

    Directory of Open Access Journals (Sweden)

    Sorana BOLBOACĂ

    2005-06-01

    Full Text Available The antituberculotic activity of some polyhydroxyxanthones was estimated using the Molecular Descriptors Family on Structure Activity Relationships methodology. From a total number of 298110 real and distinct calculated descriptors, 94843 were significantly different and entered into multiple linear regression analysis. The best performing bi-varied model was obtained by use of all polyhydroxyxanthones. The MDF SAR model was validated splitting the molecules into training and test sets. A correlated correlations analysis was applied in other to compare the MDF SAR models with the previous SAR model. The prediction ability of antituberculotic activity of polyhydroxyxanthones with MDF SAR methodology is sustained by three arguments: leave-one-out procedure, training vs. test procedure, and the correlated correlations analysis. Looking at the bi-varied MDF SAR model, we can conclude that the antituberculotic activity of polyhydroxyxanthones is almost of geometrical nature (99% and is strongly dependent on partial atomic charge and group electronegativity.

  13. Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

    Science.gov (United States)

    Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

    2006-11-01

    In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition. PMID:17077558

  14. Structure-activity relationships of heterogeneous catalysts from time-resolved X-ray absorption spectroscopy

    International Nuclear Information System (INIS)

    Knowing the composition and the evolution of the bulk structure of a heterogeneous catalyst under working conditions (in situ) is a pre-requisite for understanding structure-activity relationships. X-ray absorption spectroscopy can be employed to study a catalytically active material in situ. In addition to steady-state investigations, the technique permits experiments with a time-resolution in the sub-second range to elucidate the solid-state kinetics of the reactions involved. Combined with mass spectrometry, the evolution of the short-range order structure of a heterogeneous catalyst, the average valence of the constituent metals, and the phase composition can be obtained. Here we present results obtained from time-resolved studies on the reduction of MoO3 in propene and in propene and oxygen

  15. Benzazepines: Structure-activity relationships between D1 receptor blockade and selected pharmacological effects

    International Nuclear Information System (INIS)

    This chapter describes the displacement of 3H-23390 and 3H-spiperone binding by dopamine agonists and antagonists. The authors undertook an evaluation of the ability of selected analogs of SCH 23390 to displace 3H-SCH 23390 and 3H-spiperone. Structure-activity relationships of SCH 23390 analogs: 7-position substituents, is shown. It is shown that, in general, benzazepines with a variety of substituents in the 7-position retain their selectivity for D1 sites. Substituents at the 8-position and at the N-position are also discussed. The authors determine a correlation between displacement of 3H-SCH 23390 and blockade of dopamine-sensitive adenylate cyclase (DSAC). These effects and inhibition of conditioned avoidance responsing (CAS) in rats was also studied. A detailed evaluation is presented of the effects of SCH 23390 and haloperidol in the Inclined Screen and CAR tests

  16. Structure-activity relationship of lysophosphatidylcholines in HL-60 human leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Eun-hee LEE; Mi-ran YUN; Wei-hong WANG; Jee H JUNG; Dong-soon IM

    2004-01-01

    AIM: To explore the structure-activity relationship of lysophosphatidylcholine (LPC) and lysolipid molecules from a marine sponge and ladybirds. METHODS: We tested three synthetic LPCs and four natural lysolipids on Ca2+mobilization in HL-60 human leukemia cells. RESULTS: We observed lysolipid-mediated Ca2+ mobilization. The activity was the same in both ester- and ether-linked lysolipids, and introduction of a double bond or methoxy group on the alkyl chain did not significantly modulate the activity. However, replacement of trimethylammonium moiety in the choline structure with ammonium moiety reduced the activity. Furthermore, change of the alkyl chain length influenced the Ca2+ response. CONCLUSION: LPC-induced Ca2+ mobilization might be dependent on the length of alkyl chain and the presence of choline moiety in HL-60 leukemia cells.

  17. Chemistry and Structure-Activity Relationship of the Styrylquinoline-Type HIV Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Didier Desmaële

    2010-04-01

    Full Text Available In spite of significant progress in anti-HIV-1 therapy, current antiviral chemo-therapy still suffers from deleterious side effects and emerging drug resistance. Therefore, the development of novel antiviral drugs remains a crucial issue for the fight against AIDS. HIV-1 integrase is a key enzyme in the replication cycle of the retrovirus since it catalyzes the integration of the reverse transcribed viral DNA into the chromosomal DNA. Efforts to develop anti-integrase drugs started during the early nineties, culminating with the recent approval of Raltegravir. The discovery and the development of the styrylquinoline inhibitor class was an important step in the overall process. In this review we have described the key synthetic issues and the structure-activity relationship of this family of integrase inhibitors. Crystallographic and docking studies that shed light on their mechanism of action are also examined.

  18. Quantitative Structure-activity Relationship Study on the Antioxidant Activity of Carotenoids

    Institute of Scientific and Technical Information of China (English)

    SUN Yu-Jing; PANG Jie; YE Xing-Qian; Lü Yuan; LI Jun

    2009-01-01

    Carotenoids are a family of effective active oxygen scavengers, which can reduce the danger of occurrence of chronic diseases such as cardiovascular disease, cataract, cancer, and so on. The quantitative structure-activity relationship (QSAR) equation between carotenoids and antioxidant activity was established by quantum chemistry AMI, molecular mechanism (MM+) and stepwise regression analysis methods, and the model was evaluated by leave-one-out approach. The results showed that the significant molecular descriptors related to the antioxidant activity of carotenoids were the energy difference (EHL) between the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) and ionization energy (Eiso). The model showed a good predictive ability (Q2 > 0.5).

  19. Defensive sesquiterpenes from Senecio candidans and S. magellanicus, and their structure-activity relationships.

    Science.gov (United States)

    Reina, Matías; Santana, Omar; Domínguez, Dulce M; Villarroel, Luis; Fajardo, Víctor; Rodríguez, Matías L; González-Coloma, Azucena

    2012-03-01

    Eleven eremophilanolides, 1-3 and 6-13, and two eremophilanes, 24 and 25, were isolated from Senecio candidans and S. magellanicus from the Magallanes Region (Chile). Compounds 2, 3, 9, and 10 have not been previously reported as natural products. Their structures were established by NMR spectroscopic analysis and chemical transformations. The X-ray analysis of compounds 11, 13, and 17 were also performed. Different semisynthetic analogs from eremophilanolide 11 were generated to carry out a structure-activity relationship study. Their possible plant defensive role was tested against herbivorous insects (Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae) and plants (Lactuca sativa). Additionally, their effects on insect (Sf9) and mammalian (CHO) cell lines were tested. PMID:22422530

  20. Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.

    Science.gov (United States)

    Bouley, Renee; Ding, Derong; Peng, Zhihong; Bastian, Maria; Lastochkin, Elena; Song, Wei; Suckow, Mark A; Schroeder, Valerie A; Wolter, William R; Mobashery, Shahriar; Chang, Mayland

    2016-05-26

    We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure-activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model. PMID:27088777

  1. Percutaneous absorption of herbicides derived from 2,4-dichlorophenoxyacid: structure-activity relationship.

    Science.gov (United States)

    Beydon, Dominique; Payan, Jean-Paul; Ferrari, Elisabeth; Grandclaude, Marie-Christine

    2014-08-01

    Ethyl to octyl esters of 2,4-dichlorophenoxy-acetic acids (2,4DAA), 2,4-dichlorophenoxy-propionic acids (2,4DPA) or 2,4-dichlorophenoxy-butyric acids (2,4DBA) are present in the most commonly used herbicides. Their use involves a significant risk of skin exposure, but little is known about the percutaneous flux of these substances. Studies have shown that percutaneous transition of esters may be dependent on their hydrolysis by esterases present in the skin. In this study, we describe ex vivo percutaneous absorption of seven pure esters (methyl to decyl) with a 2,4DA structure for rats (n=6) and humans (n=7). Esters were applied at 50 μL cm(-2) to dermatomed skin (approximately 0.5 mm thick) for 24 h. The enzymatic constants for hydrolysis of each ester by skin esterases were determined in vitro using skin homogenates from both species. Structure-activity relationships linking the evolution of the ex vivo percutaneous flux of esters and the 2,4D structure with enzymatic (Vmax; Km) and/or physical parameters (molecular weight, molecular volume, size of the ester, log(kow)) were examined to develop a good flux estimation model. Although the percutaneous penetration of all of the esters of the 2,4D family are "esterase-dependent", the decreasing linear relationship between percutaneous penetration and hyrophobicity defined by the logarithm for the octanol-water partition coefficient (log(kow)) is the most pertinent model for estimating the percutaneous absorption of esters for both species. The mean flux of the free acid production by the esterases of the skin is not the limiting factor for percutaneous penetration. The rate of hydrolysis of the esters in the skin decreases linearly with log(kow), which would suggest that either the solubility of the esters in the zones of the skin that are rich in esterases or the accessibility to the active sites of the enzyme is the key factor. The structure-activity relationship resulting from this study makes it possible, in

  2. Quantitative structure activity relationship and toxicity mechanisms of chlorophenols on cells in vitro

    Institute of Scientific and Technical Information of China (English)

    JIANG Jie; CHEN Jiangning; YU Hongxia; ZHANG Feng; ZHANG Junfeng; WANG Liansheng

    2004-01-01

    3-(4,5-dimethylthiazd-2-yl)-2,5-diphenylentrazolium bromide (MTT) reduction assay was used to investigate the acute toxicity of 8 different chlorophenols (CPs) on rat connective tissue fibroblast L929 cells and human liver cancer HepG2 cells. Combined with the data from Quantitative Structure Activity Relationship (QSAR) approach of CPs by using the octanol-water partition coefficients (Kow), an effective model was deduced to evaluate the cytotoxicity of these chemicals. Furthermore, the relationship between the structures of CPs and their cytotoxicity was proposed. The results show that 2-chlorophenol (2-CP), 4-chlorophenol (4-CP), 2,6-dichlorophenol (2,6-DCP), 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP) and 2,3,4-trichlorophenol (2,3,4-TCP) induced apoptosis, whereas, 2,3,5,6-tetrachlorophenol (2,3,5,6-TeCP) and pentachlorophenl (PCP)demonstrated more characteristic of necrosis than apoptosis.These results establish a good experimental base both for developing the comparative evaluation of toxicity of CPs in vitro and for elucidating the toxicity mechanisms of them.

  3. Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents.

    Science.gov (United States)

    Ghanbari, Zahra; Housaindokht, Mohammad R; Izadyar, Mohammad; Bozorgmehr, Mohammad R; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R; Matin, Maryam M; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  4. Applying quantitative structure-activity relationship approaches to nanotoxicology: current status and future potential.

    Science.gov (United States)

    Winkler, David A; Mombelli, Enrico; Pietroiusti, Antonio; Tran, Lang; Worth, Andrew; Fadeel, Bengt; McCall, Maxine J

    2013-11-01

    The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure-toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure-toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure-activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes. PMID:23165187

  5. New Descriptors of Amino Acids and Its Applications to Peptide Quantitative Structure-activity Relationship

    Institute of Scientific and Technical Information of China (English)

    SHU Mao; HUO Dan-Qun; MEI Hua; LIANG Gui-Zhao; ZHANG Mei; LI Zhi-Liang

    2008-01-01

    A new set of descriptors, HSEHPCSV (component score vector of hydrophobic, steric, and electronic properties together with hydrogen bonding contributions), were derived from principal component analyses of 95 physicochemical variables of 20 natural amino acids separately according to different kinds of properties described, namely, hydrophobic, steric, and electronic properties as well as hydrogen bonding contributions. HSEHPCSV scales were then employed to express structures of angiotensin-converting enzyme inhibitors, bitter tasting thresholds and bactericidal 18 peptide, and to construct QSAR models based on partial least square (PLS). The results obtained are as follows: the multiple correlation coefficient (R2cum) of 0.846, 0.917 and 0.993, leave-one-out cross validated Q2cum of 0.835, 0.865 and 0.899, and root-mean-square error for estimated error (RMSEE) of 0.396, 0.187and 0.22, respectively. Satisfactory results showed that, as new amino acid scales, data of HSEHPCSV may be a useful structural expression methodology for the studies on peptide QSAR (quantitative structure-activity relationship) due to many advantages such as plentiful structural information, definite physical and chemical meaning and easy interpretation.

  6. Structure-Activity Relationships of the Bioactive Thiazinoquinone Marine Natural Products Thiaplidiaquinones A and B

    Directory of Open Access Journals (Sweden)

    Jacquie L. Harper

    2015-08-01

    Full Text Available In an effort to more accurately define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A and B, we have evaluated not only the natural products but also dioxothiazine regioisomers and two precursor quinones in a range of bioassays. While the natural products were found to be weak inducers of ROS in Jurkat cells, the dioxothiazine regioisomer of thiaplidiaquinone A and a synthetic precursor to thiaplidiaquinone B were found to be moderately potent inducers. Intriguingly, and in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis was found to be dependent upon the positioning of one of the geranyl sidechains in the compounds with thiaplidiaquinone A and its dioxothiazine regioisomer causing death dominantly by necrosis, while thiaplidiaquinone B and its dioxothiazine isomer caused cell death via apoptosis. The dioxothiazine regioisomer of thiaplidiaquinone A exhibited more potent in vitro antiproliferative activity against human tumor cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active in antiplasmodial and anti-farnesyltransferase assays than their natural product counterparts. The results highlight the important role that natural product total synthesis can play in not only helping understand the structural basis of biological activity of natural products, but also the discovery of new bioactive scaffolds.

  7. Quantitative Structure activity relationship and risk analysis of some pesticides in the cattle milk

    Directory of Open Access Journals (Sweden)

    Faqir Muhammad*, Ijaz Javed, Masood Akhtar1, Zia-ur-Rahman, Mian Muhammad Awais1, Muhammad Kashif Saleemi2 and Muhammad Irfan Anwar3

    2012-10-01

    Full Text Available Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR models were used to predict the residues of unknown pesticides in the milk of cattle using their known physicochemical properties such as molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w as well as the milk characteristics such as pH, % fat, and specific gravity (SG in this species. The analysis revealed good correlation coefficients (R2 = 0.91 for cattle QSAR model. The coefficient for Ko/w for the studied pesticides was higher in cattle milk. Risk analysis was conducted based upon the determined pesticide residues and their provisional tolerable daily intakes. The daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study were 3, 11, 2.5 times higher, respectively in cattle milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

  8. Structure-Activity Relationships for Rates of Aromatic Amine Oxidation by Manganese Dioxide.

    Science.gov (United States)

    Salter-Blanc, Alexandra J; Bylaska, Eric J; Lyon, Molly A; Ness, Stuart C; Tratnyek, Paul G

    2016-05-17

    New energetic compounds are designed to minimize their potential environmental impacts, which includes their transformation and the fate and effects of their transformation products. The nitro groups of energetic compounds are readily reduced to amines, and the resulting aromatic amines are subject to oxidation and coupling reactions. Manganese dioxide (MnO2) is a common environmental oxidant and model system for kinetic studies of aromatic amine oxidation. In this study, a training set of new and previously reported kinetic data for the oxidation of model and energetic-derived aromatic amines was assembled and subjected to correlation analysis against descriptor variables that ranged from general purpose [Hammett σ constants (σ(-)), pKas of the amines, and energies of the highest occupied molecular orbital (EHOMO)] to specific for the likely rate-limiting step [one-electron oxidation potentials (Eox)]. The selection of calculated descriptors (pKa, EHOMO, and Eox) was based on validation with experimental data. All of the correlations gave satisfactory quantitative structure-activity relationships (QSARs), but they improved with the specificity of the descriptor. The scope of correlation analysis was extended beyond MnO2 to include literature data on aromatic amine oxidation by other environmentally relevant oxidants (ozone, chlorine dioxide, and phosphate and carbonate radicals) by correlating relative rate constants (normalized to 4-chloroaniline) to EHOMO (calculated with a modest level of theory). PMID:27074054

  9. Phytotoxicity of umbelliferone and its analogs: Structure-activity relationships and action mechanisms.

    Science.gov (United States)

    Pan, Le; Li, Xiu-Zhuang; Yan, Zhi-Qiang; Guo, Hong-Ru; Qin, Bo

    2015-12-01

    Two coumarins, umbelliferone and daphnoretin, were isolated from roots of Stellera chamaejasme L; the former had been identified as one of the main allelochemicals in our previous studies. Both of them have the skeleton of 7-hydroxycoumarin, but showed different phytotoxic effects. Umbelliferone and its analogs were then prepared to investigate the structure-activity relationship of hydroxycoumarins and screened for phytotoxicity. The inhibitory effects varied observably in response to the coumarin derivatives, especially umbelliferone (1), 7-hydroxy-4-methylcoumarin (3) and coumarin (10) displayed strong inhibition of lettuce and two field weeds, Setaria viridis and Amaranthus retroflexus, and compounds 11 and 12 also exhibited phytotoxic activity with species specificity. The number and location of hydroxyl groups were importantly responsible for the phytotoxicity. A C7 hydroxyl group was considered to be a potentially active site and methyl substitution at the C4 position contributed significantly to the activity. The phytotoxic mechanism was briefly studied with umbelliferone by evaluating the reactive oxygen species (ROS) and chlorophylls level in lettuce seedlings. The results showed that umbelliferone induced the accumulation of ROS in the root tip and significantly decreased the chlorophyll content in the leaves. Thus, a ROS-mediated regulation pathway and the inhibition of photosynthesis were definitely involved in the phytotoxicity of umbelliferone. PMID:26509496

  10. Quorum Sensing Inhibition and Structure-Activity Relationships of β-Keto Esters.

    Science.gov (United States)

    Forschner-Dancause, Stephanie; Poulin, Emily; Meschwitz, Susan

    2016-01-01

    Traditional therapeutics to treat bacterial infections have given rise to multi-drug resistant pathogens, which pose a major threat to human and animal health. In several pathogens, quorum sensing (QS)-a cell-cell communication system in bacteria-controls the expression of genes responsible for pathogenesis, thus representing a novel target in the fight against bacterial infections. Based on the structure of the autoinducers responsible for QS activity and other QS inhibitors, we hypothesize that β-keto esters with aryl functionality could possess anti-QS activity. A panel of nineteen β-keto ester analogs was tested for the inhibition of bioluminescence (a QS-controlled phenotype) in the marine pathogen Vibrio harveyi. Initial screening demonstrated the need of a phenyl ring at the C-3 position for antagonistic activity. Further additions to the phenyl ring with 4-substituted halo groups or a 3- or 4-substituted methoxy group resulted in the most active compounds with IC50 values ranging from 23 µM to 53 µM. The compounds additionally inhibit green fluorescent protein production by E. coli JB525. Evidence is presented that aryl β-keto esters may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding. Expansion of the β-keto ester panel will enable us to obtain more insight into the structure-activity relationships needed to allow for the development of novel anti-virulence agents. PMID:27463706

  11. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    Science.gov (United States)

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs. PMID:22998569

  12. Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

    Directory of Open Access Journals (Sweden)

    Arielle Butts

    Full Text Available Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1 the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2 an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3 electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

  13. Structure-activity relationship of a u-type antimicrobial microemulsion system.

    Directory of Open Access Journals (Sweden)

    Hui Zhang

    Full Text Available The structure-activity relationship of a U-type antimicrobial microemulsion system containing glycerol monolaurate and ethanol at a 1∶1 mass ratio as oil phase and Tween 20 as surfactant were investigated along a water dilution line at a ratio of 80∶20 mass% surfactant/oil phase, based on a pseudo-ternary phase diagram. The differential scanning calorimetry results showed that in the region of up to 33% water, all water molecules are confined to the hydrophilic core of the reverse micelles, leading to the formation of w/o microemulsion. As the water content increases, the water gains mobility, and transforms into bicontinuous in the region of 33-39% water, and finally the microemulsion become o/w in the region of above 39% water. The microstructure characterization was confirmed by the dynamic light scattering measurements and freeze-fracture transmission electron microscope observation. The antimicrobial activity assay using kinetics of killing analysis demonstrated that the microemulsions in w/o regions exhibited relatively high antimicrobial activity against Escherichia coli and Staphylococcus aureus due to the antimicrobial oil phase as the continuous phase, while the antimicrobial activity started to decrease when the microemulsions entered the bicontinuous region, and decreased rapidly as the water content increased in the o/w region, as a result of the dilution of antimicrobial oil droplets in the aqueous continuous phase.

  14. Synthesis and antioxidant evaluation of isochroman-derivatives of hydroxytyrosol: structure-activity relationship.

    Science.gov (United States)

    Mateos, Raquel; Madrona, Andrés; Pereira-Caro, Gema; Domínguez, Vanessa; Cert, Rosa M A; Parrado, Juan; Sarriá, Beatriz; Bravo, Laura; Espartero, José Luis

    2015-04-15

    Isochroman-derivatives of the natural olive oil phenol hydroxytyrosol (HT) have been synthesised via Oxa-Pictet-Spengler reaction in high yields. Lipophilicity and antioxidant activity were determined to establish the structure-activity relationship of isochromans compared to HT, BHT and α-tocopherol. Antioxidant capacity was tested in two different media: bulk oils, using the Rancimat test, and brain homogenates, by measuring malondialdehyde (MDA) levels as a lipoperoxidation biomarker. In addition, other antioxidant assays (FRAP, ABTS and ORAC) were carried out. Rancimat and MDA results show that antioxidant activity was related with lipophilicity, directly in brain homogenates and inversely in the oils, in agreement with the polar paradox. Free o-diphenolic groups positively determined the activity in the oils, whereas reducing and radical-scavenging activities were related to the number of free hydroxyl moieties. BHT and α-tocopherol showed lower antioxidant activity than isochromans and HT. We conclude that HT-isochromans present significant potential as bioactive compounds. PMID:25466028

  15. Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study

    Directory of Open Access Journals (Sweden)

    Zhiwei Cao

    2011-05-01

    Full Text Available The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI-H446, BxPC-3, SW1990 and NCI-H157. Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others.

  16. Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.

    Science.gov (United States)

    Singh, Anamika; Kast, Johannes; Dirain, Marvin L S; Huang, Huisuo; Haskell-Luevano, Carrie

    2016-02-17

    The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R(1), R(2), R(3)), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 μM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R(1) position, bulky aromatic groups at the R(2) position, and benzyl group at the R(3) position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands. PMID:26645732

  17. Representation of molecular structure using quantum topology with inductive logic programming in structure-activity relationships.

    Science.gov (United States)

    Buttingsrud, Bård; Ryeng, Einar; King, Ross D; Alsberg, Bjørn K

    2006-06-01

    The requirement of aligning each individual molecule in a data set severely limits the type of molecules which can be analysed with traditional structure activity relationship (SAR) methods. A method which solves this problem by using relations between objects is inductive logic programming (ILP). Another advantage of this methodology is its ability to include background knowledge as 1st-order logic. However, previous molecular ILP representations have not been effective in describing the electronic structure of molecules. We present a more unified and comprehensive representation based on Richard Bader's quantum topological atoms in molecules (AIM) theory where critical points in the electron density are connected through a network. AIM theory provides a wealth of chemical information about individual atoms and their bond connections enabling a more flexible and chemically relevant representation. To obtain even more relevant rules with higher coverage, we apply manual postprocessing and interpretation of ILP rules. We have tested the usefulness of the new representation in SAR modelling on classifying compounds of low/high mutagenicity and on a set of factor Xa inhibitors of high and low affinity. PMID:17054018

  18. Quantitative structure-activity relationship and prediction of mixture toxicity of alkanols

    Institute of Scientific and Technical Information of China (English)

    WANG Bin; YU Gang; ZHANG Zulin; HU Hongying; WANG Liansheng

    2006-01-01

    Alkanols, which are narcotic compounds,were studied. The acute toxicities (15min-EG50) of 15alkanols, which have a large span of hydrophobicity,to Photobacterium phosphoreum were measured.Quantitative structure-activity relationship (QSAR)analysis of single toxicity of alkanols was conducted by using octanol-water partition coefficient (logKow).The polynomial expression was used instead of linear equation to develop QSAR model, and a QSAR model with a good predictive potential was achieved.Furthermore, the mixture toxicity of alkanols was studied. In order to predict joint toxicity of mixtures that contain very hydrophobic alkanols, the adjustment of octanol-water partition coefficient was performed, considering the influence of volume effect.And equivalent octanol-water partition coefficient was introduced. The QSAR model of mixture toxicity was developed by using equivalent mixture octanol-water partition coefficient. The result showed that even a linear model could predict mixture toxicity well by using equivalent mixture octanol-water partition coefficient.

  19. Quantitative structure-activity relationships for the toxicity of nitrobenzenes to Tetrahymena thermophila.

    Science.gov (United States)

    Xu, Jing-Bo; Jing, Ti-Song; Pauli, W; Berger, S

    2002-01-01

    In this study IGC50 (50% inhibitory growth concentration) values of 26 nitrobenzenes were determined for population growth endpoint of Tetrahymena thermophila. The toxicity order of the observed compounds has been found as follows: dinitro compounds > mono-nitro compounds; dichloronitrobenzenes > monochloronitrobenzenes; and meta-substituted nitrobenzenes > ortho-/para-substituted nitrobenzenes (NT, NPh, NAnis) except for the dinitrobenzenes and nitroanilines (DNB, NAn). Quantitative structure activity relationships (QSARs) were developed using log of the inverse of the IGC50 (logIGC50(-1)) in mole liter as the dependent variable and six molecular descriptors--logP, 1X(V), I, K alpha, sigma sigma- and E(LUMO) as the independent variables. Through multiplicate regression analysis, one best equation was obtained: log IGC50(-1) = 2.93 + 0.830sigma sigma- + 0.350I, n = 26, r = 0.923, r2 = 0.852, s = 0.265, f = 66.4 The equation was used to estimate IGC50 for seven analogues. PMID:12046656

  20. Natural and Synthetic Flavonoids: Structure-Activity Relationship and Chemotherapeutic Potential for the Treatment of Leukemia.

    Science.gov (United States)

    Menezes, José C J M D S; Orlikova, Barbora; Morceau, Franck; Diederich, Marc

    2016-07-29

    Flavonoids and their derivatives are polyphenolic secondary metabolites with an extensive spectrum of pharmacological activities, including antioxidants, antitumor, anti-inflammatory, and antiviral activities. These flavonoids can also act as chemopreventive agents by their interaction with different proteins and can play a vital role in chemotherapy, suggesting a positive correlation between a lower risk of cancer and a flavonoid-rich diet. These agents interfere with the main hallmarks of cancer by various individual mechanisms, such as inhibition of cell growth and proliferation by arresting the cell cycle, induction of apoptosis and differentiation, or a combination of these mechanisms. This review is an effort to highlight the therapeutic potential of natural and synthetic flavonoids as anticancer agents in leukemia treatment with respect to the structure-activity relationship (SAR) and their molecular mechanisms. Induction of cell death mechanisms, production of reactive oxygen species, and drug resistance mechanisms, including p-glycoprotein efflux, are among the best-described effects triggered by the flavonoid polyphenol family. PMID:26463658

  1. Extracellular melanogenesis inhibitory activity and the structure-activity relationships of ugonins from Helminthostachys zeylanica roots.

    Science.gov (United States)

    Yamauchi, Kosei; Mitsunaga, Tohru; Itakura, Yuki; Batubara, Irmanida

    2015-07-01

    Ugonin J, K, and L, which are luteolin derivatives, were isolated from Helminthostachys zeylanica roots by a series of chromatographic separations of a 50% ethanol/water extract. They were identified using nuclear magnetic resonance (NMR), ultraviolet (UV) spectra, and ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS). In this study, the intra and extracellular melanogenic activity of the ugonins were determined using B16 melanoma cells. The results showed that ugonin J at 12.5, 25, and 50μM reduced extracellular melanin contents to 75, 16, and 14%, respectively, compared to the control. This indicates that ugonin J showed a stronger activity than arbutin, used as the positive control. Moreover, ugonin K showed a more potent inhibition with 19, 8, and 9% extracellular melanin reduction at the same concentrations, than that shown by ugonin J. In contrast, ugonin L did not inhibit intra- or extracellular melanogenic activity. Furthermore, in order to investigate the structure-activity relationships of the ugonins, the intra- and extracellular melanogenic activity of luteolin, methylluteolin, quercetin, eriodictyol, apigenin, and chrysin were determined. Consequently, it was suggested that the catechol and flavone skeleton of ugonin K is essential for the extracellular melanogenic inhibitory activity, and the low polarity substituent groups on the A ring of ugonin K may increase the activity. PMID:25979512

  2. Antimicrobial profile of some novel keto esters: Synthesis, crystal structures and structure-activity relationship studies.

    Science.gov (United States)

    Khan, Imtiaz; Saeed, Aamer; Arshad, Mohammad Ifzan; White, Jonathan Michael

    2016-01-01

    Rapid increase in bacterial resistance has become a major public concern by escalating alongside a lack of development of new anti-infective drugs. Novel remedies in the battle against multidrug-resistant bacterial strains are urgently needed. So, in this context, the present work is towards the investigation of antimicrobial efficacy of some novel keto ester derivatives, which are prepared by the condensation of substituted benzoic acids with various substituted phenacyl bromides in dimethylformamide at room temperature using triethylamine as a catalyst. The structural build-up of the target compounds was accomplished by spectroscopic techniques including FTIR, (1)H and (13)C NMR spectroscopy and mass spectrometry. The purity of the synthesized compounds was ascertained by elemental analysis. The molecular structures of compounds (4b) and (4l) were established by X-ray crystallographic analysis. The prepared analogues were evaluated for their antimicrobial activity against Gram-positive (Staphylococcus aureus, Micrococcus leuteus) and Gram-negative (Pseudomonas picketti, Salmonella setuball) bacteria and two fungal pathogenic strains (Aspergillus niger, Aspergillus flavus), respectively. Among the screened derivatives, several compounds were found to possess significant activity but (4b) and (4l) turned out to be lead molecules with remarkable antimicrobial efficacy. The structure-activity relationship analysis of this study also revealed that structural modifications on the basic skeleton affected the antimicrobial activity of the synthesized compounds. PMID:26826838

  3. Deep neural nets as a method for quantitative structure-activity relationships.

    Science.gov (United States)

    Ma, Junshui; Sheridan, Robert P; Liaw, Andy; Dahl, George E; Svetnik, Vladimir

    2015-02-23

    Neural networks were widely used for quantitative structure-activity relationships (QSAR) in the 1990s. Because of various practical issues (e.g., slow on large problems, difficult to train, prone to overfitting, etc.), they were superseded by more robust methods like support vector machine (SVM) and random forest (RF), which arose in the early 2000s. The last 10 years has witnessed a revival of neural networks in the machine learning community thanks to new methods for preventing overfitting, more efficient training algorithms, and advancements in computer hardware. In particular, deep neural nets (DNNs), i.e. neural nets with more than one hidden layer, have found great successes in many applications, such as computer vision and natural language processing. Here we show that DNNs can routinely make better prospective predictions than RF on a set of large diverse QSAR data sets that are taken from Merck's drug discovery effort. The number of adjustable parameters needed for DNNs is fairly large, but our results show that it is not necessary to optimize them for individual data sets, and a single set of recommended parameters can achieve better performance than RF for most of the data sets we studied. The usefulness of the parameters is demonstrated on additional data sets not used in the calibration. Although training DNNs is still computationally intensive, using graphical processing units (GPUs) can make this issue manageable. PMID:25635324

  4. Quantitative structure-activity relationship to predict acute fish toxicity of organic solvents.

    Science.gov (United States)

    Levet, A; Bordes, C; Clément, Y; Mignon, P; Chermette, H; Marote, P; Cren-Olivé, C; Lantéri, P

    2013-10-01

    REACH regulation requires ecotoxicological data to characterize industrial chemicals. To limit in vivo testing, Quantitative Structure-Activity Relationships (QSARs) are advocated to predict toxicity of a molecule. In this context, the topic of this work was to develop a reliable QSAR explaining the experimental acute toxicity of organic solvents for fish trophic level. Toxicity was expressed as log(LC50), the concentration in mmol.L(-1) producing the 50% death of fish. The 141 chemically heterogeneous solvents of the dataset were described by physico-chemical descriptors and quantum theoretical parameters calculated via Density Functional Theory. The best subsets of solvent descriptors for LC50 prediction were chosen both through the Kubinyi function associated with Enhanced Replacement Method and a stepwise forward multiple linear regressions. The 4-parameters selected in the model were the octanol-water partition coefficient, LUMO energy, dielectric constant and surface tension. The predictive power and robustness of the QSAR developed were assessed by internal and external validations. Several techniques for training sets selection were evaluated: a random selection, a LC50-based selection, a balanced selection in terms of toxic and non-toxic solvents, a solvent profile-based selection with a space filling technique and a D-optimality onions-based selection. A comparison with fish LC50 predicted by ECOSAR model validated for neutral organics confirmed the interest of the QSAR developed for the prediction of organic solvent aquatic toxicity regardless of the mechanism of toxic action involved. PMID:23866172

  5. Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

    Science.gov (United States)

    Milelli, Andrea; Tumiatti, Vincenzo; Micco, Marialuisa; Rosini, Michela; Zuccari, Guendalina; Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito; Fernando Díaz, J; Pera, Benet; Trigili, Chiara; Barasoain, Isabel; Musetti, Caterina; Toniolo, Marianna; Sissi, Claudia; Alcaro, Stefano; Moraca, Federica; Zini, Maddalena; Stefanelli, Claudio; Minarini, Anna

    2012-11-01

    Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID:22819507

  6. Acute toxicity estimation by calculation--Tubifex assay and quantitative structure-activity relationships.

    Science.gov (United States)

    Tichý, Milon; Rucki, Marian; Hanzlíková, Iveta; Roth, Zdenek

    2008-11-01

    A quantitative structure-activity relationship (QSAR) model dependent on log P(n - octanol/water), or log P(OW), was developed with acute toxicity index EC50, the median effective concentration measured as inhibition of movement of the oligochaeta Tubifex tubifex with 3 min exposure, EC50(Tt) (mol/L): log EC50(Tt) = -0.809 (+/-0.035) log P(OW) - 0.495 (+/-0.060), n=82, r=0.931, r2=0.867, residual standard deviation of the estimate 0.315. A learning series for the QSAR model with the oligochaete contained alkanols, alkenols, and alkynols; saturated and unsaturated aldehydes; aniline and chlorinated anilines; phenol and chlorinated phenols; and esters. Three cross-validation procedures proved the robustness and stability of QSAR models with respect to the chemical structure of compounds tested within a series of compounds used in the learning series. Predictive ability was described by q2 .801 (cross-validated r2; predicted variation estimated with cross-validation) in LSO (leave-a structurally series-out) cross-validation. PMID:18522479

  7. Red Wine Tannin Structure-Activity Relationships during Fermentation and Maceration.

    Science.gov (United States)

    Yacco, Ralph S; Watrelot, Aude A; Kennedy, James A

    2016-02-01

    The correlation between tannin structure and corresponding activity was investigated by measuring the thermodynamics of interaction between tannins isolated from commercial red wine fermentations and a polystyrene divinylbenzene HPLC column. Must and/or wine samples were collected throughout fermentation/maceration from five Napa Valley wineries. By varying winery, fruit source, maceration time, and cap management practice, it was considered that a reasonably large variation in commercially relevant tannin structure would result. Tannins were isolated from samples collected using low pressure chromatography and were then characterized by gel permeation chromatography and acid-catalyzed cleavage in the presence of excess phloroglucinol (phloroglucinolysis). Corresponding tannin activity was determined using HPLC by measuring the thermodynamics of interaction between isolated tannin and a polystyrene divinylbenzene HPLC column. This measurement approach was designed to determine the ability of tannins to hydrophobically interact with a hydrophobic surface. The results of this study indicate that tannin activity is primarily driven by molecular size. Compositionally, tannin activity was positively associated with seed tannins and negatively associated with skin and pigmented tannins. Although measured indirectly, the extent of tannin oxidation as determined by phloroglucinolysis conversion yield suggests that tannin oxidation at this stage of production reduces tannin activity. Based upon maceration time, this study indicates that observed increases in perceived astringency quality, if related to tannin chemistry, are driven by tannin molecular mass as opposed to pigmented tannin formation or oxidation. Overall, the results of this study give new insight into tannin structure-activity relationships which dominate during extraction. PMID:26766301

  8. The Structure-Activity Relationship between Marine Algae Polysaccharides and Anti-Complement Activity

    Directory of Open Access Journals (Sweden)

    Weihua Jin

    2015-12-01

    Full Text Available In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal to fucose (Fuc was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation.

  9. Introducing Spectral Structure Activity Relationship (S-SAR Analysis. Application to Ecotoxicology

    Directory of Open Access Journals (Sweden)

    Ana-Maria Lacrămă

    2007-05-01

    Full Text Available A novel quantitative structure-activity (property relationship model, namelySpectral-SAR, is presented in an exclusive algebraic way replacing the old-fashionedmulti-regression one. The actual S-SAR method interprets structural descriptors as vectorsin a generic data space that is further mapped into a full orthogonal space by means of theGram-Schmidt algorithm. Then, by coordinated transformation between the data andorthogonal spaces, the S-SAR equation is given under simple determinant form for anychemical-biological interactions under study. While proving to give the same analyticalequation and correlation results with standard multivariate statistics, the actual S-SARframe allows the introduction of the spectral norm as a valid substitute for the correlationfactor, while also having the advantage to design the various related SAR models throughthe introduced “minimal spectral path” rule. An application is given performing a completeS-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reportedeco-toxicity activities among relevant classes of xenobiotics. By representing the spectralnorm of the endpoint models against the concerned structural coordinates, the obtainedS-SAR endpoints hierarchy scheme opens the perspective to further design the eco-toxicological test batteries with organisms from different species.

  10. Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.

    Science.gov (United States)

    Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping

    2013-06-28

    A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity. PMID:23657615

  11. Predicting Cell Association of Surface-Modified Nanoparticles Using Protein Corona Structure - Activity Relationships (PCSAR).

    Science.gov (United States)

    Kamath, Padmaja; Fernandez, Alberto; Giralt, Francesc; Rallo, Robert

    2015-01-01

    Nanoparticles are likely to interact in real-case application scenarios with mixtures of proteins and biomolecules that will absorb onto their surface forming the so-called protein corona. Information related to the composition of the protein corona and net cell association was collected from literature for a library of surface-modified gold and silver nanoparticles. For each protein in the corona, sequence information was extracted and used to calculate physicochemical properties and statistical descriptors. Data cleaning and preprocessing techniques including statistical analysis and feature selection methods were applied to remove highly correlated, redundant and non-significant features. A weighting technique was applied to construct specific signatures that represent the corona composition for each nanoparticle. Using this basic set of protein descriptors, a new Protein Corona Structure-Activity Relationship (PCSAR) that relates net cell association with the physicochemical descriptors of the proteins that form the corona was developed and validated. The features that resulted from the feature selection were in line with already published literature, and the computational model constructed on these features had a good accuracy (R(2)LOO=0.76 and R(2)LMO(25%)=0.72) and stability, with the advantage that the fingerprints based on physicochemical descriptors were independent of the specific proteins that form the corona. PMID:25961528

  12. Predicting Flash Point of Organosilicon Compounds Using Quantitative Structure Activity Relationship Approach

    Directory of Open Access Journals (Sweden)

    Chen-Peng Chen

    2014-01-01

    Full Text Available The flash point (FP of a compound is the primary property used in the assessment of fire hazards for flammable liquids and is amongst the crucial information that people handling flammable liquids must possess as far as industrial safety is concerned. In this work, the FPs of 236 organosilicon compounds were collected and used to construct a quantitative structure activity relationship (QSAR model for predicting their FPs. The CODESSA PRO software was adopted to calculate the required molecular descriptors, and 350 molecular descriptors were developed for each compound. A modified stepwise regression algorithm was applied to choose descriptors that were highly correlated with the FP of organosilicon compounds. The proposed model was a linear regression model consisting of six descriptors. This 6-descriptor model gave an R2 value of 0.9174, QLOO2 value of 0.9106, and Q2 value of 0.8989. The average fitting error and the average predictive error were found to be of 10.34 K and 11.22 K, respectively, and the average fitting error in percentage and the average predictive error in percentage were found to be of 3.30 and 3.60%, respectively. Compared with the known reproducibility of FP measurement using standard test method, these predicted results were of a satisfactory precision.

  13. Prediction of Toxicity of Phenols and Anilines to Algae by Quantitative Structure-activity Relationship

    Institute of Scientific and Technical Information of China (English)

    GUANG-HUA LU; CHAO WANG; XIAO-LING GUO

    2008-01-01

    Objective To measure the toxicity of phenol, aniline, and their derivatives to algae and to assess, model and predict the toxicity using quantitative structure-activity relationship (QSAR) method. Methods Oxygen production was used as the response endpoint for assessing the toxic effects of chemicals on algal photosynthesis. The energy of the lowest unoccupied molecular orbital (ELUMO) and the energy of the highest occupied molecular orbital (E) Were obtained from the ChemOffice 2004 program using the quantum chemical method MOPAC, and the frontier orbital energy gap (ΔE) was obtained. Results The compounds exhibited a reasonably wide range of algal toxicity. The most toxic compound was α-naphthol, whereas the least toxic one was aniline. A two-descriptor model was derived from the algal toxicity and structural parameters:logl/EC50=0.268logKow-1.006ΔE+11.769 (n=20,r2=0.946). This model was stable and satisfactory for predicting toxicity. Conclusion Phenol aniline, and their derivatives axe polar narcotics. Their toxicity is greater than estimated by hydrophobicity only, and addition of the frontier orbital energy gap ΔE can significantly improve the prediction of logKow-dependont models.

  14. Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols

    Energy Technology Data Exchange (ETDEWEB)

    Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. (Gradient Corporation, Cambridge, MA (United States))

    1991-12-01

    Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. The authors have therefore developed a 'toxicity equivalence approach' for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. The authors evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of 'milligram aspirin equivalence,' without correction for absorption differences. They recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.38 references.

  15. Synthesis, Biological Evaluation and Structure-Activity Relationships of New Quinoxaline Derivatives as Anti-Plasmodium falciparum Agents

    Directory of Open Access Journals (Sweden)

    Ana Gil

    2014-02-01

    Full Text Available We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.

  16. Antileishmanial structure-activity relationships of synthetic phospholipids : In vitro and in vivo activities of selected derivatives

    NARCIS (Netherlands)

    Seifert, Karin; Lemke, Andreas; Croft, Simon L.; Kayser, Oliver

    2007-01-01

    Antileishmanial activities of 91 synthetic phospholipids against Leishmania donovani were evaluated in vitro and cytotoxicity assessed against two mammalian cell lines. Promising compounds were tested further in vivo. In vitro structure-activity relationships showed a positive contribution of head g

  17. Quantitative structure activity relationship and risk analysis of some pesticides in the goat milk.

    Science.gov (United States)

    Muhammad, Faqir; Awais, Mian Muhammad; Akhtar, Masood; Anwar, Muhammad Irfan

    2013-01-01

    The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean±SEM levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34±0.007, 0.063±0.002, 0.034±0.002 and 0.092±0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR) models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW), melting point (MP), and log octanol to water partition coefficient (Ko/w) in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985) for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality. PMID:23369514

  18. Quantitative Structure Activity Relationship and Risk Analysis of Some Pesticides in the Goat milk

    Directory of Open Access Journals (Sweden)

    Faqir Muhammad

    2013-01-01

    Full Text Available The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean+/-SEM levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34+/-0.007, 0.063+/-0.002, 0.034+/-0.002 and 0.092+/-0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985 for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

  19. Quantitative structure-activity relationships for organophosphates binding to trypsin and chymotrypsin.

    Science.gov (United States)

    Ruark, Christopher D; Hack, C Eric; Robinson, Peter J; Gearhart, Jeffery M

    2011-01-01

    Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that cholinergic-independent pathways over a wide range are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation, and protein processing. Inhibition of these proteases by OP was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSAR were used to predict OP bimolecular rate constants for trypsin and α-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R(2) values of .94 and .92 and leave-one-out Q(2) values of 0.9 and 0.87 for trypsin and α-chymotrypsin. To validate the general model, training sets were split into independent subsets for test set evaluation. A y-randomization procedure, used to estimate chance correlation, was performed 10,000 times, resulting in mean R(2) values of .24 and .3 for trypsin and α-chymotrypsin. The results show that these models are highly predictive and capable of delineating the complex mechanism of action between OP and serine proteases, and ultimately, by applying this approach to other OP enzyme reactions such as AChE, facilitate the development of biologically based

  20. Structure Activity Relationship of Phenolic Acid inhibitors of α-Synuclein Fibril Formation and Toxicity

    Directory of Open Access Journals (Sweden)

    Mustafa eArdah

    2014-08-01

    Full Text Available The aggregation of α-synuclein (α-syn is considered the key pathogenic event in many neurological disorders such as Parkinson’s disease (PD, dementia with Lewy bodies and multiple system atrophy, giving rise to a whole category of neurodegenerative diseases known as synucleinopathies. Although the molecular basis of α-syn toxicity has not been precisely elucidated, a great deal of effort has been put into identifying compounds that could inhibit or even reverse the aggregation process. Previous reports indicated that many phenolic compounds are potent inhibitors of α-syn aggregation. The aim of the present study was to assess the anti-aggregating effect of gallic acid (GA (3,4,5-trihydroxybenzoic acid, a benzoic acid derivative that belongs to a group of phenolic compounds known as phenolic acids. By employing an array of biophysical and biochemical techniques and a cell-viability assay, GA was shown not only to inhibit α-syn fibrillation and toxicity but also to disaggregate preformed α-syn amyloid fibrils. Interestingly, GA was found to bind to soluble, non-toxic oligomers with no β-sheet content, and to stabilize their structure. The binding of GA to the oligomers may represent a potential mechanism of action. Additionally, by using structure activity relationship data obtained from fourteen structurally similar benzoic acid derivatives, it was determined that the inhibition of α-syn fibrillation by GA is related to the number of hydroxyl moieties and their position on the phenyl ring. GA may represent the starting point for designing new molecules that could be used for the treatment of PD and related disorders.

  1. Multiobjective optimization in quantitative structure-activity relationships: deriving accurate and interpretable QSARs.

    Science.gov (United States)

    Nicolotti, Orazio; Gillet, Valerie J; Fleming, Peter J; Green, Darren V S

    2002-11-01

    Deriving quantitative structure-activity relationship (QSAR) models that are accurate, reliable, and easily interpretable is a difficult task. In this study, two new methods have been developed that aim to find useful QSAR models that represent an appropriate balance between model accuracy and complexity. Both methods are based on genetic programming (GP). The first method, referred to as genetic QSAR (or GPQSAR), uses a penalty function to control model complexity. GPQSAR is designed to derive a single linear model that represents an appropriate balance between the variance and the number of descriptors selected for the model. The second method, referred to as multiobjective genetic QSAR (MoQSAR), is based on multiobjective GP and represents a new way of thinking of QSAR. Specifically, QSAR is considered as a multiobjective optimization problem that comprises a number of competitive objectives. Typical objectives include model fitting, the total number of terms, and the occurrence of nonlinear terms. MoQSAR results in a family of equivalent QSAR models where each QSAR represents a different tradeoff in the objectives. A practical consideration often overlooked in QSAR studies is the need for the model to promote an understanding of the biochemical response under investigation. To accomplish this, chemically intuitive descriptors are needed but do not always give rise to statistically robust models. This problem is addressed by the addition of a further objective, called chemical desirability, that aims to reward models that consist of descriptors that are easily interpretable by chemists. GPQSAR and MoQSAR have been tested on various data sets including the Selwood data set and two different solubility data sets. The study demonstrates that the MoQSAR method is able to find models that are at least as good as models derived using standard statistical approaches and also yields models that allow a medicinal chemist to trade statistical robustness for chemical

  2. Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

    Science.gov (United States)

    Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

    2016-05-01

    Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors. PMID:26832327

  3. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.

    Directory of Open Access Journals (Sweden)

    Vignir Isberg

    Full Text Available Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

  4. Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives.

    Science.gov (United States)

    Srivastava, Sanjay K; Jha, Amrita; Agarwal, Shiv K; Mukherjee, Rama; Burman, Anand C

    2007-11-01

    The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy. PMID:18045063

  5. Quantitative structure-activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment.

    Science.gov (United States)

    Lee, Yunho; von Gunten, Urs

    2012-12-01

    Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(·) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. PMID:22939392

  6. Quantitative Structure--Activity Relationship (QSAR) for the Oxidation of Trace Organic Contaminants by Sulfate Radical.

    Science.gov (United States)

    Xiao, Ruiyang; Ye, Tiantian; Wei, Zongsu; Luo, Shuang; Yang, Zhihui; Spinney, Richard

    2015-11-17

    The sulfate radical anion (SO4•–) based oxidation of trace organic contaminants (TrOCs) has recently received great attention due to its high reactivity and low selectivity. In this study, a meta-analysis was conducted to better understand the role of functional groups on the reactivity between SO4•– and TrOCs. The results indicate that compounds in which electron transfer and addition channels dominate tend to exhibit a faster second-order rate constants (kSO4•–) than that of H–atom abstraction, corroborating the SO4•– reactivity and mechanisms observed in the individual studies. Then, a quantitative structure activity relationship (QSAR) model was developed using a sequential approach with constitutional, geometrical, electrostatic, and quantum chemical descriptors. Two descriptors, ELUMO and EHOMO energy gap (ELUMO–EHOMO) and the ratio of oxygen atoms to carbon atoms (#O:C), were found to mechanistically and statistically affect kSO4•– to a great extent with the standardized QSAR model: ln kSO4•– = 26.8–3.97 × #O:C – 0.746 × (ELUMO–EHOMO). In addition, the correlation analysis indicates that there is no dominant reaction channel for SO4•– reactions with various structurally diverse compounds. Our QSAR model provides a robust predictive tool for estimating emerging micropollutants removal using SO4•– during wastewater treatment processes. PMID:26451961

  7. A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

    OpenAIRE

    Denmark, Scott E.; Gould, Nathan D.; Wolf, Larry M

    2011-01-01

    While the synthetic utility of asymmetric phase transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a pro...

  8. Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

    Directory of Open Access Journals (Sweden)

    Gullbo Joachim

    2009-06-01

    ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. Conclusion According to this structure-activity relationship (SAR study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

  9. Novel antineoplastic platinum(IV) complexes: synthesis, characterization, biological investigations and structure-activity relationships

    International Nuclear Information System (INIS)

    Platinum(II) complexes represent one of the most widely used classes of cytostatics in anticancer chemotherapy. Their clinical effectiveness is accompanied by severe doselimiting side effects, intrinsic and/or acquired tumor resistance and the inconvenient and cost intensive way of intravenous administration. Platinum(IV) complexes also possess antitumor activity and their physicochemical and chemical properties could be utilized in order to overcome the main drawbacks of platinum(II)-based drugs. The successful design of platinum(IV) chemotherapeutics requires a careful examination of their pharmacology and toxicology, the formulation of structure-activity relationships and the development of new synthetic approaches. Within this PhD work, novel bis-, tris- and tetrakis(carboxylato)platinum(IV) complexes, designed as prodrugs for cis-[Pt(EtNH2)2Cl2] (cisplatin analogue with higher lipophilicity), carboplatin and nedaplatin were synthesized. For this purpose, the respective platinum(II) complexes were oxidized with H2O2 in aqueous media and further carboxylated using different cyclic anhydrides (succinic, glutaric, 3-methylglutaric and 3,3-dimethylglutaric anhydride). The resulting compounds were subsequently derivatized by activation of their free carboxylic groups with CDI (1,1’-carbonyldiimidazol), followed by reaction with various amines or alcohols, yielding the desired amides and esters, respectively. All complexes were fully characterized, using multinuclear (1H, 13C, 15N and 195Pt) 1D and 2D NMR spectroscopy, elemental analysis, ESI-MS, ATR-FTIR, HPLC and exemplarily X-ray diffraction for some of the compounds. In vitro cytotoxicity of the novel complexes was examined in four human tumor cell lines originating from ovarian carcinoma (CH1 and SK-OV-3), colon carcinoma (SW480) and non-small cell lung cancer (A549) by means of the MTT colorimetrical assay. Comparative analysis of the lipophilicity, electrochemistry and rate of reduction by ascorbic acid of

  10. Quantitative structure-activity relationship of the curcumin-related compounds using various regression methods

    Science.gov (United States)

    Khazaei, Ardeshir; Sarmasti, Negin; Seyf, Jaber Yousefi

    2016-03-01

    Quantitative structure activity relationship were used to study a series of curcumin-related compounds with inhibitory effect on prostate cancer PC-3 cells, pancreas cancer Panc-1 cells, and colon cancer HT-29 cells. Sphere exclusion method was used to split data set in two categories of train and test set. Multiple linear regression, principal component regression and partial least squares were used as the regression methods. In other hand, to investigate the effect of feature selection methods, stepwise, Genetic algorithm, and simulated annealing were used. In two cases (PC-3 cells and Panc-1 cells), the best models were generated by a combination of multiple linear regression and stepwise (PC-3 cells: r2 = 0.86, q2 = 0.82, pred_r2 = 0.93, and r2m (test) = 0.43, Panc-1 cells: r2 = 0.85, q2 = 0.80, pred_r2 = 0.71, and r2m (test) = 0.68). For the HT-29 cells, principal component regression with stepwise (r2 = 0.69, q2 = 0.62, pred_r2 = 0.54, and r2m (test) = 0.41) is the best method. The QSAR study reveals descriptors which have crucial role in the inhibitory property of curcumin-like compounds. 6ChainCount, T_C_C_1, and T_O_O_7 are the most important descriptors that have the greatest effect. With a specific end goal to design and optimization of novel efficient curcumin-related compounds it is useful to introduce heteroatoms such as nitrogen, oxygen, and sulfur atoms in the chemical structure (reduce the contribution of T_C_C_1 descriptor) and increase the contribution of 6ChainCount and T_O_O_7 descriptors. Models can be useful in the better design of some novel curcumin-related compounds that can be used in the treatment of prostate, pancreas, and colon cancers.

  11. Effects of Polychlorinated Biphenyls on the Development of Neuronal Cells in Growth Period; Structure-Activity Relationship

    OpenAIRE

    Do, Youngrok; Lee, Dong Kuck

    2012-01-01

    Polychlorinated biphenyls (PCBs) are accumulated in our body through food chain and cause a variety of adverse health effects including neurotoxicities such as cognitive deficits and motor dysfunction. In particular, neonates are considered as a high risk group for the neurotoxicity of PCBs exposure. The present study attempted to analyze the structure-activity relationship among PCB congeners and the mechanism of PCBs-induced neurotoxicity. We measured total protein kinase C (PKC) activities...

  12. Interaction of neurosteroids with NMDA receptors: Current Insight into Structure-Activity Relationships and Their Neuroprotective Effect

    Czech Academy of Sciences Publication Activity Database

    Kudová, Eva; Chodounská, Hana; Slavíková, Barbora; Kapras, Vojtěch; Valeš, Karel; Rambousek, Lukáš; Borovská, Jiřina; Vyklický, Vojtěch; Krausová, Barbora; Vyklický ml., Ladislav

    Torino : -, 2013. [International Meeting Steroids and Nervous System /7./. 16.02.2013-20.02.2013, Toronto] R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : neurosteroid * NMDA-receptor * structure-activity relationship * pregnanolone Subject RIV: CC - Organic Chemistry; ED - Physiology (FGU-C)

  13. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, Domain of Application and Prediction

    OpenAIRE

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif

    2016-01-01

    International audience Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and...

  14. Data mining and machine learning techniques for the identification of mutagenicity inducing substructures and structure activity relationships of noncongeneric compounds

    OpenAIRE

    Helma, Christoph; Cramer, Tobias; Kramer, Stefan; De Raedt, Luc

    2004-01-01

    This paper explores the utility of data mining and machine learning algorithms for the induction of mutagenicity structure-activity relationships (SARs) from noncongeneric data sets. We compare (i) a newly developed algorithm (MOLFEA) for the generation of descriptors (molecular fragments) for noncongeneric compounds with traditional SAR approaches (molecular properties) and (ii) different machine learning algorithms for the induction of SARs from these descriptors. In addition we investigate...

  15. Extended Functional Groups (EFG: An Efficient Set for Chemical Characterization and Structure-Activity Relationship Studies of Chemical Compounds

    Directory of Open Access Journals (Sweden)

    Elena S. Salmina

    2015-12-01

    Full Text Available The article describes a classification system termed “extended functional groups” (EFG, which are an extension of a set previously used by the CheckMol software, that covers in addition heterocyclic compound classes and periodic table groups. The functional groups are defined as SMARTS patterns and are available as part of the ToxAlerts tool (http://ochem.eu/alerts of the On-line CHEmical database and Modeling (OCHEM environment platform. The article describes the motivation and the main ideas behind this extension and demonstrates that EFG can be efficiently used to develop and interpret structure-activity relationship models.

  16. Probing the structure-activity relationship of endogenous histone deacetylase complexes with immobilized peptide-inhibitors.

    Science.gov (United States)

    Sindlinger, Julia; Bierlmeier, Jan; Geiger, Lydia-Christina; Kramer, Katharina; Finkemeier, Iris; Schwarzer, Dirk

    2016-05-01

    Histone deacetylases (HDACs) are key regulators of numerous cellular proteins by removing acetylation marks from modified lysine residues. Peptide-based HDAC probes containing α-aminosuberic acid ω-hydroxamate have been established as useful tools for investigating substrate selectivity and composition of endogenous HDAC complexes in cellular lysates. Here we report a structure-activity study of potential HDAC-probes containing derivatives of the hydroxamate moieties. While most of these probes did not recruit significant amounts of endogenous HDACs from cellular lysates, peptides containing Nε-acetyl-Nε-hydroxy-L-lysine served as HDAC probe. The recruitment efficiency varied between HDACs and was generally lower than that of α-aminosuberic acid ω-hydroxamate probes, but showed a similar global interaction profile. These findings indicate that Nε-acetyl-Nε-hydroxy-L-lysine might be a useful tool for investigations on HDAC complexes and the development of HDAC inhibitors. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27071932

  17. The Structure-Activity Relationship of the Antioxidant Peptides from Natural Proteins

    Directory of Open Access Journals (Sweden)

    Tang-Bin Zou

    2016-01-01

    Full Text Available Peptides derived from dietary proteins, have been reported to display significant antioxidant activity, which may exert notably beneficial effects in promoting human health and in food processing. Recently, much research has focused on the generation, separation, purification and identification of novel peptides from various protein sources. Some researchers have tried to discover the structural characteristics of antioxidant peptides in order to lessen or avoid the tedious and aimless work involving the ongoing generated peptide preparation schemes. This review aims to summarize the current knowledge on the relationship between the structural features of peptides and their antioxidant activities. The relationship between the structure of the precursor proteins and their abilities to release antioxidant fragments will also be summarized and inferred. The preparation methods and antioxidant capacity evaluation assays of peptides and a prediction scheme of quantitative structure–activity relationship (QSAR will also be pointed out and discussed.

  18. Progress and perspectives of quantitative structure-activity relationships used for ecological risk assessment of toxic organic compounds

    Institute of Scientific and Technical Information of China (English)

    CHEN JingWen; LI XueHua; YU HaiYing; WANG YaNan; QIAO XianLiang

    2008-01-01

    Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR), collec-tively referred to as (Q)SARs, play an important role in ecological risk assessment (ERA) of organic chemicals. (Q)SARs can fill the data gap for physical-chemical, environmental behavioral and ecotoxicological parameters of organic compounds; they can decrease experimental expenses and reduce the extent of experimental testing (especially animal testing); they can also be used to assess the uncertainty of the experimental data. With the development for several decades, (Q)SARs in envi-ronmental sciences show three features: application orientation, multidisciplinary integration, and in-telligence. Progress of (Q)SAR technology for ERA of toxic organic compounds, including endpoint selection and mathematic methods for establishing simple, transparent, easily interpretable and portable (Q)SAR models, is reviewed. The recent development on defining application domains and diagnosing outliers is summarized. Model characterization with respect to goodness-of-fit, stability and predictive power is specially presented. The purpose of the review is to promote the development of (Q)SARs orientated to ERA of organic chemicals.

  19. Progress and perspectives of quantitative structure-activity relationships used for ecological risk assessment of toxic organic compounds

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR), collec- tively referred to as (Q)SARs, play an important role in ecological risk assessment (ERA) of organic chemicals. (Q)SARs can fill the data gap for physical-chemical, environmental behavioral and ecotoxicological parameters of organic compounds; they can decrease experimental expenses and reduce the extent of experimental testing (especially animal testing); they can also be used to assess the uncertainty of the experimental data. With the development for several decades, (Q)SARs in envi- ronmental sciences show three features: application orientation, multidisciplinary integration, and in- telligence. Progress of (Q)SAR technology for ERA of toxic organic compounds, including endpoint selection and mathematic methods for establishing simple, transparent, easily interpretable and portable (Q)SAR models, is reviewed. The recent development on defining application domains and diagnosing outliers is summarized. Model characterization with respect to goodness-of-fit, stability and predictive power is specially presented. The purpose of the review is to promote the development of (Q)SARs orientated to ERA of organic chemicals.

  20. Design and analysis of structure-activity relationship of novel antimicrobial peptides derived from the conserved sequence of cecropin.

    Science.gov (United States)

    Hao, Gang; Shi, Yong-Hui; Han, Jing-Hui; Li, Qi-Hui; Tang, Ya-Li; Le, Guo-Wei

    2008-03-01

    We have de novo designed four antimicrobial peptides AMP-A/B/C/D, the 51-residues peptides, which are based on the conserved sequence of cecropin. In the present study, the four peptides were chemically synthesized and their activities assayed. Their secondary structure, amphipathic property, electric field distribution and transmembrane domain were subsequently predicted by bioinformatics tools. Finally, the structure-activity relationship was analyzed from the results of activity experiments and prediction. The results of activity experiments indicated that AMP-B/C/D clearly possessed excellent broad-spectrum activity against bacteria, whereas AMP-A was almost inactive against most of the bacterial strains tested. AMP-B/C/D showed more potent activity against Gram-positive bacteria than against Gram-negative bacteria. By utilizing bioinformatics analysis tools, we found that the secondary structure of the four cation peptides was mainly alpha-helix, and the result of CD spectrum also displayed that all the peptides had considerable alpha-helix in the presence of either 50% TFE or SDS micelles. AMP-C showed much better activity than other peptides against most of the bacteria tested, owing to its remarkable cation property and the amphipathic character of its N-terminal. The study of structure-activity relationship of the designed peptides confirmed that amphipathic structure and high net positive charge were prerequisites for maintaining their activities. PMID:17929330

  1. Structural interpretation of activity cliffs revealed by systematic analysis of structure-activity relationships in analog series.

    Science.gov (United States)

    Sisay, Mihiret T; Peltason, Lisa; Bajorath, Jürgen

    2009-10-01

    Discontinuity in structure-activity relationships (SARs) is caused by so-called activity cliffs and represents one of the major caveats in SAR modeling and lead optimization. At activity cliffs, small structural modifications of compounds lead to substantial differences in potency that are essentially unpredictable using quantitative structure-activity relationship (QSAR) methods. In order to better understand SAR discontinuity at the molecular level of detail, we have analyzed different compound series in combinatorial analog graphs and determined substitution patterns that introduce activity cliffs of varying magnitude. So identified SAR determinants were then analyzed on the basis of complex crystal structures to enable a structural interpretation of SAR discontinuity and underlying activity cliffs. In some instances, SAR discontinuity detected within analog series could be well rationalized on the basis of structural data, whereas in others a structural explanation was not possible. This reflects the intrinsic complexity of small molecule SARs and suggests that the analysis of short-range receptor-ligand interactions seen in X-ray structures is insufficient to comprehensively account for SAR discontinuity. However, in other cases, SAR information extracted from ligands was incomplete but could be deduced taking X-ray data into account. Thus, taken together, these findings illustrate the complementarity of ligand-based SAR analysis and structural information. PMID:19761254

  2. Review on Structure-Activity Relationships among Sweeteners%甜味剂构性关系研究进展

    Institute of Scientific and Technical Information of China (English)

    樊可可; 欧阳平凯; 吴锡军

    1999-01-01

      本文对国内外甜味剂构性关系研究进行了较全面的综述。重点阐述了甜味剂构效理论的发展及其对各种类型甜味分子结构甜味关系的解释,并提出了该研究领域内面临的问题和最新发展趋势。%  Researches in structure-activity relationships among sweeteners were reviewed systematically in this paper. Emphasis was given to those hypothesises and their explanations for structure-sweet taste relationships of various sweeteners. The current problems and latest development trend in this field were also referred.

  3. Toll-like receptor 4-related immunostimulatory polysaccharides: Primary structure, activity relationships, and possible interaction models.

    Science.gov (United States)

    Zhang, Xiaorui; Qi, Chunhui; Guo, Yan; Zhou, Wenxia; Zhang, Yongxiang

    2016-09-20

    Toll-like receptor (TLR) 4 is an important polysaccharide receptor; however, the relationships between the structures and biological activities of TLR4 and polysaccharides remain unknown. Many recent findings have revealed the primary structure of TLR4/MD-2-related polysaccharides, and several three-dimensional structure models of polysaccharide-binding proteins have been reported; and these models provide insights into the mechanisms through which polysaccharides interact with TLR4. In this review, we first discuss the origins of polysaccharides related to TLR4, including polysaccharides from higher plants, fungi, bacteria, algae, and animals. We then briefly describe the glucosidic bond types of TLR4-related heteroglycans and homoglycans and describe the typical molecular weights of TLR4-related polysaccharides. The primary structures and activity relationships of polysaccharides with TLR4/MD-2 are also discussed. Finally, based on the existing interaction models of LPS with TLR4/MD-2 and linear polysaccharides with proteins, we provide insights into the possible interaction models of polysaccharide ligands with TLR4/MD-2. To our knowledge, this review is the first to summarize the primary structures and activity relationships of TLR4-related polysaccharides and the possible mechanisms of interaction for TLR4 and TLR4-related polysaccharides. PMID:27261743

  4. Quantitative Structure-Activity Relationships in the Lithium and Sodium Affinities of n-Alkyl Fluorides

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    B3LYP/6-31+g (d, p) method was used to calculate the lithium and sodium affinities of n-alkyl fluoride. These affinities were found to obey the Holmes relationship, i.e. they correlate linearly with the quotient n/(n+1), where n is the number of carbon atoms in the alkyl chain. From the correlation the limiting values of lithium and sodium affinities for very long alkyl chain were predicted to be -153.3 kJ/mol and -108.4 kJ/mol, respectively.

  5. Relationships between Categorical Perception of Phonemes, Phoneme Awareness, and Visual Attention Span in Developmental Dyslexia

    Science.gov (United States)

    Zoubrinetzky, Rachel; Collet, Gregory; Serniclaes, Willy; Nguyen-Morel, Marie-Ange; Valdois, Sylviane

    2016-01-01

    We tested the hypothesis that the categorical perception deficit of speech sounds in developmental dyslexia is related to phoneme awareness skills, whereas a visual attention (VA) span deficit constitutes an independent deficit. Phoneme awareness tasks, VA span tasks and categorical perception tasks of phoneme identification and discrimination using a d/t voicing continuum were administered to 63 dyslexic children and 63 control children matched on chronological age. Results showed significant differences in categorical perception between the dyslexic and control children. Significant correlations were found between categorical perception skills, phoneme awareness and reading. Although VA span correlated with reading, no significant correlations were found between either categorical perception or phoneme awareness and VA span. Mediation analyses performed on the whole dyslexic sample suggested that the effect of categorical perception on reading might be mediated by phoneme awareness. This relationship was independent of the participants’ VA span abilities. Two groups of dyslexic children with a single phoneme awareness or a single VA span deficit were then identified. The phonologically impaired group showed lower categorical perception skills than the control group but categorical perception was similar in the VA span impaired dyslexic and control children. The overall findings suggest that the link between categorical perception, phoneme awareness and reading is independent from VA span skills. These findings provide new insights on the heterogeneity of developmental dyslexia. They suggest that phonological processes and VA span independently affect reading acquisition. PMID:26950210

  6. Relationships between Categorical Perception of Phonemes, Phoneme Awareness, and Visual Attention Span in Developmental Dyslexia.

    Science.gov (United States)

    Zoubrinetzky, Rachel; Collet, Gregory; Serniclaes, Willy; Nguyen-Morel, Marie-Ange; Valdois, Sylviane

    2016-01-01

    We tested the hypothesis that the categorical perception deficit of speech sounds in developmental dyslexia is related to phoneme awareness skills, whereas a visual attention (VA) span deficit constitutes an independent deficit. Phoneme awareness tasks, VA span tasks and categorical perception tasks of phoneme identification and discrimination using a d/t voicing continuum were administered to 63 dyslexic children and 63 control children matched on chronological age. Results showed significant differences in categorical perception between the dyslexic and control children. Significant correlations were found between categorical perception skills, phoneme awareness and reading. Although VA span correlated with reading, no significant correlations were found between either categorical perception or phoneme awareness and VA span. Mediation analyses performed on the whole dyslexic sample suggested that the effect of categorical perception on reading might be mediated by phoneme awareness. This relationship was independent of the participants' VA span abilities. Two groups of dyslexic children with a single phoneme awareness or a single VA span deficit were then identified. The phonologically impaired group showed lower categorical perception skills than the control group but categorical perception was similar in the VA span impaired dyslexic and control children. The overall findings suggest that the link between categorical perception, phoneme awareness and reading is independent from VA span skills. These findings provide new insights on the heterogeneity of developmental dyslexia. They suggest that phonological processes and VA span independently affect reading acquisition. PMID:26950210

  7. Design, synthesis and structure-activity relationship of novel diphenylamine derivatives.

    Science.gov (United States)

    Li, Huichao; Guan, Aiying; Huang, Guang; Liu, Chang-Ling; Li, Zhinian; Xie, Yong; Lan, Jie

    2016-02-01

    Diphenylamine derivatives have been reported with good fungicidal, insecticidal, acaricidal, rodenticidal and/or herbicidal activities. To find new lead compound of this kind, a series of novel diphenylamine derivatives were designed and synthesized by the approach of Intermediate Derivatization Methods. All compounds were identified by (1)H NMR and elemental analysis. Bioassays demonstrated that some compounds substituted at 2,4,6-positions or 2,4,5-positions of phenyl ring B exhibited excellent fungicidal activities. The optimal compounds P30 and P33 showed 80% and 85% control respectively against cucumber downy mildew at 12.5mgL(-1), both 100% control against rice blast at 0.3mgL(-1) and both 100% control against cucumber gray mold at 0.9mgL(-1). The relationship between structure and fungicidal activities was discussed as well. PMID:26432603

  8. Molecular Descriptors Family on Structure Activity Relationships 6. Octanol-Water Partition Coefficient of Polychlorinated Biphenyls

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2006-01-01

    Full Text Available Octanol-water partition coefficient of two hundred and six polychlorinated biphenyls was model by the use of an original method based on complex information obtained from compounds structure. The regression analysis shows that best results are obtained in four-varied model (r2 = 0.9168. The prediction ability of the model was studied through leave-one-out analysis (r2cv(loo = 0.9093 and in training and test sets analysis. Modeling the octanol-water partition coefficient of polychlorinated biphenyls by integration of complex structural information provide a stable and performing four-varied model, allowing us to make remarks about relationship between structure of polychlorinated biphenyls and associated octanol-water partition coefficients.

  9. In vitro studies of acute toxicity mechanisms and structure-activity relationships of nonionic surfactants in fish

    Energy Technology Data Exchange (ETDEWEB)

    Bodishbauah, D.F. [Duke Univ. Marine Lab., Beaufort, NC (United States)

    1994-12-31

    In fish, gills are believed to be a primary target for a number of toxicants. Gills perform the essential systemic functions of gas exchange, waste elimination, and ion/pH balance, and are exposed to ambient environmental toxicant levels. Qualitative gill morphology changes are easily observed, but quantitative measures of impaired function are difficult. This in vitro technique utilizes the opercular epithelium of the mummichog, Fundulus heteroclitus, as a surrogate for gill epithelium in mechanistic toxicity and structure-activity studies. This model has long been used by electrophysiologists studying osmoregulation in marine fish. Effects on trans-epithelial potential (TEP) and/or short-circuit current (I{sub sc}) across the opercular epithelium can be made for any pollutant of interest, using an epithelial voltage clamp and Ussing chamber. The nonionic synthetic surfactant class, alkylphenol ethoxylates, were chosen as a model toxicant class to test this experimental model. Synthetic surfactants are ubiquitous waterborne pollutants, with annual North American usage approaching eight billion pounds. Surfactants are recognized as potent, acute gill toxicants in fish. The exact mechanism of toxicity has yet to be elucidated. These compounds proved to be potent inhibitors of both TEP and I{sub sc} in vitro, at dose levels comparable to those causing lethality, suggesting that impaired osmoregulation plays a role in their acute toxicity. Similar structure-activity relationships were found for the endpoints of acute lethality to F. heteroclitus and impaired in vitro epithelial transport.

  10. Quantitative Structure-activity Relationships for Anaerobic Biodegradation of Substituted Azobenzenes

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-yi; ZHU Huai-wu; LUO Shi-xia; WANG Zheng-wu; XIAO Han

    2004-01-01

    The degradation rates of the azo-bonds of a series of substituted azobenzenes caused by anaerobic sludge digestion were determined by measuring the biggest change of the absorption peak area of the UV-Vis spectra of the anaerobic sludge system before and after degradation. The electronic structure of the molecules was calculated by using the quantum chemistry semiempirical method AM1. The research on the correlation between the biodegradability of the azo-bond and the molecular structure descriptors has led to the following results. (1) There is an obvious relationship between the degradation rate D and the difference Δqπ in π-charge density of the azo-bond. (2) The different substituents in the molecules result in a wave pattern of π-charge distribution and the increasing of the flowability of π-electron. A good flowability of the π-charge favors the reduction between electron contributing azo groups. (3) The effect of the substituents on the π-electron system depends on the electromerization of the substituents in combination with the conjugated systems.

  11. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    Energy Technology Data Exchange (ETDEWEB)

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))

    1988-02-01

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

  12. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    International Nuclear Information System (INIS)

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of 125I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini

  13. Holographic quantitative structure-activity relationship for prediction of the toxicity of polybrominated diphenyl ether congeners

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Polybrominated diphenyl ether congeners (PBDEs) might activate the AhR (aromatic hydrocarbon receptor) signal transduction,and thus might have an adverse effect on the health of humans and wildlife. Because of the limited experimental data,it is important and necessary to develop structure-based models for prediction of the toxicity of the compounds. In this study,a new molecular structure representation,molecular hologram,was employed to investigate the quantitative relationship between toxicity and molecular structures for 18 PBDEs. The model with the significant correlation and robustness (r2 = 0.991,q2LOO = 0.917) was developed. To verify the robustness and prediction capacity of the derived model,14 PBDEs were randomly selected from the database as the training set,while the rest were used as the test set. The results generated under the same modeling conditions as the optimal model are as follows:r2 = 0.988,q2LOO = 0.598,r2pred = 0.955,and RMSE (root-mean-square of errors) = 0.155,suggesting the excellent ability of the derived model to predict the toxicity of PBDEs. Furthermore,the structural features and molecular mechanism related to the toxicity of PBDEs were explored using HQSAR color coding.

  14. Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase

    International Nuclear Information System (INIS)

    Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k i values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%

  15. Mechanism of mitochondrial uncouplers, inhibitors, and toxins: focus on electron transfer, free radicals, and structure-activity relationships.

    Science.gov (United States)

    Kovacic, Peter; Pozos, Robert S; Somanathan, Ratnasamy; Shangari, Nandita; O'Brien, Peter J

    2005-01-01

    The biology of the mitochondrial electron transport chain is summarized. Our approach to the mechanism of uncouplers, inhibitors, and toxins is based on electron transfer (ET) and reactive oxygen species (ROS). Extensive supporting evidence, which is broadly applicable, is cited. ROS can be generated either endogenously or exogenously. Generally, the reactive entities arise via redox cycling by ET functionalities, such as, quinones (or precursors), metal compounds, imines (or iminiums), and aromatic nitro compounds (or reduced metabolites). In most cases, the ET functions are formed metabolically. The toxic substances belong to many categories, e.g., medicinals, industrial chemicals, abused drugs, and pesticides. Structure-activity relationships are presented from the ET-ROS perspective, and also quantitatively. Evidence for the theoretical framework is provided by the protective effect of antioxidants. Among other topics addressed are proton flux, membrane pores, and apoptosis. There is support for the thesis that mitochondrial insult may contribute to illnesses and aging. PMID:16248817

  16. Screening of 397 chemicals and development of a quantitative structure-activity relationship model for androgen receptor antagonism

    DEFF Research Database (Denmark)

    Vinggaard, Annemarie; Niemelä, Jay Russell; Wedebye, Eva Bay; Jensen, Gunde Egeskov

    2008-01-01

    We have screened 397 chemicals for human androgen receptor (AR) antagonism by a sensitive reporter gene assay to generate data for the development of a quantitative structure-activity relationship (QSAR) model. A total of 523 chemicals comprising data on 292 chemicals from our laboratory and data...... synthetic androgen R1881. The MultiCASE expert system was used to construct a QSAR model for AR antagonizing potential. A "5 Times, 2-Fold 50% Cross Validation" of the model showed a sensitivity of 64%, a specificity of 84%, and a concordance of 76%. Data for 102 chemicals were generated for an external...... validation of the model resulting in a sensitivity of 57%, a specificity of 98%, and a concordance of 92% of the model. The model was run on a set of 176103 chemicals, and 47% were within the domain of the model. Approximately 8% of chemicals was predicted active for AR antagonism. We conclude that the...

  17. Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.

    Science.gov (United States)

    Espíndola, José Wanderlan Pontes; Cardoso, Marcos Veríssimo de Oliveira; Filho, Gevanio Bezerra de Oliveira; Oliveira E Silva, Dayane Albuquerque; Moreira, Diogo Rodrigo Magalhaes; Bastos, Tanira Matutino; Simone, Carlos Alberto de; Soares, Milena Botelho Pereira; Villela, Filipe Silva; Ferreira, Rafaela Salgado; Castro, Maria Carolina Accioly Brelaz de; Pereira, Valéria Rego Alves; Murta, Silvane Maria Fonseca; Sales Junior, Policarpo Ademar; Romanha, Alvaro José; Leite, Ana Cristina Lima

    2015-08-28

    The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones. PMID:26231082

  18. A Structure-activity Relationship(SAR)Study of Fluoroquinolones with Biological Activity against Anti-S.pneumoniae

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; ZHANG Rui-Zhou; CHENG Xin-Lu; YANG Xiang-Dong

    2006-01-01

    Structure-activity relationship techniques were employed to classify fluoroquino- lones against S.pneumoniae. Density functional theory (DFT) was used to calculate a set of mo- lecular descriptors (properties) for eighteen fluoroquinolones. The descriptors were further analyzed using the principal component analysis (PCA), hierarchical cluster analysis (HCA) and K-nearest neighbor (KNN) chemometeric method. The PCA and HCA methods are quite efficient to classify the eighteen compounds into two groups (active and inactive) according to their degrees of anti- S.pneumoniae activity. The classified result is consistent with the clinic experimental result. The PCA shows that the variables Q3 (net charge on atom 3), QA (net charge on ring A), QB (net charge on ring B), VOL (molecular volume) and A (surface area) are found to be responsible for the sepa- ration between compounds with higher and lower anti-S.pneumoniae.

  19. Synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors.

    Science.gov (United States)

    Zeng, Debin; Ma, Yuying; Zhang, Rui; Nie, Quandeng; Cui, Zhengjie; Wang, Yaxin; Shang, Luqing; Yin, Zheng

    2016-04-01

    α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1' and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50=1.32±0.26μM, 1.88±0.35μM and 1.52±0.31μM, respectively) and favorable CC50 values (CC50>100μM). α-Keto amide may represent a good choice as a warhead for EV71 3C(pro) inhibitor. PMID:26916437

  20. New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.

    Science.gov (United States)

    Zghaib, Zahraa; Guichou, Jean-François; Vappiani, Johanna; Bec, Nicole; Hadj-Kaddour, Kamel; Vincent, Laure-Anaïs; Paniagua-Gayraud, Stéphanie; Larroque, Christian; Moarbess, Georges; Cuq, Pierre; Kassab, Issam; Deleuze-Masquéfa, Carine; Diab-Assaf, Mona; Bonnet, Pierre-Antoine

    2016-06-01

    Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin. PMID:27094151

  1. Structure-activity relationships of 3-substituted-5,5- diphenylhydantoins as potential antiproliferative and antimicrobial agents

    Directory of Open Access Journals (Sweden)

    Trišović Nemanja

    2011-01-01

    Full Text Available A series of twelve 3-substituted-5,5-diphenylhydantoins was synthesized, including some whose anticonvulsant activities have already been reported in the literature. Their antiproliferative activities against HCT-116 human colon carcinoma cells were evaluated to determine structure-activity relationships. Almost all of the compounds exhibited statistically significant antiproliferative effects at a concentration of 100 μM, while the derivative bearing a benzyl group was active even at lower concentrations. Moreover, their in vitro antibacterial activities against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and clinical isolates of Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus were evaluated. Only the 3-iso-propyl and 3-benzyl derivatives showed weak antibacterial activities against the Gram-positive bacterium E. faecalis and the Gram-negative bacteria E. coli ATCC 25922 and E. coli.

  2. Sedative effects of inhaled essential oil components of traditional fragrance Pogostemon cablin leaves and their structure-activity relationships.

    Science.gov (United States)

    Ito, Ken; Akahoshi, Yasuko; Ito, Michiho; Kaneko, Shuji

    2016-04-01

    Plants rich in essential oils, such as Pogostemon cablin (P. cablin; guǎng huò xiāng), have been used for aromas and as herbal medicines since ancient times because of their sedative effects. We investigated the sedative effects of hexane extract from P. cablin using locomotor activity in mice. Inhalation of P. cablin hexane extract exhibited significant sedative activity in a dose-dependent manner. In order to isolate the active constituents, the extract was fractionated and diacetone alcohol was identified as an active compound. Inhalation of diacetone alcohol significantly reduced murine locomotor activity in a dose-dependent manner, and this effect was not observed in olfaction-impaired mice. We examined the structure-activity relationship of diacetone alcohol and similar compounds. The ketone group at the two-position and number of carbons may play important roles in the sedative activity of diacetone alcohol. PMID:27114936

  3. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    Science.gov (United States)

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v. PMID:23891182

  4. Studies on the Synthesis of Derivatives of Marine-Derived Bostrycin and Their Structure-Activity Relationship against Tumor Cells

    Directory of Open Access Journals (Sweden)

    Zhigang She

    2012-04-01

    Full Text Available A series of new derivatives (529 of marine-derived bostrycin (1 were synthesized. The in vitro cytotoxic activities of all compounds were evaluated against MCF-7, MDA-MB-435, A549, HepG2, HCT-116 and MCF-10A cells using the MTT method. The compounds 7, 8, 22, 23, 25, 28 and 29 of the total showed comparable activity to epirubicin, the positive control, against the tested cancer cell lines. However, these compounds also exhibited cytotoxicity towards MCF-10A cells. The structure-activity relationship (SAR of bostrycin derivatives was also discussed based on the obtained experimental data.

  5. Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH analogs: iron chelation, anti-oxidant and cytotoxic properties.

    Directory of Open Access Journals (Sweden)

    Eliška Potůčková

    Full Text Available Salicylaldehyde isonicotinoyl hydrazone (SIH is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability. Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O, which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

  6. Antiproliferative and apoptotic activities of triterpenoid saponins from the roots of Platycodon grandiflorum and their structure-activity relationships.

    Science.gov (United States)

    Chun, Jaemoo; Ha, In Jin; Kim, Yeong Shik

    2013-05-01

    The present study was undertaken to investigate the antiproliferative and apoptotic activities of Platycodon saponins, including platycodin D, 2''-O-acetylplatycodin D, 3''-O-acetylplatycodin D, polygalacin D, 2''-O-acetylpolygalacin D, and 3''-O-acetylpolygalacin D, isolated from Platycodon grandiflorum, and prosapogenins which lack the C-3 or C-28 sugar residues, obtained from hydrolysis of platycodin D. We also clarified the structure-activity relationships of these molecules to define structural features that are crucial for the biological activity of Platycodon saponins and prosapogenins. The results showed that all Platycodon saponins had antiproliferative effects on the seven types of cancer cell lines tested. In particular, O-acetylation at the C-2 or C-3 position of rhamnose and dehydroxylation at C-24 increase the compound's cytotoxicity, while the loss of sugar residues linked to C-3 or C-28 dramatically reduced cytotoxicity. This cytotoxicity was associated with apoptosis, which was indicated by DNA fragmentation, phosphatidylserine externalization, and the activation of caspases in AGS cells. Furthermore, Platycodon saponins suppressed the phosphorylation of Akt, which resulted in the inhibition of mTOR and NF-κB signaling following the inhibition of their downstream proteins. In conclusion, six Platycodon saponins have antiproliferative activity, and the presence of sugar residues, an O-acetyl group on the rhamnose, and a methyl group at C-4 contributes to their cytotoxicity and apoptotic activity. These findings may be useful in evaluating the structure-activity relationships of Platycodon saponins and modifying them as a potent apoptosis-inducing agent. PMID:23576176

  7. Designing anti-influenza aptamers: novel quantitative structure activity relationship approach gives insights into aptamer-virus interaction.

    Directory of Open Access Journals (Sweden)

    Boaz Musafia

    Full Text Available This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus' infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer's binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers' binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2 = 0.702 for the training set, and R2 = 0.66 for the independent test set. Moreover, in the test set the model's sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer's binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction

  8. Defining RNA motif-aminoglycoside interactions via two-dimensional combinatorial screening and structure-activity relationships through sequencing.

    Science.gov (United States)

    Velagapudi, Sai Pradeep; Disney, Matthew D

    2013-10-15

    RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3×3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure-activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif-aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. PMID:23719281

  9. In vitro modification of substituted cysteines as tool to study receptor functionality and structure-activity relationships.

    Science.gov (United States)

    Rathmann, Daniel; Pedragosa-Badia, Xavier; Beck-Sickinger, Annette G

    2013-08-15

    Mutagenic investigations of expressed membrane proteins are routine, but the variety of modifications is limited by the twenty canonical amino acids. We describe an easy and effective cysteine substitution mutagenesis method to modify and investigate distinct amino acids in vitro. The approach combines the substituted cysteine accessibility method (SCAM) with a functional signal transduction readout system using different thiol-specific reagents. We applied this approach to the prolactin-releasing peptide receptor (PrRPR) to facilitate biochemical structure-activity relationship studies of eight crucial positions. Especially for D(6.59)C, the treatment with the positively charged methanethiosulfonate (MTS) ethylammonium led to an induced basal activity, whereas the coupling of the negatively charged MTS ethylsulfonate nearly reconstituted full activity, obviously by mimicking the wild-type charged side chain. At E(5.26)C, W(5.28)C, Y(5.38)C, and Q(7.35)C, accessibility was observed but hindered transfer into the active receptor conformation. Accordingly, the combination of SCAM and signaling assay is feasible and can be adapted to other G-protein-coupled receptors (GPCRs). This method circumvents the laborious way of inserting non-proteinogenic amino acids to investigate activity and ligand binding, with rising numbers of MTS reagents allowing selective side chain modification. This method pinpoints to residues being accessible but also presents potential molecular positions to investigate the global conformation. PMID:23624320

  10. Structural Characterization and Evaluation of the Antioxidant Activity of Phenolic Compounds from Astragalus taipaishanensis and Their Structure-Activity Relationship

    Science.gov (United States)

    Pu, Wenjun; Wang, Dongmei; Zhou, Dan

    2015-09-01

    Eight phenolic compounds were isolated using bio-guided isolation and purified from the roots of Astragalus taipaishanensis Y. C. Ho et S. B. Ho (A. taipaishanensis) for the first time. Their structures were elucidated by ESI-MS, HR-ESI-MS, 1D-NMR and 2D-NMR as 7,2‧-dihydroxy-3‧,4‧-dimethoxy isoflavan (1), formononetin (2), isoliquiritigenin (3), quercetin (4), kaempferol (5), ononin (6), p-hydroxybenzoic acid (7) and vanillic acid (8). Six flavonoids (compounds 1-6) exhibited stronger antioxidant activities (determined by DPPH, ABTS, FRAP and lipid peroxidation inhibition assays) than those of BHA and TBHQ and also demonstrated noticeable protective effects (particularly quercetin and kaempferol) on Escherichia coli under oxidative stress. Additionally, the chemical constituents compared with those of Astragalus membranaceus and the structure-activity relationship of the isolated compounds were both analyzed. The results clearly demonstrated that A. taipaishanensis has the potential to be selected as an alternative medicinal and food plant that can be utilized in health food products, functional tea and pharmaceutical products.

  11. Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study.

    Science.gov (United States)

    Dostanić, J; Lončarević, D; Zlatar, M; Vlahović, F; Jovanović, D M

    2016-10-01

    A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31+G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σp constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO2 photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups. PMID:27209516

  12. Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources.

    Science.gov (United States)

    Chen, Baiyang; Zhang, Tian; Bond, Tom; Gan, Yiqun

    2015-12-15

    Quantitative structure-activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application. PMID:26142156

  13. Dihydro-β-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

    Science.gov (United States)

    Núñez, Marvin J; Jiménez, Ignacio A; Mendoza, Cristina R; Chavez-Sifontes, Marvin; Martinez, Morena L; Ichiishi, Eiichiro; Tokuda, Ryo; Tokuda, Harukuni; Bazzocchi, Isabel L

    2016-03-23

    Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-β-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of β-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model. PMID:26854381

  14. Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders--A Review of Structure-Activity Relationships.

    Science.gov (United States)

    Gunia-Krzyżak, Agnieszka; Pańczyk, Katarzyna; Waszkielewicz, Anna M; Marona, Henryk

    2015-08-01

    The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ-aminobutyric acid type A (GABAA ) receptors, N-methyl-D-aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage-gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target-based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure-activity relationships discussed. PMID:26083325

  15. Structure-Activity Relationships of Antimicrobial Gallic Acid Derivatives from Pomegranate and Acacia Fruit Extracts against Potato Bacterial Wilt Pathogen.

    Science.gov (United States)

    Farag, Mohamed A; Al-Mahdy, Dalia A; Salah El Dine, Riham; Fahmy, Sherifa; Yassin, Aymen; Porzel, Andrea; Brandt, Wolfgang

    2015-06-01

    Bacterial wilts of potato, tomato, pepper, and or eggplant caused by Ralstonia solanacearum are among the most serious plant diseases worldwide. In this study, the issue of developing bactericidal agents from natural sources against R. solanacearum derived from plant extracts was addressed. Extracts prepared from 25 plant species with antiseptic relevance in Egyptian folk medicine were screened for their antimicrobial properties against the potato pathogen R. solancearum by using the disc-zone inhibition assay and microtitre plate dilution method. Plants exhibiting notable antimicrobial activities against the tested pathogen include extracts from Acacia arabica and Punica granatum. Bioactivity-guided fractionation of A. arabica and P. granatum resulted in the isolation of bioactive compounds 3,5-dihydroxy-4-methoxybenzoic acid and gallic acid, in addition to epicatechin. All isolates displayed significant antimicrobial activities against R. solanacearum (MIC values 0.5-9 mg/ml), with 3,5-dihydroxy-4-methoxybenzoic acid being the most effective one with a MIC value of 0.47 mg/ml. We further performed a structure-activity relationship (SAR) study for the inhibition of R. solanacearum growth by ten natural, structurally related benzoic acids. PMID:26080741

  16. Application of quantitative structure-activity relationship to the determination of binding constant based on fluorescence quenching

    Energy Technology Data Exchange (ETDEWEB)

    Wen Yingying [Department of Applied Chemistry, Yantai University, Yantai 264005 (China); Liu Huitao, E-mail: liuht-ytu@163.co [Department of Applied Chemistry, Yantai University, Yantai 264005 (China); Luan Feng; Gao Yuan [Department of Applied Chemistry, Yantai University, Yantai 264005 (China)

    2011-01-15

    Quantitative structure-activity relationship (QSAR) model was used to predict and explain binding constant (log K) determined by fluorescence quenching. This method allowed us to predict binding constants of a variety of compounds with human serum albumin (HSA) based on their structures alone. Stepwise multiple linear regression (MLR) and nonlinear radial basis function neural network (RBFNN) were performed to build the models. The statistical parameters provided by the MLR model (R{sup 2}=0.8521, RMS=0.2678) indicated satisfactory stability and predictive ability while the RBFNN predictive ability is somewhat superior (R{sup 2}=0.9245, RMS=0.1736). The proposed models were used to predict the binding constants of two bioactive components in traditional Chinese medicines (isoimperatorin and chrysophanol) whose experimental results were obtained in our laboratory and the predicted results were in good agreement with the experimental results. This QSAR approach can contribute to a better understanding of structural factors of the compounds responsible for drug-protein interactions, and can be useful in predicting the binding constants of other compounds. - Research Highlights: QSAR models for binding constants of some compounds to HSA were developed. The models provide a simple and straightforward way to predict binding constant. QSAR can give some insight into structural features related to binding behavior.

  17. A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

    Science.gov (United States)

    Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

    2016-08-01

    A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units. PMID:27586364

  18. Structure-Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity.

    Science.gov (United States)

    André, Sonia; Washington, Shannon K; Darby, Emily; Vega, Marvin M; Filip, Ari D; Ash, Nathaniel S; Muzikar, Katy A; Piesse, Christophe; Foulon, Thierry; O'Leary, Daniel J; Ladram, Ali

    2015-10-16

    Short antimicrobial peptides represent attractive compounds for the development of new antibiotic agents. Previously, we identified an ultrashort hydrophobic and phenylalanine-rich peptide, called temporin-SHf, representing the smallest natural amphibian antimicrobial peptide known to date. Here, we report on the first structure-activity relationship study of this peptide. A series of temporin-SHf derivatives containing insertion of a basic arginine residue as well as residues containing neutral hydrophilic (serine and α-hydroxymethylserine) and hydrophobic (α-methyl phenylalanine and p-(t)butyl phenylalanine) groups were designed to improve the antimicrobial activity, and their α-helical structure was investigated by circular dichroism and nuclear magnetic resonance spectroscopy. Three compounds were found to display higher antimicrobial activity with the ability to disrupt (permeabilization/depolarization) the bacterial membrane while retaining the nontoxic character of the parent peptide toward rat erythrocytes and human cells (THP-1 derived macrophages and HEK-293). Antimicrobial assays were carried out to explore the influence of serum and physiological salt concentration on peptide activity. Analogs containing d-amino acid residues were also tested. Our study revealed that [p-(t)BuF(2), R(5)]SHf is an attractive ultrashort candidate that is highly potent (bactericidal) against Gram-positive bacteria (including multidrug resistant S. aureus) and against a wider range of clinically interesting Gram-negative bacteria than temporin-SHf, and also active at physiological salt concentrations and in 30% serum. PMID:26181487

  19. Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae: Structure/Activity Relationships

    Directory of Open Access Journals (Sweden)

    Thiago R. Morais

    2014-05-01

    Full Text Available Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae, and nine semi-synthetic derivatives were investigated against Leishmania (L. infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR data as well as electrospray ionization mass spectrometry (ESI-MS. Additionally, structure-activity relationships were performed using Decision Trees.

  20. Synthesis, biological evaluation, mechanism of action and quantitative structure-activity relationship studies of chalcones as antibacterial agents.

    Science.gov (United States)

    Sivakumar, Ponnurengam Malliappan; Priya, Sobana; Doble, Mukesh

    2009-04-01

    Forty-eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure-activity relationships were developed for all the cases (r(2) = 0.68-0.79; r(2)(adj) = 0.58-0.78; q(2) = 0.51-0.68; F = 13.02-61.51). Size, polarizability, electron-donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram-positive and Gram-negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more hydrophobic organisms. The more active chalcones have log P between 1.5 and 3. Compound 24, one of the most active compounds, was found to act by damaging the cell wall of S. aureus. Slimicidal activity of five of the most active compounds (24, 31, 32, 34 and 37) was found to be in the range of 48-60% against S. aureus and 40-54% against E. coli. A correlation was observed among the hydrophobicity of the compounds, hydrophobicity of the bacterial cell surface and the antibacterial activity of the compound. PMID:19291103

  1. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction.

    Science.gov (United States)

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif

    2016-02-13

    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides. PMID:26513561

  2. The signature molecular descriptor. 3. Inverse-quantitative structure-activity relationship of ICAM-1 inhibitory peptides.

    Science.gov (United States)

    Churchwell, Carla J; Rintoul, Mark D; Martin, Shawn; Visco, Donald P; Kotu, Archana; Larson, Richard S; Sillerud, Laurel O; Brown, David C; Faulon, Jean-Loup

    2004-03-01

    We present a methodology for solving the inverse-quantitative structure-activity relationship (QSAR) problem using the molecular descriptor called signature. This methodology is detailed in four parts. First, we create a QSAR equation that correlates the occurrence of a signature to the activity values using a stepwise multilinear regression technique. Second, we construct constraint equations, specifically the graphicality and consistency equations, which facilitate the reconstruction of the solution compounds directly from the signatures. Third, we solve the set of constraint equations, which are both linear and Diophantine in nature. Last, we reconstruct and enumerate the solution molecules and calculate their activity values from the QSAR equation. We apply this inverse-QSAR method to a small set of LFA-1/ICAM-1 peptide inhibitors to assist in the search and design of more-potent inhibitory compounds. Many novel inhibitors were predicted, a number of which are predicted to be more potent than the strongest inhibitor in the training set. Two of the more potent inhibitors were synthesized and tested in-vivo, confirming them to be the strongest inhibiting peptides to date. Some of these compounds can be recycled to train a new QSAR and develop a more focused library of lead compounds. PMID:15177078

  3. Insights into the structure activity relationship of mPGES-1 inhibitors: Hints for better inhibitor design.

    Science.gov (United States)

    Gupta, Ashish; Aparoy, Polamarasetty

    2016-07-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane protein which plays crucial role in arachidonic acid metabolism, in the catalysis of PGH2 to PGE2. It is a potential drug target involved in variety of human cancers and inflammatory disorders. In the present study we made an attempt to identify crucial amino acid residues involved in the effective binding of its inhibitors at the active site. Molecular docking and Structure Activity Relationship (SAR) studies were performed. In the present study 127 inhibitors having significant variability in parent scaffold were considered. The results clearly indicated that in the GSH and PGH2 binding site Arg70, Arg73, Asn74, Glu77, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 consistently form crucial interactions with inhibitors of different classes/scaffolds. These findings are consistent with that of existing reports on the active site residues pivotal at mPGES-1 active site. Further analysis suggested that out of all important amino acid residues identified; Arg73, Asn74, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 play a crucial role in hydrogen and π-π interactions. The identified amino acid residues can act as target sites for the design and development of drug candidates against mPGES-1. PMID:27012893

  4. An advanced application of the quantitative structure-activity relationship concept in electrokinetic chromatography of metal complexes.

    Science.gov (United States)

    Oszwałdowski, Sławomir; Timerbaev, Andrei R

    2008-02-01

    The relevance of the quantitative structure-activity relationship (QSAR) principle in MEKC and microemulsion EKC (MEEKC) of metal-ligand complexes was evaluated for a better understanding of analyte migration mechanism. A series of gallium chelates were applied as test solutes with available experimental migration data in order to reveal the molecular properties that govern the separation. The QSAR models operating with n-octanol-water partition coefficients or van der Waals volumes were found to be valid for estimation of the retention factors (log k') of neutral compounds when using only an aqueous MEEKC electrolyte. On the other hand, consistent approximations of log k' for both uncharged and charged complexes in either EKC mode (and also with hydro-organic BGEs) were achievable with two-parametric QSARs in which the dipole moment is additionally incorporated as a structural descriptor, reflecting the electrostatic solute-pseudostationary phase interaction. The theoretical analysis of significant molecular parameters in MEKC systems, in which the micellar BGE is modified with an organic solvent, confirmed that concomitant consideration of hydrophobic, electrostatic, and solvation factors is essential for explaining the migration behavior of neutral metal complexes. PMID:18219650

  5. Application of quantitative structure-activity relationship to the determination of binding constant based on fluorescence quenching

    International Nuclear Information System (INIS)

    Quantitative structure-activity relationship (QSAR) model was used to predict and explain binding constant (log K) determined by fluorescence quenching. This method allowed us to predict binding constants of a variety of compounds with human serum albumin (HSA) based on their structures alone. Stepwise multiple linear regression (MLR) and nonlinear radial basis function neural network (RBFNN) were performed to build the models. The statistical parameters provided by the MLR model (R2=0.8521, RMS=0.2678) indicated satisfactory stability and predictive ability while the RBFNN predictive ability is somewhat superior (R2=0.9245, RMS=0.1736). The proposed models were used to predict the binding constants of two bioactive components in traditional Chinese medicines (isoimperatorin and chrysophanol) whose experimental results were obtained in our laboratory and the predicted results were in good agreement with the experimental results. This QSAR approach can contribute to a better understanding of structural factors of the compounds responsible for drug-protein interactions, and can be useful in predicting the binding constants of other compounds. - Research Highlights: → QSAR models for binding constants of some compounds to HSA were developed. → The models provide a simple and straightforward way to predict binding constant. → QSAR can give some insight into structural features related to binding behavior.

  6. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    Science.gov (United States)

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds. PMID:26795018

  7. Structure activity relationship studies on cytotoxicity and the effects on steroid receptors of AB-functionalized cholestanes.

    Science.gov (United States)

    Rárová, Lucie; Steigerová, Jana; Kvasnica, Miroslav; Bartůněk, Petr; Křížová, Kateřina; Chodounská, Hana; Kolář, Zdeněk; Sedlák, David; Oklestkova, Jana; Strnad, Miroslav

    2016-05-01

    Structure-activity relationship analysis and profiling of a library of AB-functionalized cholestane derivatives closely related to brassinosteroids (BRs) were performed to examine their antiproliferative activities and activities on steroid hormone receptors. Some of the compounds were found to have strong cytotoxic activity in several human normal and cancer cell lines. The presence of a 3-hydroxy or 3-oxo group and 2,3-vicinal diol or 3,4-vicinal diol moiety were found to be necessary for optimum biological activity, as well as a six-membered B ring. According to the profiling of all steroid receptors in both agonist and antagonist mode, the majority of the cholestanes were weakly active or inactive compared to the natural ligands. Estrogenic activity was detected for two compounds, two compounds possessed antagonistic properties on estrogen receptors and seven compounds showed agonistic activity. Two active cholestane derivatives were shown to strongly influence cell viability, proliferation, cell cycle distribution, apoptosis and molecular pathways responsible for these processes in hormone-sensitive/insensitive (MCF7/MDA-MB-468) breast cancer cell lines. PMID:26976651

  8. Structure-activity relationship for the estimation of OH-oxidation rate constants of carbonyl compounds in the aqueous phase

    Directory of Open Access Journals (Sweden)

    J. F. Doussin

    2013-06-01

    Full Text Available In the atmosphere, one important class of reactions occurs in the aqueous phase in which organic compounds are known to undertake oxidation towards a number of radicals, among which OH radicals are the most reactive oxidants. In 2008, Monod and Doussin have proposed a new structure activity relationship (SAR to calculate OH-oxidation rate constants in the aqueous phase. This estimation method is based on the group-additivity principle and was until now limited to alkanes, alcohols, acids, bases and related polyfunctional compounds. In this work, the initial SAR is extended to carbonyl compounds, including aldehydes, ketones, dicarbonyls, hydroxy-carbonyls, acidic carbonyls, their conjugated bases, and the hydrated form of all these compounds. To do so, only five descriptors have been added and none of the previously attributed descriptors were modified. This extension leads now to a SAR which is based on a database of 102 distinct compounds for which 252 experimental kinetic rate constants have been gathered and reviewed. The efficiency of this updated SAR is such that 58% of the rate constants could be calculated within ±20% of the experimental data and 76% within ±40%.

  9. Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

    Science.gov (United States)

    Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

    2013-09-01

    Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone. PMID:23597248

  10. Natural products as insecticides: the biology, biochemistry and quantitative structure-activity relationships of spinosyns and spinosoids.

    Science.gov (United States)

    Sparks, T C; Crouse, G D; Durst, G

    2001-10-01

    The spinosyns, a novel family of insecticidal macrocyclic lactones, are active on a wide variety of insect pests, especially lepidopterans and dipterans. The biological activity of a mixture (spinosad; Tracer, Spin-Tor, Success) of the two most abundant spinosyns (spinosyns A and D) against pest insects is on a par with that of many pyrethroid insecticides. The spinosyns also exhibit a very favorable environmental and toxicological profile, and possess a mode of action that appears unique, with studies to date suggesting that both nicotinic and gamma-aminobutryic acid receptor functions are altered in a novel manner. Compared to pyrethroids such as cypermethrin, spinosyn A is slow to penetrate into insect larvae such as tobacco budworm larvae (Heliothis virescens); however, once inside the insect, spinosyn A is not readily metabolized. To date, more than 20 spinosyns and more than 800 spinosoids (semi-synthetic analogs) have been isolated or synthesized, respectively. Artificial neural network-based quantitative structure activity relationship (QSAR) studies for the spinosyns suggested that modification of the 2',3',4'-tri-O-methylrhamnosyl moiety could improve activity and several spinosoids incorporating these modifications exhibited markedly improved lepidopteran activity compared to spinosad. Multiple linear regression-based QSAR studies also suggest that whole molecule properties such as CLogP and MOPAC dipole moment can explain much of the biological activity observed for the spinosyns and closely related spinosoids. PMID:11695182

  11. Quantitative structure-activity relationships and toxicity studies of mixtures of chemicals with anaesthetic potency: Acute lethal and sublethal toxicity to Daphnia magna

    NARCIS (Netherlands)

    Hermens, J.L.M.; Canton, H.; Janssen, P.; Jong, R. de

    1984-01-01

    In this study quantitative structure-activity relationships (QSARs) were calculated between hydrophobicity of a group of organic chemicals with anaesthetic potency and toxicity (immobilization, mortality and inhibition of reproduction) to Daphnia magna. Differences in slopes of the high quality QSAR

  12. Structure-activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53-hDM2 inhibitors.

    Science.gov (United States)

    Tian, Yuan; Ma, Yao; Gibeau, Craig R; Lahue, Brian R; Shipps, Gerald W; Strickland, Corey; Bogen, Stéphane L

    2016-06-01

    Led by the structural information of the screening hit with mDM2 protein, a structure modification of Leu26 moiety of the novel p53-hDM2 inhibitors was conducted. A structure-activity relationship study of 4-substituted piperidines revealed compound 20t with good potencies and excellent CYP450 profiles. PMID:27080185

  13. Development of acute toxicity quantitative structure activity relationships (QSAR) and their use in linear alkylbenzene sulfonate species sensitivity distributions.

    Science.gov (United States)

    Belanger, Scott E; Brill, Jessica L; Rawlings, Jane M; Price, Brad B

    2016-07-01

    Linear Alkylbenzene Sulfonate (LAS) is high tonnage and widely dispersed anionic surfactant used by the consumer products sector. A range of homologous structures are used in laundry applications that differ primarily on the length of the hydrophobic alkyl chain. This research summarizes the development of a set of acute toxicity QSARs (Quantitative Structure Activity Relationships) for fathead minnows (Pimephales promelas) and daphnids (Daphnia magna, Ceriodaphnia dubia) using accepted test guideline approaches. A series of studies on pure chain length LAS from C10 to C14 were used to develop the QSARs and the robustness of the QSARs was tested by evaluation of two technical mixtures of differing compositions. All QSARs were high quality (R(2) were 0.965-0.997, p < 0.0001). Toxicity normalization employing QSARs is used to interpret a broader array of tests on LAS chain length materials to a diverse group of test organisms with the objective of developing Species Sensitivity Distributions (SSDs) for various chain lengths of interest. Mixtures include environmental distributions measured from exposure monitoring surveys of wastewater effluents, various commercial mixtures, or specific chain lengths. SSD 5th percentile hazardous concentrations (HC5s) ranged from 0.129 to 0.254 mg/L for wastewater effluents containing an average of 11.26-12 alkyl carbons. The SSDs are considered highly robust given the breadth of species (n = 19), use of most sensitive endpoints from true chronic studies and the quality of the underlying statistical properties of the SSD itself. The data continue to indicate a low hazard to the environment relative to expected environmental concentrations. PMID:27105149

  14. Broad spectrum antibacterial and antifungal polymeric paint materials: synthesis, structure-activity relationship, and membrane-active mode of action.

    Science.gov (United States)

    Hoque, Jiaul; Akkapeddi, Padma; Yadav, Vikas; Manjunath, Goutham B; Uppu, Divakara S S M; Konai, Mohini M; Yarlagadda, Venkateswarlu; Sanyal, Kaustuv; Haldar, Jayanta

    2015-01-28

    Microbial attachment and subsequent colonization onto surfaces lead to the spread of deadly community-acquired and hospital-acquired (nosocomial) infections. Noncovalent immobilization of water insoluble and organo-soluble cationic polymers onto a surface is a facile approach to prevent microbial contamination. In the present study, we described the synthesis of water insoluble and organo-soluble polymeric materials and demonstrated their structure-activity relationship against various human pathogenic bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and beta lactam-resistant Klebsiella pneumoniae as well as pathogenic fungi such as Candida spp. and Cryptococcus spp. The polymer coated surfaces completely inactivated both bacteria and fungi upon contact (5 log reduction with respect to control). Linear polymers were more active and found to have a higher killing rate than the branched polymers. The polymer coated surfaces also exhibited significant activity in various complex mammalian fluids such as serum, plasma, and blood and showed negligible hemolysis at an amount much higher than minimum inhibitory amounts (MIAs). These polymers were found to have excellent compatibility with other medically relevant polymers (polylactic acid, PLA) and commercial paint. The cationic hydrophobic polymer coatings disrupted the lipid membrane of both bacteria and fungi and thus showed a membrane-active mode of action. Further, bacteria did not develop resistance against these membrane-active polymers in sharp contrast to conventional antibiotics and lipopeptides, thus the polymers hold great promise to be used as coating materials for developing permanent antimicrobial paint. PMID:25541751

  15. Structure-activity relationship studies on derivatives of eudesmanolides from Inula helenium as toxicants against Aedes aegypti larvae and adults.

    Science.gov (United States)

    Cantrell, Charles L; Pridgeon, Julia W; Fronczek, Frank R; Becnel, James J

    2010-07-01

    An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds, two eudesmanolides, alantolactone, and isoalantolactone showed larvicidal activities against Ae. aegypti and, therefore, were chosen for further structure-activity relationship study. In this study, structural modifications were performed on both alantolactone and isoalantolactone in an effort to understand the functional groups necessary for maintaining and/or increasing its activity, and to possibly lead to more effective insect-control agents. All parent compounds and synthetic modification reaction products were evaluated for their toxic activities against Ae. aegypti larvae and adults. Structure modifications included epoxidations, reductions, catalytic hydrogenations, and Michael additions to the alpha,beta-unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae. aegypti larvae were more active than isoalantolactone itself which had an LC(50) value of 10.0 microg/ml. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activities ranging from 12.4 to 69.9 microg/ml. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propylamine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC(50) value of 1.07 microg/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuK(alpha) radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms. PMID:20658657

  16. Cyclodextrin- and calixarene-based polycationic amphiphiles as gene delivery systems: a structure-activity relationship study.

    Science.gov (United States)

    Gallego-Yerga, Laura; Lomazzi, Michela; Franceschi, Valentina; Sansone, Francesco; Ortiz Mellet, Carmen; Donofrio, Gaetano; Casnati, Alessandro; García Fernández, José M

    2015-02-14

    Multi-head/multi-tail facial amphiphiles built on cyclodextrin (CD) and calixarene (CA) scaffolds are paradigmatic examples of monodisperse gene delivery systems. The possibility to precisely control the architectural features at the molecular level offers unprecedented opportunities for conducting structure-activity relationship studies. A major requirement for those channels is the design of a sufficiently diverse ensemble of compounds for parallel evaluation of their capabilities to condense DNA into transfection nanoparticles where the gene material is protected from the environment. Here we have undertaken the preparation of an oriented library of β-cyclodextrin (βCD) and calix[4]arene (CA4) vectors with facial amphiphilic character designed to ascertain the effect of the cationic head nature (aminothiourea-, arginine- or guanidine-type groups) and the macrocyclic platform on the abilities to complex plasmid DNA (pDNA) and in the efficiency of the resulting nanocomplexes to transfect cells in vitro. The hydrophobic domain, formed by hexanoyl or hexyl chains, remains constant in each series, matching the overall structure found to be optimal in previous studies. DLS, TEM and AFM data support that all the compounds self-assemble in the presence of pDNA through a process that involves initially electrostatic interactions followed by formation of βCD or CA4 bilayers between the oligonucleotide filaments. Spherical transfectious nanoparticles that are monomolecular in DNA are thus obtained. Evaluation in epithelial COS-7 and human rhabdomyosarcoma RD-4 cells evidenced the importance of having primary amino groups in the vector to warrant high levels of transfection, probably because of their buffering capacity. The results indicate that the optimal cationic head depends on the macrocyclic core, aminothiourea groups being preferred in the βCD series and arginine groups in the CA4 series. Whereas the transfection efficiency relationships remain essentially

  17. Antibacterial activities and structure-activity relationships of a panel of 48 compounds from Kenyan plants against multidrug resistant phenotypes.

    Science.gov (United States)

    Omosa, Leonidah K; Midiwo, Jacob O; Mbaveng, Armelle T; Tankeo, Simplice B; Seukep, Jackson A; Voukeng, Igor K; Dzotam, Joachim K; Isemeki, John; Derese, Solomon; Omolle, Ruth A; Efferth, Thomas; Kuete, Victor

    2016-01-01

    In the current study forty eight compounds belonging to anthraquinones, naphthoquinones, benzoquinones, flavonoids (chalcones and polymethoxylated flavones) and diterpenoids (clerodanes and kauranes) were explored for their antimicrobial potential against a panel of sensitive and multi-drug resistant Gram-negative and Gram-positive bacteria. The minimal inhibitory concentration (MIC) determinations on the tested bacteria were conducted using modified rapid INT colorimetric assay. To evaluate the role of efflux pumps in the susceptibility of Gram-negative bacteria to the most active compounds, they were tested in the presence of phenylalanine arginine β-naphthylamide (PAβN) (at 30 µg/mL) against selected multidrug resistance (MDR) bacteria. The anthraquinone, emodin, naphthaquinone, plumbagin and the benzoquinone, rapanone were active against methicillin resistant Staphylococcus aureus (MRSA) strains of bacteria with MIC values ranging from 2 to 128 μg/mL. The structure activity relationships of benzoquinones against the MDR Gram-negative phenotype showed antibacterial activities increasing with increase in side chain length. In the chalcone series the presence of a hydroxyl group at C3' together with a methoxy group and a second hydroxyl group in meta orientation in ring B of the chalcone skeleton appeared to be necessary for minimal activities against MRSA. In most cases, the optimal potential of the active compounds were not attained as they were extruded by bacterial efflux pumps. However, the presence of the PAβN significantly increased the antibacterial activities of emodin against Gram-negative MDR E. coli AG102, 100ATet; K. pneumoniae KP55 and KP63 by >4-64 g/mL. The antibacterial activities were substantially enhanced and were higher than those of the standard drug, chloramphenicol. These data clearly demonstrate that the active compounds, having the necessary pharmacophores for antibacterial activities, including some quinones and chalcones are

  18. Derivation of structure-activity relationships from the anticancer properties of ruthenium(II) arene complexes with 2-aryldiazole ligands.

    Science.gov (United States)

    Martínez-Alonso, Marta; Busto, Natalia; Jalón, Félix A; Manzano, Blanca R; Leal, José M; Rodríguez, Ana M; García, Begoña; Espino, Gustavo

    2014-10-20

    The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(η(6)-arene)Ru(OH2)(κ(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(η(6)-arene)Ru(9-MeG)(κ(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(η(6)-arene)RuCl(κ(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(η(6)-p-cym)RuCl(κ(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity. PMID:25302401

  19. In Silico Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series

    Directory of Open Access Journals (Sweden)

    Kothandan Gugan

    2011-01-01

    Full Text Available Abstract Background Multidrug resistance (MDR is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy. Results Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis and HQSAR (Hologram Quantitative Structure Activity Relationship models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2 = 0.536 and non-cross validated correlation coefficient (r2 = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956 with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730. Conclusions The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1

  20. The influence of R and S configurations of a series of amphetamine derivatives on quantitative structure-activity relationship models

    Energy Technology Data Exchange (ETDEWEB)

    Fresqui, Maira A.C., E-mail: maira@iqsc.usp.br [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil); Ferreira, Marcia M.C., E-mail: marcia@iqm.unicamp.br [Institute of Chemistry, University of Campinas - UNICAMP, POB 6154, 13083-970 Campinas, SP (Brazil); Trsic, Milan, E-mail: cra612@gmail.com [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil)

    2013-01-08

    Highlights: Black-Right-Pointing-Pointer The QSAR model is not dependent of ligand conformation. Black-Right-Pointing-Pointer Amphetamines were analyzed by quantum chemical, steric and hydrophobic descriptors. Black-Right-Pointing-Pointer CHELPG atomic charges on the benzene ring are one of the most important descriptors. Black-Right-Pointing-Pointer The PLS models built were extensively validated. Black-Right-Pointing-Pointer Manual docking supports the QSAR results by pi-pi stacking interactions. - Abstract: Chiral molecules need special attention in drug design. In this sense, the R and S configurations of a series of thirty-four amphetamines were evaluated by quantitative structure-activity relationship (QSAR). This class of compounds has antidepressant, anti-Parkinson and anti-Alzheimer effects against the enzyme monoamine oxidase A (MAO A). A set of thirty-eight descriptors, including electronic, steric and hydrophobic ones, were calculated. Variable selection was performed through the correlation coefficients followed by the ordered predictor selection (OPS) algorithm. Six descriptors (CHELPG atomic charges C3, C4 and C5, electrophilicity, molecular surface area and log P) were selected for both configurations and a satisfactory model was obtained by PLS regression with three latent variables with R{sup 2} = 0.73 and Q{sup 2} = 0.60, with external predictability Q{sup 2} = 0.68, and R{sup 2} = 0.76 and Q{sup 2} = 0.67 with external predictability Q{sup 2} = 0.50, for R and S configurations, respectively. To confirm the robustness of each model, leave-N-out cross validation (LNO) was carried out and the y-randomization test was used to check if these models present chance correlation. Moreover, both automated or a manual molecular docking indicate that the reaction of ligands with the enzyme occurs via pi-pi stacking interaction with Tyr407, inclined face-to-face interaction with Tyr444, while aromatic hydrogen-hydrogen interactions with Tyr197 are preferable

  1. Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme

    Directory of Open Access Journals (Sweden)

    Eugene Demchuk

    2012-03-01

    Full Text Available Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR, and structure-activity relationship (SAR models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors

  2. Three Dimensional Quantitative Structure-Activity Relationship of 5H-Pyrido[4,3-b]indol-4-carboxamide JAK2 Inhibitors

    OpenAIRE

    Wu, Xiaoyun; Wan, Shanhe; Zhang, Jiajie

    2013-01-01

    Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA), and comparative molecular simil...

  3. Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

    OpenAIRE

    Chiara Cheng Lim; Martin Philpott; Ferguson, Lynnette R

    2009-01-01

    DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl- radical scavenging, this may not...

  4. Structure-Activity Relationships and Identification of Optmized CC-Chemokine Receptor CCR1, 5, and 8 Metal-Ion Chelators

    DEFF Research Database (Denmark)

    Chalikiopoulos, Alexander; Thiele, Stefanie; Malmgaard-Clausen, Mikkel;

    2013-01-01

    Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2'-bipyridine...... bipyridine (23). The structure-activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation....

  5. Thinking in Terms of Structure-Activity-Relationships (T-SAR): A Tool to Better Understand Nanofiltration Membranes

    OpenAIRE

    Stefan Stolte; Jorg Thöming; Fernández, José F.; Bernd Jastorff; Reinhold Störmann

    2011-01-01

    A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. “Thinking in terms of Structure-Activity-Relationships” (T-SAR) is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis bec...

  6. Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations.

    Science.gov (United States)

    Fang, Jiansong; Pang, Xiaocong; Wu, Ping; Yan, Rong; Gao, Li; Li, Chao; Lian, Wenwen; Wang, Qi; Liu, Ai-Lin; Du, Guan-Hua

    2016-05-01

    A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least-square had a conventional correlation coefficient of the training set (R(2) ) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (ΔEvdw ) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives. PMID:26648584

  7. Thinking in Terms of Structure-Activity-Relationships (T-SAR: A Tool to Better Understand Nanofiltration Membranes

    Directory of Open Access Journals (Sweden)

    Stefan Stolte

    2011-07-01

    Full Text Available A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. “Thinking in terms of Structure-Activity-Relationships” (T-SAR is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis become more complex with increasing size of the molecules considered. In this study, T-SAR was combined with classical membrane characterization methods, resulting in a new methodology which allowed us not only to explain membrane characteristics, but also provides evidence for the importance of the chemical structure for separation performance. We demonstrate an application of the combined approach and its potential to discover stereochemistry, molecular interaction potentials, and reactivity of two FilmTec nanofiltration membranes (NF-90 and NF-270. Based on these results, it was possible to predict both properties and performance in the recovery of hydrophobic ionic liquids from aqueous solution.

  8. Use of a (Quantitative) Structure-Activity Relationship [(Q)SAR] model to predict the toxicity of naphthenic acids

    DEFF Research Database (Denmark)

    Frank, Richard; Sanderson, Hans; Kavanagh, Richard;

    2010-01-01

    -Activity Relationship ((Q)SAR) model to accurately predict the toxicity of NA-like surrogates was investigated.  The USEPA’s ECOSAR model predicted the toxicity of NA-like surrogates with acceptable accuracy in comparison to observed toxicity values from Vibrio fischeri and Daphnia magna assays, indicating that the...

  9. Study on the quantitative structure-activity relationship of C-10 substituted artemisinin (QHS)'s derivatives using rough set theory

    Institute of Scientific and Technical Information of China (English)

    LIU Hao; QU LingBo; GAO HongBin; WANG JinXiang; HAN LiPing; XIANG BingRen

    2008-01-01

    The structure-activity relationship study of C-10 substituted artemisinin (QHS) derivatives that are used as antimalarial was performed with the RS (rough sets) method. An RS process is a concise nonlinear process, and it has broad application foreground in the data mining of nonlinear life courses. In this work, initially the parameters of C-10 substituted QHS's derivatives were computed with the quantum chemistry method, and the information table was constructed from the parameters (condition attributes) and biological activity (decision attributes). Based on the analysis of rough set theory, the core and reduction of attributes sets were obtained. Then the decision rules were extracted and the structure-activity relationship was analyzed. As a nonlinear system, RS theory can extract the special relation in the database. It has the advantage of being nonlinear over multiple linear regression (MLR), principal component analysis (PCA), partial least square (PLS), etc., and the advantage of obtaining results with unambiguous physical meanings over artificial neuron networks (ANNs), etc. The result obtained in this study is instructive to the study of pharmacodynamics, resistance mechanism of QHS and development of QHS's derivatives.

  10. Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

    International Nuclear Information System (INIS)

    Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

  11. Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

    Energy Technology Data Exchange (ETDEWEB)

    Ma Bin; Chen Huaihai; Xu Minmin; Hayat, Tahir [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); He Yan, E-mail: yhe2006@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); Xu Jianming, E-mail: jmxu@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China)

    2010-08-15

    Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

  12. Quantitative structure-activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods.

    Science.gov (United States)

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

    P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure-activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7-7-1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure-activity relationship model suggested is robust and satisfactory. PMID:26600858

  13. Quantitative structure-activity relationship analysis to elucidate the clearance mechanisms of Tc-99m labeled quinolone antibiotics

    International Nuclear Information System (INIS)

    This study aims to establish molecular modeling methods for predicting the liver and kidney uptakes of Tc-99m labeled quinolone antibiotics. Some three-dimensional quantitative-activity relationships (3D-QSAR) models were developed using comparative molecular field analysis and grid-independent descriptors procedures. As a first report on 3D-QSAR modeling, the predicted liver and kidney uptakes for quinolone antibiotics were in good agreement with the experimental values. The obtained results confirm the importance of hydrophobic interactions, size and steric hindrance of antibiotic molecules in their liver uptakes, while the electrostatic interactions and hydrogen bonding ability have impressive effects on their kidney uptakes. (author)

  14. A best​ comprehension about the toxicity of phenylsulfonyl carboxylates in Vibrio fischeri using quantitative structure activity/property relationship methods.

    Science.gov (United States)

    de Melo, Eduardo Borges; Martins, João Paulo Athaíde; Miranda, Eduardo Hösel; Ferreira, Márcia Miguel Castro

    2016-03-01

    Aromatic sulfones comprise a class of chemicals used in agrochemical and pharmaceutical industries and as floatation and extractant agents in petrochemical and metallurgy industries. In this study, new QSA(P)R studies were carried out to predict the toxicity against Vibrio fischeri of a set of 52 aromatic sulfones. The same approach was used to evaluate the relationship between these endpoint and the water solubility, another important environmental endpoint. The study resulted in models of good statistical quality and mechanistic interpretation with a possible correlation between the two endpoints, but the toxic effect is also likely to depend on other physicochemical properties. The use of the PLS2, a method not commonly used in QSA(P)R studies, also produced models of greater reliability, and the relationship between the two endpoints was reinforced to some degree. These results are useful for better understanding the process by which these compounds exert their environmental toxicity, thus aiding in the development of industrially useful compounds with less potential environmental damage. PMID:26551227

  15. Quantitative structure activity relationship study of anticonvulsant activity of α_substituted acetamido-N-benzylacetamide derivatives

    Directory of Open Access Journals (Sweden)

    Usman Abdulfatai

    2016-12-01

    Full Text Available To develop the quantitative structure–activity relationship (QSAR for predicting the anticonvulsant activity of α_substituted acetamido-N-benzylacetamide derivatives. Density Functional Theory (B3LYP/6-31G* quantum chemical calculation method was used to find the optimized geometry of the studied molecules. Nine types of molecular descriptors were used to derive a quantitative relation between anticonvulsant activity and structural properties. The relevant molecular descriptors were selected by genetic algorithm approximation. The high value of the correlation coefficient, (R2 of 0.98, indicates that the model was satisfactory. The proposed model has good stability, robustness, and predictability on verifying with internal and external validation.

  16. Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.

    Science.gov (United States)

    Perucca, Paola; Savio, Monica; Cazzalini, Ornella; Mocchi, Roberto; Maccario, Cristina; Sommatis, Sabrina; Ferraro, Daniela; Pizzala, Roberto; Pretali, Luca; Fasani, Elisa; Albini, Angelo; Stivala, Lucia Anna

    2014-11-01

    The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue. PMID:25105482

  17. Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

    Directory of Open Access Journals (Sweden)

    Stefanie Zimmermann

    2014-03-01

    Full Text Available Sesquiterpene lactones (STLs are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness and mammalian cancer cells (rat bone myoblast L6 cells. It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethylacrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

  18. Development of Quantitative Structure-Activity Relationship Models for Predicting Chronic Toxicity of Substituted Benzenes to Daphnia Magna.

    Science.gov (United States)

    Fan, Deling; Liu, Jining; Wang, Lei; Yang, Xianhai; Zhang, Shenghu; Zhang, Yan; Shi, Lili

    2016-05-01

    The chronic toxicity of anthropogenic molecules such as substituted benzenes to Daphnia magna is a basic eco-toxicity parameter employed to assess their environmental risk. As the experimental methods are laborious, costly, and time-consuming, development in silico models for predicting the chronic toxicity is vitally important. In this study, on the basis of five molecular descriptors and 48 compounds, a quantitative structure-property relationship model that can predict the chronic toxicity of substituted benzenes were developed by employing multiple linear regressions. The correlation coefficient (R (2)) and root-mean square error (RMSE) for the training set were 0.836 and 0.390, respectively. The developed model was validated by employing 10 compounds tested in our lab. The R EXT (2) and RMSE EXT for the validation set were 0.736 and 0.490, respectively. To further characterizing the toxicity mechanism of anthropogenic molecules to Daphnia, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed. PMID:27016939

  19. Structure-activity relationship study of oxindole-based inhibitors of cyclin-dependent kinases based on least-squares support vector machines

    Energy Technology Data Exchange (ETDEWEB)

    Li Jiazhong [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China); Liu Huanxiang [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China); Yao Xiaojun [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China)]. E-mail: xjyao@lzu.edu.cn; Liu Mancang [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China); Hu Zhide [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China); Fan Botao [Universite Paris 7-Denis Diderot, ITODYS 1, rue Guy de la Brosse, 75005 Paris (France)

    2007-01-09

    The least-squares support vector machines (LS-SVMs), as an effective modified algorithm of support vector machine, was used to build structure-activity relationship (SAR) models to classify the oxindole-based inhibitors of cyclin-dependent kinases (CDKs) based on their activity. Each compound was depicted by the structural descriptors that encode constitutional, topological, geometrical, electrostatic and quantum-chemical features. The forward-step-wise linear discriminate analysis method was used to search the descriptor space and select the structural descriptors responsible for activity. The linear discriminant analysis (LDA) and nonlinear LS-SVMs method were employed to build classification models, and the best results were obtained by the LS-SVMs method with prediction accuracy of 100% on the test set and 90.91% for CDK1 and CDK2, respectively, as well as that of LDA models 95.45% and 86.36%. This paper provides an effective method to screen CDKs inhibitors.

  20. Isolation of nematicidal compounds from Tagetes patula L. yellow flowers: structure-activity relationship studies against cyst nematode Heterodera zeae infective stage larvae.

    Science.gov (United States)

    Faizi, Shaheen; Fayyaz, Shahina; Bano, Samina; Iqbal, Erum Yawar; Lubna; Siddiqi, Humaira; Naz, Aneela

    2011-09-14

    Bioassay-guided isolation studies on the extracts of yellow flowers of Tagetes patula L. against the Heterodera zeae were carried out to identify phytochemicals lethal to this economically important cyst nematode. In vitro investigation of a polar extract and fractions showing activity led to the isolation of phenolic compounds (flavonoids and phenolic acids). In the nonpolar extract, a few fatty acids, their methyl esters, and thiophenes (including α-terthienyl) were detected. In studies of compounds obtained commercially, α-terthienyl and gallic and linoleic acids showed 100% mortality at concentrations of 0.125% after 24 h. Assessment of structure-activity relationships revealed that an increase in the number of hydroxyl groups in phenolic acids increased the activity; with fatty acids, activity depended on chain length and the number and position of double bonds. Crude extracts of the flowers of different colors also have promising activity. PMID:21780738

  1. Structural and spectroscopic characterisation of C4 oxygenates relevant to structure/activity relationships of the hydrogenation of α,β-unsaturated carbonyls

    Science.gov (United States)

    Parker, Stewart F.; Silverwood, Ian P.; Hamilton, Neil G.; Lennon, David

    2016-01-01

    In the present work, we have investigated the conformational isomerism and calculated the vibrational spectra of the C4 oxygenates: 3-butyne-2-one, 3-butene-2-one, 2-butanone and 2-butanol using density functional theory. The calculations are validated by comparison to structural data where available and new, experimental inelastic neutron scattering and infrared spectra of the compounds. We find that for 3-butene-2-one and 2-butanol the spectra show clear evidence for the presence of conformational isomerism and this is supported by the calculations. Complete vibrational assignments for all four molecules are provided and this provides the essential information needed to generate structure/activity relationships for the sequential catalytic hydrogenation of 3-butyne-2-one to 2-butanol.

  2. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte; Demmer, Charles S; Hansen, Jeanette; Han, Liwei; Monrad, Rune N; Nielsen, Birgitte; Tapken, Daniel; Pickering, Darryl S; Kastrup, Jette S; Frydenvang, Karla; Bunch, Lennart

    2015-01-01

    Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and...

  3. Modern trends in the development of surface science as applied to catalysis. The elucidation of the structure-activity relationships in heterogeneous catalysts

    International Nuclear Information System (INIS)

    A fundamental approach to the development of heterogeneous catalysts consisting of the study of the structure-activity relationships using surface science methods and techniques is proposed. According to this approach, a study should start with an investigation into well-ordered single crystals under ultrahigh vacuum conditions and then move along the way of both increasing the gas phase pressure (to address the 'pressure gap' problem) and complicating the samples under study from single crystals to supported clusters (to address the 'material gap' problem). The case studies cited in the review prove the efficacy of the proposed approach to investigations into the reactivity of active component particles for the subsequent molecular design of catalysts with improved performance (activity, selectivity and stability) and demonstrate that it conforms with the modern trends in the development of surface science as applied to heterogeneous catalysis.

  4. Structure-Activity Relationships of a Diverse Class of Halogenated Phenazines That Targets Persistent, Antibiotic-Tolerant Bacterial Biofilms and Mycobacterium tuberculosis.

    Science.gov (United States)

    Garrison, Aaron T; Abouelhassan, Yasmeen; Norwood, Verrill M; Kallifidas, Dimitris; Bai, Fang; Nguyen, Minh Thu; Rolfe, Melanie; Burch, Gena M; Jin, Shouguang; Luesch, Hendrik; Huigens, Robert W

    2016-04-28

    Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells. PMID:27018907

  5. Studies of the quantitative structure activity relationship for phenylethylthiazolylthiourea of anti-HIV drug using new three-dimensional structure descriptors

    International Nuclear Information System (INIS)

    A newly developed three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 61 anti-HIV drugs as phenylethylthiazolylthiourea derivatives. Here one quantitative structure activity relationship (QSAR) model was built by partial least square regression (PLS). The estimation stability and generalization ability of the model were strictly analyzed by both internal and external validations. The correlation coefficient of established PLS model (Rcum), leave-one-out cross-validation (QVV) , predicted values versus experimental ones of external samples (Qext) were 0.907, 0.878, 0.913, respectively. The results indicated that QSAR model had both favorable estimation stability and good prediction capabilities. Satisfactory results showed that 3D-HoVAIF can preferably express information related to biological activity of phenylethylthiazolylthiourea derivatives. (authors)

  6. QSAR for cholinesterase inhibition by organophosphorus esters and CNDO/2 calculations for organophosphorus ester hydrolysis. [quantitative structure-activity relationship, complete neglect of differential overlap

    Science.gov (United States)

    Johnson, H.; Kenley, R. A.; Rynard, C.; Golub, M. A.

    1985-01-01

    Quantitative structure-activity relationships were derived for acetyl- and butyrylcholinesterase inhibition by various organophosphorus esters. Bimolecular inhibition rate constants correlate well with hydrophobic substituent constants, and with the presence or absence of cationic groups on the inhibitor, but not with steric substituent constants. CNDO/2 calculations were performed on a separate set of organophosphorus esters, RR-primeP(O)X, where R and R-prime are alkyl and/or alkoxy groups and X is fluorine, chlorine or a phenoxy group. For each subset with the same X, the CNDO-derived net atomic charge at the central phosphorus atom in the ester correlates well with the alkaline hydrolysis rate constant. For the whole set of esters with different X, two equations were derived that relate either charge and leaving group steric bulk, or orbital energy and bond order to the hydrolysis rate constant.

  7. Structure-activity relationships of vanillic acid ester analogs in inhibitory effect of antigen-mediated degranulation in rat basophilic leukemia RBL-2H3 cells.

    Science.gov (United States)

    Ishimata, Nao; Ito, Hideyuki; Tai, Akihiro

    2016-08-01

    Methyl vanillate (1) showed strong degranulation inhibitory activity among vanillin derivatives tested. In order to find structure-activity relationships for developing anti-allergic agents with simple structures and potent activity, we synthesized several vanillic acid (VA) ester derivatives with C1-C4 and C8 alkyl chains and evaluated their degranulation inhibitory activities. The most active compound of VA ester derivatives was derivative 5 with a C4 straight alkyl chain, and derivative 5 exhibited approximately three-fold greater inhibitory activity than that of 1. Moreover, we designed 8 types of analogs based on 5, and we found that the minimum structure for potent degranulation inhibitory activity requires direct connection of the butyl ester moiety on the benzene ring and at least one hydroxyl group on the benzene ring. Butyl meta or para hydroxyl benzoate (10 or 11) has a simpler structure than that of 5 and exhibited more potent degranulation inhibitory activity than that of 5. PMID:27324979

  8. Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.

    Science.gov (United States)

    Chilin, Adriana; Battistutta, Roberto; Bortolato, Andrea; Cozza, Giorgio; Zanatta, Samuele; Poletto, Giorgia; Mazzorana, Marco; Zagotto, Giuseppe; Uriarte, Eugenio; Guiotto, Adriano; Pinna, Lorenzo A; Meggio, Flavio; Moro, Stefano

    2008-02-28

    Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model. PMID:18251491

  9. Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships

    DEFF Research Database (Denmark)

    Arnau, E G; Andersen, Klaus Ejner; Bruze, M;

    2000-01-01

    Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application...... chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance...

  10. Structure-activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors.

    Science.gov (United States)

    Song, Gaopeng; Shen, Xintian; Li, Sumei; Li, Yibin; Liu, Yunpeng; Zheng, Yushan; Lin, Ruheng; Fan, Jihong; Ye, Hanming; Liu, Shuwen

    2015-03-26

    A series of methyl ursolate 3-O-β-chacotrioside analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 3 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 3 indicated that both the type of pentacyclic triterpene and the subtle modification of ursolic acid as an aglycon had key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of ursolic acid or alteration of the C-3 configuration of ursolic acid from 3β-to 3α-forms was helpful to significantly improve the selective index while keeping their antiviral activities. PMID:25728024

  11. Inhibition of 125I-labeled ristocetin binding to Micrococcus luteus cells by the peptides related to bacterial cell wall mucopeptide precursors: quantitative structure-activity relationships

    International Nuclear Information System (INIS)

    Quantitative structure-activity relationships (QSAR) of N-Ac amino acids, N-Ac dipeptides, and N-Ac tripeptides in inhibition of 125I-labeled ristocetin binding to Micrococcus luteus cell wall have been developed to probe the details of the binding between ristocetin and N-acetylated peptides. The correlation equations indicate that (1) the binding is stronger for peptides in which the side chain of the C-terminal amino acid has a large molar refractivity (MR) value, (2) the binding is weaker for peptides with polar than for those with nonpolar C-terminal side chains, (3) the N-terminal amino acid in N-Ac dipeptides contributes 12 times that of the C-terminal amino acid to binding affinity, and (4) the interactions between ristocetin and the N-terminal amino acid of N-acetyl tripeptides appear to be much weaker than those with the first two amino acids

  12. Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic Acid Amides

    Directory of Open Access Journals (Sweden)

    Shijie Du

    2015-05-01

    Full Text Available A series of novel 3-(difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-ylphenyl-3-(difluoro-methyl-1-methyl-1H-pyrazole-4-carboxamide (9m exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

  13. Triazolines. 14. 1,2,3-Triazolines and triazoles, a new class of anticonvulsants. Drug design and structure-activity relationships.

    Science.gov (United States)

    Kadaba, P K

    1988-01-01

    Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles

  14. Toxicity in relation to mode of action for the nematode Caenorhabditis elegans: Acute-to-chronic ratios and quantitative structure-activity relationships.

    Science.gov (United States)

    Ristau, Kai; Akgül, Yeliz; Bartel, Anna Sophie; Fremming, Jana; Müller, Marie-Theres; Reiher, Luise; Stapela, Frederike; Splett, Jan-Paul; Spann, Nicole

    2015-10-01

    Acute-to-chronic ratios (ACRs) and quantitative structure-activity relationships (QSARs) are of particular interest in chemical risk assessment. Previous studies focusing on the relationship between the size or variation of ACRs to substance classes and QSAR models were often based on data for standard test organisms, such as daphnids and fish. In the present study, acute and chronic toxicity tests were performed with the nematode Caenorhabditis elegans for a total of 11 chemicals covering 3 substance classes (nonpolar narcotics: 1-propanol, ethanol, methanol, 2-butoxyethanol; metals: copper, cadmium, zinc; and carbamates: methomyl, oxamyl, aldicarb, dioxacarb). The ACRs were variable, especially for the carbamates and metals, although there was a trend toward small and less variable ACRs for nonpolar narcotic substances. The octanol-water partition coefficient was a good predictor for explaining acute and chronic toxicity of nonpolar narcotic substances to C. elegans, but not for carbamates. Metal toxicity could be related to the covalent index χm2r. Overall, the results support earlier results from ACR and QSAR studies with standard freshwater test animals. As such C. elegans as a representative of small soil/sediment invertebrates would probably be protected by risk assessment strategies already in use. To increase the predictive power of ACRs and QSARs, further research should be expanded to other species and compounds and should also consider the target sites and toxicokinetics of chemicals. PMID:25994998

  15. Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

    Directory of Open Access Journals (Sweden)

    Chiara Cheng Lim

    2009-03-01

    Full Text Available DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl- radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs. Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh using three chemical assays (DPPH, TRAP and ORAC, and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0oC, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37oC, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the

  16. Chiral hydroxylation at the mononuclear nonheme Fe(II center of 4-(S hydroxymandelate synthase--a structure-activity relationship analysis.

    Directory of Open Access Journals (Sweden)

    Cristiana M L Di Giuro

    Full Text Available (S-Hydroxymandelate synthase (Hms is a nonheme Fe(II dependent dioxygenase that catalyzes the oxidation of 4-hydroxyphenylpyruvate to (S-4-hydroxymandelate by molecular oxygen. In this work, the substrate promiscuity of Hms is characterized in order to assess its potential for the biosynthesis of chiral α-hydroxy acids. Enzyme kinetic analyses, the characterization of product spectra, quantitative structure activity relationship (QSAR analyses and in silico docking studies are used to characterize the impact of substrate properties on particular steps of catalysis. Hms is found to accept a range of α-oxo acids, whereby the presence of an aromatic substituent is crucial for efficient substrate turnover. A hydrophobic substrate binding pocket is identified as the likely determinant of substrate specificity. Upon introduction of a steric barrier, which is suspected to obstruct the accommodation of the aromatic ring in the hydrophobic pocket during the final hydroxylation step, the racemization of product is obtained. A steady state kinetic analysis reveals that the turnover number of Hms strongly correlates with substrate hydrophobicity. The analysis of product spectra demonstrates high regioselectivity of oxygenation and a strong coupling efficiency of C-C bond cleavage and subsequent hydroxylation for the tested substrates. Based on these findings the structural basis of enantioselectivity and enzymatic activity is discussed.

  17. Jatrophane Diterpenoids as Modulators of P-Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure-Activity Relationships and Discovery of Promising MDR Reversal Agents.

    Science.gov (United States)

    Zhu, Jianyong; Wang, Ruimin; Lou, Lanlan; Li, Wei; Tang, Guihua; Bu, Xianzhang; Yin, Sheng

    2016-07-14

    The phytochemical study of Pedilanthus tithymaloides led to the isolation of 13 jatrophane diterpenoids (1-13), of which eight (1-8) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (14-35). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemoreversal assays on adriamycin resistant human hepatocellular carcinoma cell line HepG2 (HepG2/ADR) and adriamycin resistant human breast adenocarcinoma cell line MCF-7 (MCF-7/ADR). Compounds 19, 25, and 26 were identified as potent MDR modulators with greater chemoreversal ability and less cytotoxicity than the third-generation drug tariquidar. The structure-activity relationship (SAR) was discussed, which showed that modifications beyond just increasing the lipophilicity of this class of Pgp inhibitors are beneficial to the activity. Compound 26, which exhibited a remarkable metabolic stability in vitro and a favorable antitumor effect in vivo, would serve as a promising lead for the development of new MDR reversal agents. PMID:27328029

  18. Three Dimensional Quantitative Structure-Activity Relationship of 5H-Pyrido[4,3-b]indol-4-carboxamide JAK2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jiajie Zhang

    2013-06-01

    Full Text Available Janus kinase 2 (JAK2 is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA, and comparative molecular similarity indices analysis (CoMSIA. The CoMFA model had a cross-validated coefficient q2 of 0.633, and the relation non-cross-validated coefficient r2 of 0.976. The F value is 225.030. The contributions of steric and electrostatic fields to the activity are 55.2% and 44.8%, respectively. For the CoMSIA study, the q2, r2, and F values of the model are 0.614, 0.929, and 88.771, respectively. The contributions of steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond donor fields to the activity are 27.3%, 23.9%, 16.4%, 21.7%, and 10.7%, respectively. The CoMFA and CoMSIA models showed strong predictive ability, and the 3D contour plots give the basis on the structure modification of JAK2 inhibitors.

  19. Antioxidants and α-glucosidase inhibitors from Ipomoea batatas leaves identified by bioassay-guided approach and structure-activity relationships.

    Science.gov (United States)

    Zhang, Lu; Tu, Zong-Cai; Yuan, Tao; Wang, Hui; Xie, Xing; Fu, Zhi-Feng

    2016-10-01

    Sweet potato (Ipomoea batatas) leaf (SPL) is an underused commercial vegetable with considerable bio-activities. By means of DPPH scavenging ability and α-glucosidase inhibitory oriented isolation, 9 and 7 compounds were isolated and identified, respectively. Among them, trans-N-(p-coumaroyl)tyramine (1), trans-N-feruloyltyramine (2), cis-N-feruloyltyramine (3), 4,5-feruloylcourmaoylquinic acid (8), caffeic acid ethyl ester (10), 7-hydroxy-5-methoxycoumarin (11), 7,3'-dimethylquercetin (13) and indole-3-carboxaldehyde (15), were firstly identified from SPL, and four of them (1, 2, 3 and 10) were firstly identified from genus Ipomoea. Phenethyl cinnamides and 3,4,5-triCQA exhibited the strongest α-glucosidase inhibition, while 3,4,5-triCQA and diCQAs were the dominant antioxidants. Structure-activity relationship revealed that higher caffeoylation of quinic acid and lower methoxylation of flavonols resulted in stronger antioxidant activity, and methylation and cis-configuration structure of phenethyl cinnamides weaken the α-glucosidase inhibition. Aforementioned results could help to explain the antioxidant activity and anti-diabetic activity of SPL, and provide theoretical basis for its further application. PMID:27132824

  20. Quantitative Structure-Activity Relationships Predicting the Antioxidant Potency of 17β-Estradiol-Related Polycyclic Phenols to Inhibit Lipid Peroxidation

    Directory of Open Access Journals (Sweden)

    Katalin Prokai-Tatrai

    2013-01-01

    Full Text Available The antioxidant potency of 17β-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O-H group, a shape index, the solvent-accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17β-estradiol to assist therapy development against oxidative stress-associated neurodegeneration.

  1. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    Science.gov (United States)

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity. PMID:25171780

  2. Effects of synthetic and naturally occurring flavonoids on Na+, K+-ATPase: Aspects of the structure-activity relationship and action mechanism

    International Nuclear Information System (INIS)

    A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na+, K+ -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na+, K+ -ATPase from dog kidney cortex when present at concentrations from 40-1000 μM. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC50 at 257-320 μM. Structure-activity relationships were observed among the following mono-substituted flavones as: (i) 2-cyclohexyl-benzopyran-4-one much-gt 2-phenyl-benzopyran-4-one; (ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one > 2-cyclohexyl-6-hydroxy-benzopyran-4-one > 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly and of the flavonoids were able to block [3H] ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na+, K+ -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme

  3. Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors

    Directory of Open Access Journals (Sweden)

    Utpal Chandra De

    2015-01-01

    Full Text Available Aldose reductase (AR plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC 50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux. A model with partial least squares factor 5, standard deviation 0.2482, R 2 = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

  4. Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes.

    Directory of Open Access Journals (Sweden)

    Miao Hao

    Full Text Available Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs. Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.

  5. Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.

    Science.gov (United States)

    Song, Gaopeng; Shen, Xintian; Li, Sumei; Li, Yibin; Si, Hongzong; Fan, Jihong; Li, Junhua; Gao, Erqiang; Liu, Shuwen

    2016-08-25

    A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry. PMID:27153348

  6. Structure-activity relationship of CAP-1, a cuticle peptide of the crayfish Procambarus clarkii, in terms of calcification inhibitory activity

    Institute of Scientific and Technical Information of China (English)

    A.SUGISAKA; H.INOUE; H.NAGASAWA

    2009-01-01

    CAP-I is a cuticle peptide isolated from the acid-insoluble fraction of the exoskeleton of the crayfish Procambarus clarkii. CAP-I is an acidic peptide and comprises 78 amino acid residues. The C-terminal part is especially highly acidic by a phosphoserine and an Asp-repeat, which is thought to be responsible for the calcification inhibitory activity in vitro. To examine the significance of the Asp-repeat and to get information on structure-activity relationship, various small related pep-tides with different sequences were synthesized and tested for the inhibitory activity. The results showed that 1) the activity depends not on the Asp-containing sequence but on the total number of Asp residues, 2) peptide conforma tion does not affect the activity, and 3) Asp is more effective in inhibitory activity than Glu. These character-isfics seem to be consistent with the fact that acidic matrix proteins identified so far from various biominerals have almost no sequence similarity, leading to the idea that the molecular evolution of matrix proteins and peptides in biominerals might he intrinsically different from that of enzymes, hormones and other important functional proteins possibly due to the difference in the mode of interaction between proteins and inorganic compounds, or between proteins and organic compounds.

  7. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1.

    Science.gov (United States)

    Fonseca, Nayara Cristina; da Cruz, Luana Faria; da Silva Villela, Filipe; do Nascimento Pereira, Glaécia Aparecida; de Siqueira-Neto, Jair Lage; Kellar, Danielle; Suzuki, Brian M; Ray, Debalina; de Souza, Thiago Belarmino; Alves, Ricardo José; Sales Júnior, Policarpo Ademar; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; McKerrow, James H; Caffrey, Conor R; de Oliveira, Renata Barbosa; Ferreira, Rafaela Salgado

    2015-05-01

    The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤ 10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. PMID:25712353

  8. In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii

    International Nuclear Information System (INIS)

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

  9. Effects of heterocyclic-based head group modifications on the structure-activity relationship of tocopherol-based lipids for non-viral gene delivery.

    Science.gov (United States)

    Gosangi, Mallikarjun; Mujahid, Thasneem Yoosuf; Gopal, Vijaya; Patri, Srilakshmi V

    2016-07-12

    Gene therapy, a promising strategy for the delivery of therapeutic nucleic acids, is greatly dependent on the development of efficient vectors. In this study, we designed and synthesized several tocopherol-based lipids varying in the head group region. Here, we present the structure-activity relationship of stable aqueous suspensions of lipids that were synthetically prepared and formulated with 1,2-dioleoyl phosphatidyl ethanolamine (DOPE) as the co-lipid. The physicochemical properties such as the hydrodynamic size, zeta potential, stability and morphology of these formulations were investigated. Interaction with plasmid DNA was clearly demonstrated through gel binding and EtBr displacement assays. Further, the transfection potential was examined in mouse neuroblastoma Neuro-2a, hepatocarcinoma HepG2, human embryonic kidney and Chinese hamster ovarian cell lines, all of different origins. Cell-uptake assays with N-methylpiperidinium, N-methylmorpholinium, N-methylimidazolium and N,N-dimethylaminopyridinium head group containing formulations evidently depicted efficient cell uptake as observed by particulate cytoplasmic fluorescence. Trafficking of lipoplexes using an endocytic marker and rhodamine-labeled phospholipid DHPE indicated that the lipoplexes were not sequestered in the lysosomes. Importantly, lipoplexes were non-toxic and mediated good transfection efficiency as analyzed by β-Gal and GFP reporter gene expression assays which established the superior activity of lipids whose structures correlate strongly with the transfection efficiency. PMID:27348545

  10. Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor

    Directory of Open Access Journals (Sweden)

    Alessio Lodola

    2013-10-01

    Full Text Available The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.

  11. Bispyrimidines as potent histamine H(4) receptor ligands: delineation of structure-activity relationships and detailed H(4) receptor binding mode.

    Science.gov (United States)

    Engelhardt, Harald; Schultes, Sabine; de Graaf, Chris; Nijmeijer, Saskia; Vischer, Henry F; Zuiderveld, Obbe P; Dobler, Julia; Stachurski, Katharina; Mayer, Moriz; Arnhof, Heribert; Scharn, Dirk; Haaksma, Eric E J; de Esch, Iwan J P; Leurs, Rob

    2013-06-13

    The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific. PMID:23668417

  12. Structure-activity relationship studies of strigolactone-related molecules for branching inhibition in garden pea: molecule design for shoot branching.

    Science.gov (United States)

    Boyer, François-Didier; de Saint Germain, Alexandre; Pillot, Jean-Paul; Pouvreau, Jean-Bernard; Chen, Victor Xiao; Ramos, Suzanne; Stévenin, Arnaud; Simier, Philippe; Delavault, Philippe; Beau, Jean-Marie; Rameau, Catherine

    2012-08-01

    Initially known for their role in the rhizosphere in stimulating the seed germination of parasitic weeds such as the Striga and Orobanche species, and later as host recognition signals for arbuscular mycorrhizal fungi, strigolactones (SLs) were recently rediscovered as a new class of plant hormones involved in the control of shoot branching in plants. Herein, we report the synthesis of new SL analogs and, to our knowledge, the first study of SL structure-activity relationships for their hormonal activity in garden pea (Pisum sativum). Comparisons with their action for the germination of broomrape (Phelipanche ramosa) are also presented. The pea rms1 SL-deficient mutant was used in a SL bioassay based on axillary bud length after direct SL application on the bud. This assay was compared with an assay where SLs were fed via the roots using hydroponics and with a molecular assay in which transcript levels of BRANCHED1, the pea homolog of the maize TEOSINTE BRANCHED1 gene were quantified in axillary buds only 6 h after application of SLs. We have demonstrated that the presence of a Michael acceptor and a methylbutenolide or dimethylbutenolide motif in the same molecule is essential. It was established that the more active analog 23 with a dimethylbutenolide as the D-ring could be used to control the plant architecture without strongly favoring the germination of P. ramosa seeds. Bold numerals refer to numbers of compounds. PMID:22723084

  13. Structure-Activity Relationships in NH3-SCR over Cu-SSZ-13 as Probed by Reaction Kinetics and EPR Studies

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Feng; Walter, Eric D.; Karp, Eric M.; Luo, Jin-Yong; Tonkyn, Russell G.; Kwak, Ja Hun; Szanyi, Janos; Peden, Charles HF

    2013-04-01

    Cu-SSZ-13 catalysts with various Cu loadings were prepared via solution ion exchange. The hydrated samples were studied with Electron Paramagnetic Resonance (EPR). Cu2+ ion coordination numbers were obtained by analyzing the hyperfine structures while Cu-Cu distances were estimated from line broadening of the EPR features. By coupling EPR and temperature-programmed reduction (TPR) results, two Cu2+ ion locations were suggested. Standard and fast NH3-SCR, as well as non-selective NH3 oxidation reactions were carried out over these catalysts at high space velocities. For the SCR reaction, intra-particle diffusion limitation was found throughout the reaction temperatures investigated. Although clear structure-activity relationships cannot be derived, the reaction results allow for reactant diffusivities and Cu2+ ion locations to be estimated. The slower NH3 oxidation reaction, on the other hand, is kinetically limited at low temperatures, and, therefore, allows for a correlation between Cu2+ ion location and reaction kinetics to be made. Furthermore, the dynamic Cu2+ ion motion as a function of temperature could also be derived from the NH3 oxidation kinetics.

  14. Structure-Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA-Based Vector.

    Science.gov (United States)

    Vezenkov, Lubomir L; Sanchez, Clément A; Bellet, Virginie; Martin, Vincent; Maynadier, Marie; Bettache, Nadir; Lisowski, Vincent; Martinez, Jean; Garcia, Marcel; Amblard, Muriel; Hernandez, Jean-François

    2016-02-01

    Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac-arg-O2 Oc-(Val)3-Sta-Ala-Sta-(AMPA)4-NH2; O2 Oc=8-amino-3,6-dioxaoctanoyl, Sta=statine, AMPA=ortho-aminomethylphenylacetyl], containing a new kind of cell-penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure-activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action. PMID:26639308

  15. ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

    Science.gov (United States)

    Maignan, Jordany R; Lichorowic, Cynthia L; Giarrusso, James; Blake, Lynn D; Casandra, Debora; Mutka, Tina S; LaCrue, Alexis N; Burrows, Jeremy N; Willis, Paul A; Kyle, Dennis E; Manetsch, Roman

    2016-07-28

    Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days. PMID:27291102

  16. Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 4: Role of acyl side chains on d-mannose.

    Science.gov (United States)

    Tsutsui, Nozomi; Tanabe, Genzoh; Ikeda, Nami; Okamura, Saika; Ogawa, Marika; Miyazaki, Kuniko; Kita, Ayako; Sugiura, Reiko; Muraoka, Osamu

    2016-10-01

    As part of an ongoing study on the structure-activity relationship of acremomannolipin A (1)-the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity-the role of acyl substituents on the d-mannose moiety was examined. Three partially deacylated homologs (2a-2c) and 20 homologs (2d-2w) bearing different acyloxy side chains were synthesized via the stereoselective β-mannosylation of appropriately protected mannosyl sulfoxides (3) with d-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a-2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t-2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j-2s), three (2m: C7, 2n: C9, 2o: C10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal-modulating activity, and this activity is precisely dependent on the length of four acyl side chains on d-mannose. PMID:27243802

  17. Synthesis, structure-activity, and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors.

    Science.gov (United States)

    Vitale, Romina; Ottonello, Giuliana; Petracca, Rita; Bertozzi, Sine Mandrup; Ponzano, Stefano; Armirotti, Andrea; Berteotti, Anna; Dionisi, Mauro; Cavalli, Andrea; Piomelli, Daniele; Bandiera, Tiziano; Bertozzi, Fabio

    2014-02-01

    N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptor-α (PPAR-α). Compounds that feature an α-amino-β-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-α. We synthesized and tested a series of racemic, diastereomerically pure β-substituted α-amino-β-lactones, as either carbamate or amide derivatives, investigating the structure-activity and structure-stability relationships (SAR and SSR) following changes in β-substituent size, relative stereochemistry at the α- and β-positions, and α-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. PMID:24403170

  18. Synthesis and quantitative structure-activity relationship (QSAR) study of novel 4-acyloxypodophyllotoxin derivatives modified in the A and C rings as insecticidal agents.

    Science.gov (United States)

    He, Shuzhen; Shao, Yonghua; Fan, Lingling; Che, Zhiping; Xu, Hui; Zhi, Xiaoyan; Wang, Juanjuan; Yao, Xiaojun; Qu, Huan

    2013-01-23

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have synthesized three series of novel 4-acyloxy compounds derived from podophyllotoxin modified in the A and C rings, which is isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum hexandrum . Their insecticidal activity was preliminarily evaluated against the pre-third-instar larvae of Mythimna separata in vivo. Compound 9g displayed the best promising insecticidal activity. It revealed that cleavage of the 6,7-methylenedioxy group of podophyllotoxin will lead to a less active compound and that the C-4 position of podophyllotoxin was the important modification location. A quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm combined with multiple linear regression (GA-MLR). For this model, the squared correlation coefficient (R(2)) is 0.914, the leave-one-out cross-validation correlation coefficient (Q(2)(LOO)) is 0.881, and the root-mean-square error (RMSE) is 0.024. Five descriptors, BEHm2, Mor14v, Wap, G1v, and RDF020e, are likely to influence the biological activity of these compounds. Among them, two important ones are BEHm2 and Mor14v. This study will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents. PMID:23278333

  19. Novel cationic polyene glycol phospholipids as DNA transfer reagents--lack of a structure-activity relationship due to uncontrolled self-assembling processes.

    Science.gov (United States)

    Øpstad, Christer L; Zeeshan, Muhammad; Zaidi, Asma; Sliwka, Hans-Richard; Partali, Vassilia; Nicholson, David G; Surve, Chinmay; Izower, Mitchell A; Bilchuk, Natalia; Lou, Howard H; Leopold, Philip L; Larsen, Helge; Liberska, Alexandra; Khalique, Nada Abdul; Raju, Liji; Flinterman, Marcella; Jubeli, Emile; Pungente, Michael D

    2014-10-01

    Cationic glycol phospholipids were synthesized introducing chromophoric, rigid polyenoic C20:5 and C30:9 chains next to saturated flexible alkyl chains of variable lengths C6-20:0. Surface properties and liposome formation of the amphiphilic compounds were determined, the properties of liposome/DNA complexes (lipoplexes) were established using three formulations (no co-lipid, DOPE as a co-lipid, or cholesterol as a co-lipid), and the microstructure of the best transfecting compounds inspected using small angle X-ray diffraction to explore details of the partially ordered structures of the systems that constitute the series. Transfection and cytotoxicity of the lipoplexes were evaluated by DNA delivery to Chinese hamster ovary (CHO-K1) cells using the cationic glycerol phospholipid 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) as a reference compound. The uncontrollable self-association of the molecules in water resulted in aggregates and liposomes of quite different sizes without a structure-property relationship. Likewise, adding DNA to the liposomes gave rise to unpredictable sized lipoplexes, which, again, transfected without a structure-activity relationship. Nevertheless, one compound among the novel lipids (C30:9 chain paired with a C20:0 chain) exhibited comparable transfection efficiency and toxicity to the control cationic lipid EPC. Thus, the presence of a rigid polyene chain in this best performing achiral glycol lipid did not have an influence on transfection compared with the chiral glycerolipid reference ethyl phosphocholine EPC with two flexible saturated C14 chains. PMID:24814958

  20. Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

    Directory of Open Access Journals (Sweden)

    Maciej Serda

    Full Text Available Thiosemicarbazones (TSCs are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

  1. Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

    Science.gov (United States)

    Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Simůnek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

  2. Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function

    Energy Technology Data Exchange (ETDEWEB)

    Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D. (UAB); (Connecticut); (Southern Research); (DFCI)

    2009-07-10

    We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.

  3. Immunoassay for phenylurea herbicides: application of molecular modeling and quantitative structure-activity relationship analysis on an antigen-antibody interaction study.

    Science.gov (United States)

    Yuan, Meng; Liu, Bing; Liu, Enmei; Sheng, Wei; Zhang, Yan; Crossan, Angus; Kennedy, Ivan; Wang, Shuo

    2011-06-15

    An indirect competitive enzyme-linked immunosorbent assay (icELISA) for 12 phenylurea herbicides (PUHs) was established with the half-maximum inhibition concentration (IC(50)) of 1.7-920.7 μg L(-1). A method of computer-aided molecular modeling was established in quantitative structure-activity relationship (QSAR) studies to obtain a deeper insight into the PUHs' antibody interactions on how and which molecular properties of the analytes quantitatively affect the antibody recognition. A two-dimensional (2D)-QSAR model based on the Hansch equation and a hologram QSAR (HQSAR) model were constructed, and both showed highly predictive abilities with cross-validation q(2) values of 0.820 and 0.752, respectively. It was revealed that the most important impact factor of the antibody recognition was the PUHs' hydrophobicity (log P), which provided a quadratic correlation to the antibody recognition. Hapten-carrier linking groups were less exposed to antibodies during immunization; thus, groups of the analytes in the same position were generally considered to be less contributive to antibody recognition during immunoassay. But the results of substructure-level analysis showed that these groups played an important role in the antigen-antibody interaction. In addition, the frontier-orbital energy parameter E(LUMO) was also demonstrated as a related determinant for this reaction. In short, the result demonstrated that the hydrophobicity and the lowest unoccupied molecular orbital energy (E(LUMO)) of PUH molecules were mainly responsible for antibody recognition. PMID:21539295

  4. Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin.

    Science.gov (United States)

    Thibeault, Dominic; Gauthier, Charles; Legault, Jean; Bouchard, Jimmy; Dufour, Philippe; Pichette, André

    2007-09-15

    Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3beta-O-monodesmosidic saponins derived from betulin (14-16), betulinic acid (20-22), allobetulin (23-28) and 28-oxoallobetulin (29-34) based on six different natural sugar residues (d-glucose, l-rhamnose, d-arabinose, d-galactose, d-mannose and d-xylose). This structure-activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3beta-O-alpha-d-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC(50) ranging from 7.3 to 10.1mumol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3beta-O-beta-d-glucopyranoside and 3beta-O-beta-d-galactopyranoside of allobetulin (23,24) showed moderate anticancer activity (IC(50) 30-40 micromol/L). PMID:17614290

  5. Aminooxy-naphthylpropionic acid and its derivatives are inhibitors of auxin biosynthesis targeting l-tryptophan aminotransferase: structure-activity relationships.

    Science.gov (United States)

    Narukawa-Nara, Megumi; Nakamura, Ayako; Kikuzato, Ko; Kakei, Yusuke; Sato, Akiko; Mitani, Yuka; Yamasaki-Kokudo, Yumiko; Ishii, Takahiro; Hayashi, Ken-Ichiro; Asami, Tadao; Ogura, Takehiko; Yoshida, Shigeo; Fujioka, Shozo; Kamakura, Takashi; Kawatsu, Tsutomu; Tachikawa, Masanori; Soeno, Kazuo; Shimada, Yukihisa

    2016-08-01

    We previously reported l-α-aminooxy-phenylpropionic acid (AOPP) to be an inhibitor of auxin biosynthesis, but its precise molecular target was not identified. In this study we found that AOPP targets TRYPTOPHAN AMINOTRANSFERASE of ARABIDOPSIS 1 (TAA1). We then synthesized 14 novel compounds derived from AOPP to study the structure-activity relationships of TAA1 inhibitors in vitro. The aminooxy and carboxy groups of the compounds were essential for inhibition of TAA1 in vitro. Docking simulation analysis revealed that the inhibitory activity of the compounds was correlated with their binding energy with TAA1. These active compounds reduced the endogenous indole-3-acetic acid (IAA) content upon application to Arabidopsis seedlings. Among the compounds, we selected 2-(aminooxy)-3-(naphthalen-2-yl)propanoic acid (KOK1169/AONP) and analyzed its activities in vitro and in vivo. Arabidopsis seedlings treated with KOK1169 showed typical auxin-deficient phenotypes, which were reversed by exogenous IAA. In vitro and in vivo experiments indicated that KOK1169 is more specific for TAA1 than other enzymes, such as phenylalanine ammonia-lyase. We further tested 41 novel compounds with aminooxy and carboxy groups to which we added protection groups to increase their calculated hydrophobicity. Most of these compounds decreased the endogenous auxin level to a greater degree than the original compounds, and resulted in a maximum reduction of about 90% in the endogenous IAA level in Arabidopsis seedlings. We conclude that the newly developed compounds constitute a class of inhibitors of TAA1. We designated them 'pyruvamine'. PMID:27147230

  6. Structure-activity relationship of alkyl 9-nitrocamptothecin esters%烷基9-氮硝基喜树碱酯类的构效关系

    Institute of Scientific and Technical Information of China (English)

    Zhi-Song CAO; Panayotis PANTAZIS; John MENDOZA; Janet EARLY; Anthony KOZIELSKI; Nick HARRIS; Beppino GIOVANELLA

    2003-01-01

    AIM:To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters. METHODS: Two alkyl9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhy-dride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against humanleukemia cell lines HL-60 and U-937. Flow cytometry analysis was used to identify the cell cycle phase targeted bythe esters and quantify the extent of ester-induced cell death (apoptosis). RESULTS: Esters 5b and 5c demonstratedgreat abilities to inhibit growth of the leukemia cells followed by induction of apoptosis; esters 5a, 5e, and 5ginduced slight perturbations in the cell cycle at high concentrations; and esters 5d, 5f, and 5h were completelyinactive against the cell lines tested. Thus these esters showed the cell anti-proliferative activity in an order of5b≈5c>5a≈5e≈5g>5d≈5f≈5h. Esters 5b, 5c, and 5e were tested in vivo against various human carcinomas in nudemice grown as xenografts. Only 5b and 5c showed a significant antitumor activity. Particularly, ester 5b demon-strated an antitumor activity agalnst a broad spectrum of human carcinomas including breast, lung, colon, pancreas,stomach, ovarian, and melanoma, etc. CONCLUSION: These esters act like prodrugs of their parental9-nitrocamptothecin. High drug doses need to be administered to animals in order to inhibit growth, and induceregression, of human tumor xenografts in nude mice. These compounds may be developed into potent anticancerdrugs due to their low toxicity.

  7. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3

    Energy Technology Data Exchange (ETDEWEB)

    Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J; Inampudi, Krishna K; Keyloun, Katelyn R; Zhang, Li; Hol, Wim G.J.; Verlind, Christophe L.M.J.; Merritt, Ethan A; Van Voorhis, Wesley C [UWASH

    2012-04-24

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

  8. Synthesis and quantitative structure-activity relationship (QSAR) study of novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives as nematicidal agents.

    Science.gov (United States)

    Che, Zhiping; Zhang, Shaoyong; Shao, Yonghua; Fan, Lingling; Xu, Hui; Yu, Xiang; Zhi, Xiaoyan; Yao, Xiaojun; Zhang, Rui

    2013-06-19

    In continuation of our program aimed at the discovery and development of natural-product-based pesticidal agents, 54 novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives were prepared, and their structures were well characterized by ¹H NMR, ¹³C NMR, HRMS, ESI-MS, and mp. Their nematicidal activity was evaluated against that of the pine wood nematode, Bursaphelenchus xylophilus in vivo. Among all of the derivatives, especially V-12 and V-39 displayed the best promising nematicidal activity with LC₅₀ values of 1.0969 and 1.2632 mg/L, respectively. This suggested that introduction of R¹ and R² together as the electron-withdrawing substituents, R³ as the methyl group, and R⁴ as the phenyl with the electron-donating substituents could be taken into account for further preparation of these kinds of compounds as nematicidal agents. Six selected descriptors are a WHIM descriptor (E1m), two GETAWAY descriptors (R1m+ and R3m+), a Burden eigenvalues descriptor (BEHm8), and two edge-adjacency index descriptors (EEig05x and EEig13d). Quantitative structure-activity relationship (QSAR) studies demonstrated that the structural factors, such as molecular mass (a negative correlation with the bioactivity) and molecular polarity (a positive correlation with bioactivity), are likely to govern the nematicidal activities of these compounds. For this model, the correlation coefficient (R²(training set)), the leave-one-out cross-validation correlation coefficient (Q²(LOO)), and the 7-fold cross-validation correlation coefficient (Q²(7-fold)) were 0.791, 0.701, and 0.715, respectively. The external cross-validation correlation coefficient (Q²ext) and the root-mean-square error for the test set (RMSE(test set)) were 0.774 and 3.412, respectively. This study will pave the way for future design, structural modification, and development of indole derivatives as nematicidal agents. PMID:23738496

  9. Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array.

    Science.gov (United States)

    Shinkai-Ouchi, Fumiko; Koyama, Suguru; Ono, Yasuko; Hata, Shoji; Ojima, Koichi; Shindo, Mayumi; duVerle, David; Ueno, Mika; Kitamura, Fujiko; Doi, Naoko; Takigawa, Ichigaku; Mamitsuka, Hiroshi; Sorimachi, Hiroyuki

    2016-04-01

    Calpains are intracellular Ca(2+)-regulated cysteine proteases that are essential for various cellular functions. Mammalian conventional calpains (calpain-1 and calpain-2) modulate the structure and function of their substrates by limited proteolysis. Thus, it is critically important to determine the site(s) in proteins at which calpains cleave. However, the calpains' substrate specificity remains unclear, because the amino acid (aa) sequences around their cleavage sites are very diverse. To clarify calpains' substrate specificities, 84 20-mer oligopeptides, corresponding to P10-P10' of reported cleavage site sequences, were proteolyzed by calpains, and the catalytic efficiencies (kcat/Km) were globally determined by LC/MS. This analysis revealed 483 cleavage site sequences, including 360 novel ones. Thekcat/Kms for 119 sites ranged from 12.5-1,710 M(-1)s(-1) Although most sites were cleaved by both calpain-1 and -2 with a similarkcat/Km, sequence comparisons revealed distinct aa preferences at P9-P7/P2/P5'. The aa compositions of the novel sites were not statistically different from those of previously reported sites as a whole, suggesting calpains have a strict implicit rule for sequence specificity, and that the limited proteolysis of intact substrates is because of substrates' higher-order structures. Cleavage position frequencies indicated that longer sequences N-terminal to the cleavage site (P-sites) were preferred for proteolysis over C-terminal (P'-sites). Quantitative structure-activity relationship (QSAR) analyses using partial least-squares regression and >1,300 aa descriptors achievedkcat/Kmprediction withr= 0.834, and binary-QSAR modeling attained an 87.5% positive prediction value for 132 reported calpain cleavage sites independent of our model construction. These results outperformed previous calpain cleavage predictors, and revealed the importance of the P2, P3', and P4' sites, and P1-P2 cooperativity. Furthermore, using our binary-QSAR model

  10. Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores P-glycoprotein and multidrug resistance: structure-activity relationships of modulators

    OpenAIRE

    Paula C. Huber; Cintia H. Maruiama; Wanda P. Almeida

    2010-01-01

    Multidrug resistance, MDR is a major obstacle for cancer chemotherapy. MDR can be reversed by drugs that vary in their chemical structure and main biological activity. Many efforts have been done to overcome MDR based on studies of structure-activity relationships and in this review we summarize some aspects of MDR mediated by P-glycoprotein (P-gp), as the most experimentally and clinically tested form of drug resistance. The most significant MDR mechanisms revealed until now are shortly disc...

  11. Development of a new Structure-Activity Relationship (SAR) for gas-phase reactions of NO3 radicals with organic compounds

    Science.gov (United States)

    Kerdouci, J.; Picquet-Varrault, B.; Doussin, J.

    2010-12-01

    The nitrate radical (NO3) has long been recognized as the dominant night-time oxidant of organic species, in particular of unsaturated compounds. More recently, it has been shown that it can contribute significantly to the oxidation of very reactive VOC (e.g. terpenes) even during the day[1]. Volatile organic compounds are widely emitted into the atmosphere by both anthropogenic and biogenic sources. When released into the troposphere, they can undergo either photolysis or oxidation by OH and NO3 radicals and by ozone. These chemical processes are known to be responsible for the formation of photooxidants and SOA which are involved in photochemical smog events. Hence, to estimate their impact on the tropospheric chemistry, it is necessary to know their reactivity towards the atmospheric oxidants. But because of huge number of VOCs, it is impossible to perform kinetic experiments for all of them. For this reason, estimation methods have been developed to predict rate constants. A number of methods for the estimation of rate constants have been proposed. Many of them utilize the physical or chemical properties of the organic compounds such as the ionization energy[2] or the energy of molecular orbital[3]. However, these methods are restricted in their use because of the limited database concerning molecular properties and the discrepancies between the different molecular models used to calculate these parameters. For this reason, a structure-activity relationship has been developed by Atkinson[4] to predict rate constants of the OH-oxidation of VOCs. This kind of SAR is very easy to use and has been successfully integrated in chemical models[5, 6]. Concerning the reactivity of organic compounds with NO3 radicals, it has long been considered that the number of experimental data was not sufficient to use the approach proposed by Atkinson. But during the last decade, many experimental studies, in particular on the unsaturated oxygenated compounds, have enhanced the

  12. Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes

    Directory of Open Access Journals (Sweden)

    Richard D. Beger

    2012-03-01

    Full Text Available An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP enzymes. In the present work, spectral data-activity relationship (SDAR and structure-activity relationship (SAR approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR spectral descriptors. In the present work, both 1D 13C and 1D 15N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D 13C-NMR and 15N-NMR spectra caused an increase in the tenfold cross-validation (CV performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

  13. Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.

    Science.gov (United States)

    McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Valerio, Luis G; Fuscoe, James C; Tong, Weida; Buzatu, Dan A; Wilkes, Jon G; Fowler, Bruce A; Demchuk, Eugene; Beger, Richard D

    2012-01-01

    An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants--interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D ¹³C and 1D ¹⁵N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D ¹³C-NMR and ¹⁵N-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

  14. 2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis, biological activity, structure-activity relationship and mode of action studies

    OpenAIRE

    Singh, Kamaljit; Kaur, Hardeep; Chibale, Kelly; Balzarini, Jan; Little, Susan; Prasad V. Bharatam

    2012-01-01

    2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQ(S) (3D7) and drug-resistant CQ(R) (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC(50) (3.6 nM) value (56-fold less than CQ) against CQ(R) strain. Structure-activity prof...

  15. Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.

    Science.gov (United States)

    Tomioka, Haruaki

    2014-01-01

    Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is

  16. 2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis, biological activity, structure-activity relationship and mode of action studies.

    Science.gov (United States)

    Singh, Kamaljit; Kaur, Hardeep; Chibale, Kelly; Balzarini, Jan; Little, Susan; Bharatam, Prasad V

    2012-06-01

    2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQ(S) (3D7) and drug-resistant CQ(R) (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC(50) (3.6 nM) value (56-fold less than CQ) against CQ(R) strain. Structure-activity profile and binding with heme, μ-oxo-heme have been studied. Binding assays with DNA revealed better binding with target parasite type AT rich pUC18 DNA. Most compounds were somewhat cytotoxic, but especially cytostatic. Molecular docking analysis with Pf DHFR allowed identification of stabilizing interactions. PMID:22459876

  17. Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives

    Directory of Open Access Journals (Sweden)

    Asunción Burguete

    2008-12-01

    Full Text Available A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E-3-(3,4,5-trimethoxy-phenyl-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

  18. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Directory of Open Access Journals (Sweden)

    Victoria S Paulsen

    Full Text Available Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2 terminus of the peptide and the fragment arasin 1(1-23 was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23 were shown to be non-toxic to human red blood cells and arasin 1(1-23 was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23 was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC, arasin 1(1-23 was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23 has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23 involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  19. Synthesis of octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals and their structure-activity relationship for the decomposition of hydrazine in aqueous solution to hydrogen

    Science.gov (United States)

    Li, Chun; Wang, Tao; Chu, Wei; Wu, Ping; Tong, Dong Ge

    2016-03-01

    We developed a co-reduction method to synthesize octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals. The shape/size distribution, structural characteristics, and composition of the Rh2Ni nanocrystals are investigated, and their possible formation mechanism at high temperatures in margaric acid/1-aminoheptadecane solution in the presence of tetraethylgermanium and borane trimethylamine complexes is proposed. A preliminary probing of the structure-activity dependence of the surface ``clean'' Rh2Ni nanocrystals supported on carbon towards hydrazine (N2H4) in aqueous solution dehydrogenation revealed that the higher the percentage of {111} facets, the higher is the activity and H2 selectivity of the nanocrystals. This result was attributed to the {111} facets not only introducing more basic sites, but also weakening the interaction between the produced adspecies (including H2 and NHx) and surface metal atoms in comparison with those of {100} facets. Furthermore, the as-prepared Rh2Ni nanooctahedra exhibited 100% H2 selectivity and high activity at room temperature for H2 generation via N2H4 decomposition. The activation energy of the Rh2Ni nanooctahedra was 41.6 +/- 1.2 kJ mol-1. The Rh2Ni nanooctahedra were stable catalysts for the hydrolytic dehydrogenation of N2H4, providing 27 723 total turnovers in 30 h. Our work provides a new perspective concerning the possibility of constructing hydrogen-producing systems based on N2H4 and surface ``clean'' Rh2Ni nanocrystal catalysts with defined shapes supported on carbon that possess a competitive performance in comparison with NaBH4 and NH3BH3 hydrogen-producing systems for fuel cell applications.We developed a co-reduction method to synthesize octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals. The shape/size distribution, structural characteristics, and composition of the Rh2Ni nanocrystals are investigated, and their possible formation mechanism at high temperatures in margaric acid/1

  20. Synthesis, cytotoxicity and structure-activity relationships between ester and amide functionalities in novel acridine-based platinum(II) complexes.

    Science.gov (United States)

    Bouyer, Florence; Moretto, Johnny; Pertuit, David; Szollosi, Anna; Lacaille-Dubois, Marie-Aleth; Blache, Yves; Chauffert, Bruno; Desbois, Nicolas

    2012-05-01

    In order to improve the pharmacological profile of the anticancer drug cisplatin, several new acridine-based tethered (ethane-1,2-diamine)platinum(II) complexes connected by a polymethylene chain were synthetized. Activity-structure relationship between amide or ester functionalities was explored by changing acridine-9-carboxamide into acridine-9-carboxylate chromophore. The in vitro cytotoxicity of these new complexes was assessed in human colic HCT 116, SW480 and HT-29 cancer cell lines. Series of complexes bearing the acridine-9-carboxylate chromophore displayed higher cytotoxic effect than acridine-9-carboxamide complexes, with gradual effect according to the size of the polymethylene linker. PMID:22459174

  1. Supervisor-Subordinate Relationship, Differentiation, and Employee Creativity: A Self-Categorization Perspective

    Science.gov (United States)

    Zhao, Hongdan; Kessel, Maura; Kratzer, Jan

    2014-01-01

    This study seeks to explore the effect of the quality of supervisor-subordinate relationship (i.e., leader-member exchange; LMX) on employee creativity by examining a moderated-mediation model. The model focuses on the mediating role of perceived insider status and the moderating role of perceived LMX differentiation in influencing the mediation.…

  2. [Quantitative structure activity relationship models based on heuristic method and gene expression programming for the prediction of the pK(a) values of sulfa drugs].

    Science.gov (United States)

    Li, Yu-qin; Si, Hong-zong; Xiao, Yu-liang; Liu, Cai-hong; Xia, Cheng-cai; Li, Ke; Qi, Yong-xiu

    2009-05-01

    Quantitative structure-property relationships (QSPR) were developed to predict the pK(a) values of sulfa drugs via heuristic method (HM) and gene expression programming (GEP). The descriptors of 31 sulfa drugs were calculated by the software CODESSA, which can calculate constitutional, topological, geometrical, electrostatic, and quantum chemical descriptors. HM was also used for the preselection of 4 appropriate molecular descriptors. Linear and nonlinear QSPR models were developed based on the HM and GEP separately and two prediction models lead to a good correlation coefficient (R) of 0.90 and 0.95. The two QSPR models are tseful in predicting pK(a) during the discovery of new drugs and providing theory information for studying the new drugs. PMID:19618723

  3. 2-(Substituted phenyl-3,4-dihydroisoquinolin-2-iums as Novel Antifungal Lead Compounds: Biological Evaluation and Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Xin-Juan Yang

    2013-08-01

    Full Text Available The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs. In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2–12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88–19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

  4. Structure-activity relationship study for fungicidal activity of 1-(4-phenoxymethyl-2-phenyl-[1,3]dioxolan-2-ylmethyl-1H-1,2,4-triazole derivatives against rice blast

    Directory of Open Access Journals (Sweden)

    Hoshi Tomoki

    2015-12-01

    Full Text Available To explore new antifungal agents for rice blast control, the antifungal activity of a series of novel 1,2,4-triazole derivatives against Magnaporthe oryzae has been evaluated. The antifungal activity was determined by using in vitro mycelial growth inhibition tests. Among the 19 test compounds, we found that the compound 1-(4-phenoxymethyl-2-phenyl-[1,3]dioxolan-2-ylmethyl-1H-1,2,4- triazole (Gj displayed potent antifungal activity against M. oryzae. The IC50 value was found approximately 3.8±0.5 μM and the IC50 value of propiconazole was found to be approximately 3.7±0.2 μM, respectively. Structure-activity relationship studies on aromatic ring structures provided insight and information about the structural requirements for antifungal activity of this synthetic series against M. oryzae.

  5. Design, synthesis and preliminary structure-activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives.

    Science.gov (United States)

    Liu, Haoran; Fan, Haoqun; Gao, Xiaohui; Huang, Xueqing; Liu, Xianjun; Liu, Linbo; Zhou, Chao; Tang, Jingjing; Wang, Qiuan; Liu, Wukun

    2016-08-01

    In order to study the structure-activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4 a-8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC50 value: 0.85 μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE. PMID:26186269

  6. Biocatalytic oxidation of phenolic compounds by bovine methemoglobin in the presence of H{sub 2}O{sub 2}: Quantitative structure-activity relationships

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Prior, M. Teresa, E-mail: MariaTeresa.Perez@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain); Gomez-Bombarelli, Rafael, E-mail: R.GomezBombarelli@hw.ac.uk [Department of Physics, Heriot-Watt University, David Brewster Building G.45, Edinburgh (United Kingdom); Gonzalez-Sanchez, M. Isabel, E-mail: MIsabel.Gonzalez@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain); Valero, Edelmira, E-mail: Edelmira.Valero@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer The kinetics of metHb-catalyzed oxidation of a group of phenols were analyzed. Black-Right-Pointing-Pointer Unusual kinetic behaviour was observed for the phenols here tested. Black-Right-Pointing-Pointer QSAR equations for a number of physicochemical parameters were established. Black-Right-Pointing-Pointer A relationship between the peroxidase and catalase activities of metHb was found. Black-Right-Pointing-Pointer Bovine metHb might represent a good economical alternative to other peroxidases. - Abstract: In the present work, 13 p-substituted phenols with different functional groups have been systematically evaluated as metHb substrates by means of HPLC analysis. Non-hyperbolic kinetics were observed and Hill coefficients in the 0.37-1.00 range were obtained. The catalytic constants and the Hill coefficients were found to be quantitatively correlated with two independent variables: the energy level of the highest-occupied molecular orbital (E{sub HOMO}), which describes the intrinsic redox activity of the substrates and the pK{sub a}-values, which are related to substrate ionization. Oxygen evolution in the presence of each phenol derivative was also measured, and good correlation between peroxidase-like and catalase-like activities of the protein was observed. It is also shown that bovine metHb, although less active than other peroxidases, may represent a good alternative from an economical point of view for phenol removal processes. The equations here obtained may serve as a basis to further explore the potential use of metHb-mediated reactions in the treatment of phenols in wastewaters and to predict which phenol will be removed most efficiently under this treatment with satisfactory reliability.

  7. Structure activity relationships of human galactokinase inhibitors.

    Science.gov (United States)

    Liu, Li; Tang, Manshu; Walsh, Martin J; Brimacombe, Kyle R; Pragani, Rajan; Tanega, Cordelle; Rohde, Jason M; Baker, Heather L; Fernandez, Elizabeth; Blackman, Burchelle; Bougie, James M; Leister, William H; Auld, Douglas S; Shen, Min; Lai, Kent; Boxer, Matthew B

    2015-02-01

    Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor. PMID:25553891

  8. Structure-activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870.

    Science.gov (United States)

    Zhong, Qi-Fei; Liu, Rui; Liu, Gang

    2015-11-01

    Chronic hepatitis C virus infection represents a serious global public health problem, typically resulting in fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Based on our previous discovery of lead compound 2 (Liu et al. J Med Chem 54:5747-5768, 2011), 35 new quinoxalinone derivatives were explored in this study. Outline of the structure-activity relationships (SARs) revealed that compound BH6870 (36) showed high anti-HCV potency ([Formula: see text]) and a good cell safety index (SI [Formula: see text]). SARs analysis indicated that quinoxalin-2(1H)-one containing a 4-aryl-substituted thiazol-2-amine moiety was optimal for antiviral activity. Introducing a hydrogen-bond acceptor (such as ester or amide group) at the C-3 position of quinoxalin-2(1H)-one was beneficial for the antiviral potency, and especially, N,N-disubstituted amide was far superior to N-monosubstituted amide. Incorporation of more than one halogen (fluorine or chlorine atom) or a strong electron-withdrawing group on the benzene ring of the thiazole-phenyl moiety might reduce electron atmosphere density further and resulted in a dramatical loss of activity. The NH-group of the lactam moiety was clearly required for anti-HCV activity. Design and synthesis of quinoxalin-2(1H)-one derivatives as new non-nucleoside small-molecule HCV inhibitors. BH6870 (36), showing higher antiviral potency and a good cell safety index, was identified. PMID:26205408

  9. 4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling.

    Science.gov (United States)

    Trist, Iuni M L; Nannetti, Giulio; Tintori, Cristina; Fallacara, Anna Lucia; Deodato, Davide; Mercorelli, Beatrice; Palù, Giorgio; Wijtmans, Maikel; Gospodova, Tzveta; Edink, Ewald; Verheij, Mark; de Esch, Iwan; Viteva, Lilia; Loregian, Arianna; Botta, Maurizio

    2016-03-24

    Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations. PMID:26924568

  10. Investigation of an Immunoassay with Broad Specificity to Quinolone Drugs by Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Data Sets and Advanced Quantitative Structure-Activity Relationship Analysis.

    Science.gov (United States)

    Chen, Jiahong; Lu, Ning; Shen, Xing; Tang, Qiushi; Zhang, Chijian; Xu, Jun; Sun, Yuanming; Huang, Xin-An; Xu, Zhenlin; Lei, Hongtao

    2016-04-01

    A polyclonal antibody against the quinolone drug pazufloxacin (PAZ) but with surprisingly broad specificity was raised to simultaneously detect 24 quinolones (QNs). The developed competitive indirect enzyme-linked immunosorbent assay (ciELISA) exhibited limits of detection (LODs) for the 24 QNs ranging from 0.45 to 15.16 ng/mL, below the maximum residue levels (MRLs). To better understand the obtained broad specificity, a genetic algorithm with linear assignment of hypermolecular alignment of data sets (GALAHAD) was used to generate the desired pharmacophore model and superimpose the QNs, and then advanced comparative molecular field analysis (CoMFA) and advanced comparative molecular similarity indices analysis (CoMSIA) models were employed to study the three-dimensional quantitative structure-activity relationship (3D QSAR) between QNs and the antibody. It was found that the QNs could interact with the antibody with different binding poses, and cross-reactivity was mainly positively correlated with the bulky substructure containing electronegative atom at the 7-position, while it was negatively associated with the large bulky substructure at the 1-position of QNs. PMID:26982746

  11. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    Science.gov (United States)

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  12. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2′,2′-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

    Science.gov (United States)

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-01-01

    In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were two-fold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  13. Categorizing operational radioactive wastes

    International Nuclear Information System (INIS)

    The primary objective of this publication is to improve communications among waste management professionals and Member States relative to the properties and status of radioactive waste. This is accomplished by providing a standardized approach to operational waste categorization using accepted industry practices and experience. It is a secondary objective to draw a distinction between operational waste categorization and waste disposal classification. The approach set forth herein is applicable to waste generation by mature (major, advanced) nuclear programmes, small-to-medium sized nuclear programmes, and programmes with waste from other nuclear applications. It can be used for planning, developing or revising categorization methodologies. For existing categorization programmes, the approach set forth in this publication may be used as a validation and evaluation tool for assessing communication effectiveness among affected organizations or nations. This publication is intended for use by waste management professionals responsible for creating, implementing or communicating effective categorization, processing and disposal strategies. For the users of this publication, it is important to remember that waste categorization is a communication tool. As such, the operational waste categories are not suitable for regulatory purposes nor for use in health and safety evaluations. Following Section 1 (Introduction) Section 2 of this publication defines categorization and its relationship to existing waste classification and management standards, regulations and practices. It also describes the benefits of a comprehensive categorization programme and fundamental record considerations. Section 3 provides an overview of the categorization process, including primary categories and sub-categories. Sections 4 and 5 outline the specific methodology for categorizing unconditioned and conditioned wastes. Finally, Section 6 provides a brief summary of critical considerations that

  14. Quantitative structure-activity relationship based on the interval censored data%基于区间活性数据的定量结构-活性关系

    Institute of Scientific and Technical Information of China (English)

    赵劲松

    2013-01-01

    In this study, by using Bayesian statistical analysis, quantitative structure-activity relationship ( QSAR) models of substituted anilines and phenols for Daphnia magna were developed based on the interval censored data of 24 h acute toxicities. They were compared with QSAR models built from the point estimation, i. e. , the mean and median of the interval censored dataset. The results showed that the former QSAR models could effectively use the biological activity information of specific compounds, and therefore had a better goodness-of-fit and predictive ability, and a wider range of applications. QSAR model based on the interval censored data could provide a more reliable predicted biological activity for the ecological risk assessment.%利用贝叶斯统计方法构建了基于区间活性数据的取代苯胺和苯酚类化合物对大型溞( Daphnia magna)24 h急性毒性的定量结构-活性关系模型,并与基于平均数和中位数的点估计活性数据的定量结构-活性关系模型进行了比较。结果表明,前者可以充分利用化合物的活性数据信息,模型具有更好的拟合效果与预测能力以及较宽的应用范围。基于区间活性数据的定量结构-活性关系模型可为生态风险评价等提供更加可靠的预测数据。

  15. 喹诺酮抗HIV活性及其构效关系的研究进展%Advances of Quinolones as Potent HIV Inhibitors and Their Structure-activity Relationships

    Institute of Scientific and Technical Information of China (English)

    冯连顺; 王健; 刘明亮; 吕凯; 郭慧元

    2011-01-01

    The quinolone is one of the important scaffolds to find new anti-HIV drugs in recent years. Many series of derivatives were designed and synthesized through structural modification, and some of them were found to be promising HIV integrase inhibitors, reverse transcriptase inhibitors or dual inhibitors of reverse transcriptase and integrase. It is encouraging that elvitegravir as an integrase inhibitor, the first quinolone anti-HIV drug, will be approved by US FDA for the treatment of AIDS. This article describes the research advances of quinolones as potent anti-HIV agents, their structure-activity relationships and related action mechanisms.%喹诺酮是近年来寻找抗HIV新药的重要结构骨架之一.通过结构修饰,可从中筛选出若干有希望的整合酶抑制剂、逆转录酶抑制剂以及双重(逆转录酶+整合酶)抑制剂.尤其是整合酶抑制剂elvitegravir即将上市,引起对抗HIV喹诺酮研发的关注.本文按喹诺酮的结构特征,从2-喹诺酮、4-喹诺酮、β-二酮酸和杂合体着手,综述了近年来这类化合物在抗HIV活性及其构效关系、作用机制等方面的研究进展.

  16. Three-dimensional quantitative structure activity relationship (QSAR of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA revisited study

    Directory of Open Access Journals (Sweden)

    Hamad Elgazwy Abdel-Sattar S

    2012-05-01

    Full Text Available Abstract In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity. Background Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA methods were described for evaluation of antioxidant properties. Results Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR study was initiated. Conclusions Chalcones heating provides a rapid and

  17. Categorization of fragrance contact allergens for prioritization of preventive measures

    DEFF Research Database (Denmark)

    Uter, Wolfgang; Johansen, Jeanne D; Börje, Anna;

    2013-01-01

    Contact allergy to fragrances is still relatively common, affecting ∼ 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to...... fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization...... are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (> 100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to...

  18. Practical Dyspnea Assessment: Relationship Between the 0–10 Numerical Rating Scale and the Four-Level Categorical Verbal Descriptor Scale of Dyspnea Intensity

    Science.gov (United States)

    Wysham, Nicholas G.; Miriovsky, Benjamin J.; Currow, David C.; Herndon, James E.; Samsa, Gregory P.; Wilcock, Andrew; Abernethy, Amy P.

    2016-01-01

    Context Measurement of dyspnea is important for clinical care and research. Objectives To characterize the relationship between the 0–10 Numerical Rating Scale (NRS) and four-level categorical Verbal Descriptor Scale (VDS) for dyspnea assessment. Methods This was a substudy of a double-blind randomized controlled trial comparing palliative oxygen to room air for relief of refractory breathlessness in patients with life-limiting illness. Dyspnea was assessed with both a 0–10 NRS and a four-level categorical VDS over the one-week trial. NRS and VDS responses were analyzed in cross section and longitudinally. Relationships between NRS and VDS responses were portrayed using descriptive statistics and visual representations. Results Two hundred twenty-six participants contributed responses. At baseline, mild and moderate levels of breathlessness were reported by 41.9% and 44.6% of participants, respectively. NRS scores demonstrated increasing mean and median levels for increasing VDS intensity, from a mean (SD) of 0.6 (±1.04) for VDS none category to 8.2 (1.4) for VDS severe category. The Spearman correlation coefficient was strong at 0.78 (P < 0.0001). Based on the distribution of NRS scores within VDS categories, we calculated test characteristics of two different cutpoint models. Both models yielded 75% correct translations from NRS to VDS; however, Model A was more sensitive for moderate or greater dyspnea, with fewer misses downcoded. Conclusion There is strong correlation between VDS and NRS measures for dyspnea. Proposed practical cutpoints for the relationship between the dyspnea VDS and NRS are 0 for none, 1–4 for mild, 5–8 for moderate, and 9–10 for severe. PMID:26004401

  19. [Studies on the structure-activity relationship of allyl substituted oxopyrimidines searching for the novel antagonist or agonist of barbiturates to the sleep mechanism based on the uridine receptor theory--barbituric acid to uridine (part I)].

    Science.gov (United States)

    Yamamoto, Ikuo

    2005-01-01

    Thirty-six allyl substituted oxopyrimidine analogues such as barbituric acid (BA), barbiturates, uracil, thymine, and related derivatives including 13 new compounds were synthesized and their pharmacologic effects ([hypnotic activity, anticonvulsant activity against pentylentetrazol (PTZ)-induced seizures, and LD(50)]) and interactions with the barbiturates were evaluated in mice and rats. The results are briefly and parially summarized as follows. BA prolonged pentobarbital (PB)-induced sleep and had some central depressant effects. N,5,5-triallyl-BA exhibited some hypnotic and anticonvulsant activities, although the other 5,N-allyl-compounds did not show any activity except for allobarbital (AlloB). N-allyl-BA, 5-allyl-BA, N(1),N(3),5-triallyl-BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA also prolonged PB-induced sleep. Interestingly, N,5,5-triallyl-BA was the most potent in the interaction with AlloB, phenobarbital (PheB), amobarbital (AB), PB, and thiopental (TP) but not barbital (B). N(1),N(3),5,5-tetraallyl-BA prolonged AlloB-, PB-, and AB-induced sleep but not B-, PheB-, and TP-induced sleep. N(1),N(3),5-triallyl-B prolonged only PB- and TP-induced sleep. 5,5-diallyl-BA prolonged PheB- and TP-induced sleep. N,5-diallyl-BA prolonged only TP-induced sleep. In contrast, BA and N(1),N(3),5-triallyl-AB tended to antagonize AlloB, AB, and B. N(1),N(3),5,5-tetraallyl-BA also slightly antagonized B, PheB, and TP. 5,5-diallyl-BA antagonized only AB. The prolonging effects of BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA on PB-induced sleep were dose dependent. These results indicate that the position and number of allyl groups substituted on the structure of BA play an important role in their depressant activities. This review deals with the structure-activity relationship of allyl-substituted oxopyrimidines as part of our search for antagonists and agonists of barbiturates as well as their mechanisms of action. PMID:15635282

  20. Longitudinal categorical data analysis

    CERN Document Server

    Sutradhar, Brajendra C

    2014-01-01

    This is the first book in longitudinal categorical data analysis with parametric correlation models developed based on dynamic relationships among repeated categorical responses. This book is a natural generalization of the longitudinal binary data analysis to the multinomial data setup with more than two categories. Thus, unlike the existing books on cross-sectional categorical data analysis using log linear models, this book uses multinomial probability models both in cross-sectional and longitudinal setups. A theoretical foundation is provided for the analysis of univariate multinomial responses, by developing models systematically for the cases with no covariates as well as categorical covariates, both in cross-sectional and longitudinal setups. In the longitudinal setup, both stationary and non-stationary covariates are considered. These models have also been extended to the bivariate multinomial setup along with suitable covariates. For the inferences, the book uses the generalized quasi-likelihood as w...

  1. Anti-HIV-1 activity and structure-activity relationship of pyranocoumarin analogs%吡喃香豆素衍生物对HIV-1的抑制作用及其构效关系

    Institute of Scientific and Technical Information of China (English)

    董飚; 马涛; 章天; 周春梅; 刘刚; 王琳; 陶佩珍; 张兴权

    2011-01-01

    The purpose of this study is to find out anti-HIV-1 reverse transcriptase (RT)/protease (PR) activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship. Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system. It also shows inhibition effects to HIV-1 replication in cell culture. Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design, analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system. Seven compounds were designed and tested. Several compounds showed anti-HIV-1 activity in varying degrees, especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 μmol·L-1 of IC50 against HIV-1 PR/RT and 0.036 μmol·L-1 against HIV-1 replication in PBMC cultures. V0201 with a novel structure may be a new leading compound. These new compounds are valuable for development of new anti-HIV drugs in the future.%研究香豆素衍生物对人类免疫缺陷病毒l型逆转录酶(HIV-1 RT)、蛋白酶(HIV-1 PR)和细胞内复制的抑制作用及其构效关系.不同香豆素衍生物具有抑制HIV-1 RT、HIV-1 PR活性,且在细胞内显示出抑制HIV-1复制的作用已见报道.本课题根据国内传统药学的特点,考察以天然产物为先导化合物、结合HIV-1蛋白酶三维结构计算机辅助药物设计、合成的四环双吡喃香豆素及其类似物.以HIV-1 RT及HIV-1 PR以及细胞内病毒复制为靶点,利用酶学模型和细胞培养模型进行药物筛选及其构效关系研究,设计合成的7个化合物的药效学实验结果显示.部分化合物显示了不同程度的抗HIV-1活性.其中V0201作用最强,它对HIV-1 PR和HIV-1 RT的IC50分别为3.56和0.78 μmol·L-1;

  2. Categorization Parameters and Intelligence.

    Science.gov (United States)

    Meiran, Nachshon; Fischman, Eliezer

    1989-01-01

    To establish the relationship between categorization ability and psychometric intelligence, 98 ninth graders in Israel were instructed to group 28 common Hebrew nouns into categories and were given a battery of intelligence tests. Results are discussed in terms of their impact on the design of intelligence testing. (SLD)

  3. Analysis of structure -activity relationship and toxicity of organophosphorus pesticide to plankton%有机磷农药的构效关系及其对浮游生物的毒性效应

    Institute of Scientific and Technical Information of China (English)

    王娜; 刘莉莉; 孙凯峰; 段舜山

    2012-01-01

    The toxicity of six organophosphorus pesticides to Scenedesmus quadricanda and Moina macrocopa were studied using quantitative structure-activity relationship theory (QSAR) and acute toxicity tests. According to QSAR theory, the toxicity of organophosphorus pesticides was determined mainly by the electropositivity of center phosphorus atom, which was influenced by the type. More specifically, toxicity was reduced as P=O bonds were replaced by P=S bonds. Replacement of hydroxy(-OH) by methoxy(-CH3O), ethoxy(-CH3CH2O) and propoxy(-CH3CH2CH2O), however, successively increased. Toxicity of organophosphorus pesticides was also reduced as P-0 bond were replaced by P-C bond. Specifically, the toxicity of chlorpyrifos and phoxim was higher than four other organophosphorus pesticides as -CH3CH2O replaced -CH3O, dichlorovos and trichlorphon were more toxic than glyphosate compared, while dichlorovos was more toxic than trichlorphon. Glyphosate-isophopylammianium was the least toxic compound as hydroxy(-OH) replaced by glycine isophopylammianium. Toxicity tests demonstrated that the EC-50 concentrations of chlorpyrifos, phoxim, trichlorphon, dichlorovos, dimethoate, glyphosate-isophopylammianium on S. Quadricanda were 6.34, 6.62, 59.53, 82.12, 141.37 and 7.25 mg·L-1 at 96 h, respectively, while, those on M. Macrocopa were 0.20, 0.12, 0.28, 0.17, 1.12 and 5.03 mg·L-1 at 48 h, respectively. The toxicity of the six organophosphorus pesticide to M. Macrocopa was generally ordered as -OH>=O >-O. In conclusion, this study demonstrates the utility of using QSAR with acute toxicity test for the assessment of ecological risks of organophosphorus pesticides to plankton.%以定量构效关系理论和实验室内急性毒性试验相结合研究了六种有机磷农药对四尾栅藻(S.quadricanda)和多刺裸腹溞(Moina macrocopa)的生态毒性.有机磷农药的毒性取决于磷原子的电正性,各取代基种类和构象对电荷分布作用显著.根据构效关系原理,磷

  4. Categorical Perception

    OpenAIRE

    Harnad, Stevan

    2003-01-01

    Differences can be perceived as gradual and quantitative, as with different shades of gray, or they can be perceived as more abrupt and qualitative, as with different colors. The first is called continuous perception and the second categorical perception. Categorical perception (CP) can be inborn or can be induced by learning. Formerly thought to be peculiar to speech and color perception, CP turns out to be far more general, and may be related to how the neural networks in our brains detect ...

  5. Study on the structure-activity relationship of stem bromelain in different inhibitors and activators%不同抑制剂和激活剂对菠萝茎蛋白酶酶学特性的影响

    Institute of Scientific and Technical Information of China (English)

    赵力超; 陈洁兰; 王燕; 刘欣

    2013-01-01

    菠萝蛋白酶作为一种典型的巯基类蛋白酶,具有稳定性差、易失活的特性.本文通过研究多种抑制剂和激活剂对菠萝茎蛋白酶活力、动力学参数及光谱特性等的影响,总结其构效变化规律,试图解释菠萝蛋白酶失活及激活机理.结果表明:抑制剂与激活剂作用下菠萝茎蛋白酶的CD图谱均表现为o-螺旋度降低,β-折叠、β-转角以及无规卷曲含量不同程度提高,但抑制剂作用下螺旋降低,折叠与卷曲的升高程度更明显.此外,抑制剂与激活剂作用下菠萝茎蛋白酶的紫外差吸收光谱也显示差异,激活剂作用下主要表现为230nm以下的二级结构变化,而抑制剂除上述变化外,还显示生色基团Trp、Tyr、Phe的暴露吸收,表明抑制剂作用下酶分子构象变化更剧烈.本文可为菠萝茎蛋白酶的改性研究提供理论基础.%Stem bromelain was a typical sulfhydryl protease,featured as poor stability and easy of inactivation.Inactivation and activation mechanisms to stem bromelain were examined in this paper,by studying the effects of inhibitors and activators on stem bromelain activity,kinetic parameters and spectral characteristics,and summarizing rule stem bromelain structural activity variation.Results showed that the CD spectra of stem bromelain effected by inhibitors and activators appears as decreasing α-Helix,and increasing β-Sheet,β-Tum and Random in varied degree.The inhibitors impacted on molecular conformation more than activators do.Such impact caused also UV absorption spectra varying.Activator impacted a secondary-structure reaction mainly below 230nm,while alcotate and inhibitors additionally caused exposure of Trp,Tyr and Phe,which meant a significant enzyme molecule conformation react.This study provided a theoretical basis for the consequent research of enzymatic modification.

  6. Child categorization.

    Science.gov (United States)

    Gelman, Susan A; Meyer, Meredith

    2011-01-01

    Categorization is a process that spans all of development, beginning in earliest infancy yet changing as children's knowledge and cognitive skills develop. In this review article, we address three core issues regarding childhood categorization. First, we discuss the extent to which early categories are rooted in perceptual similarity versus knowledge-enriched theories. We argue for a composite perspective in which categories are steeped in commonsense theories from a young age but also are informed by low-level similarity and associative learning cues. Second, we examine the role of language in early categorization. We review evidence to suggest that language is a powerful means of expressing, communicating, shaping, and supporting category knowledge. Finally, we consider categories in context. We discuss sources of variability and flexibility in children's categories, as well as the ways in which children's categories are used within larger knowledge systems (e.g., to form analogies, make inferences, or construct theories). Categorization is a process that is intrinsically tied to nearly all aspects of cognition, and its study provides insight into cognitive development, broadly construed. PMID:23440312

  7. Slower Implicit Categorical Learning in Adult Poor Readers

    Science.gov (United States)

    Sperling, Anne J.; Lu, Zhong-Lin; Manis, Franklin R.

    2004-01-01

    We investigated the relationship between reading and explicit and implicit categorical learning by comparing university students with poor reading to students with normal reading abilities on two categorical learning tasks. One categorical learning task involved sorting simple geometric shapes into two groups according to a unidimensional rule.…

  8. Theoretic calculation and study on structure-activity relationship of penicillin derivatives%青霉烷酸衍生物构效关系的理论计算与研究

    Institute of Scientific and Technical Information of China (English)

    梅光泉; 胡文玉; 朱峰

    2001-01-01

    Optimized structure of 10 penicillin derivatives,including antibiotics and β-lactamase inhibitor,were obtained using semiempirical method MNDO. By comparison of their bond length,energy level of molecular orbital,electric distribution and bond condensation with D-Ala-D-Ala,we have confirmed the presumed action model of the antibiotics and β-lactamase inhibitors. The quantitative relationship between the structure and effect of penicillin derivatives was also obtained.%用半经验(MNDO)方法得到了10种青霉烷酸衍生物,包括抗生素和β-内酰胺酶抑制剂的优化构型,通过对它们分子的构型参数、轨道能级、电荷分布、化学键集居数等数据的分析,证明了对抗生素和β-内酰胺酶抑制剂的药理模型的猜测。并通过对其各结构参数的分析,初步得到了各结构参数与其抗药或抑酶活性的定量关系。

  9. Categorical Pullbacks

    Directory of Open Access Journals (Sweden)

    Riccardi Marco

    2015-03-01

    Full Text Available The main purpose of this article is to introduce the categorical concept of pullback in Mizar. In the first part of this article we redefine homsets, monomorphisms, epimorpshisms and isomorphisms [7] within a free-object category [1] and it is shown there that ordinal numbers can be considered as categories. Then the pullback is introduced in terms of its universal property and the Pullback Lemma is formalized [15]. In the last part of the article we formalize the pullback of functors [14] and it is also shown that it is not possible to write an equivalent definition in the context of the previous Mizar formalization of category theory [8].

  10. Nucleoside phosphonic acids in thymidine phosphorylase inhibition: Structure - activity relationship

    Czech Academy of Sciences Publication Activity Database

    Panova, Natalya; Kóšiová, Ivana; Petrová, Magdalena; Vaněk, Václav; Liboska, Radek; Kovačková, Soňa; Kočalka, Petr; Králíková, Šárka; Točík, Zdeněk; Páv, Ondřej; Pačes, Ondřej; Rejman, Dominik; Rosenberg, Ivan

    -, č. 52 (2008), s. 665-666. ISSN 0261-3166. [Joint Symposium of the International Roundtable on Nucleosides, Nucleotides and Nucleic Acids /18./ and the International Symposium on Nucleic Acid Chemistry /35./. Kyoto, 08.09.2008-12.09.2008] R&D Projects: GA MŠk(CZ) LC06061; GA MŠk(CZ) LC06077; GA MŠk LC512 Institutional research plan: CEZ:AV0Z40550506 Keywords : thymidine phosphorylase * inhibitors * phosphonic acids Subject RIV: CC - Organic Chemistry

  11. Structure-Activity Relationship of Chlorotoxin-Like Peptides.

    Science.gov (United States)

    Ali, Syed Abid; Alam, Mehtab; Abbasi, Atiya; Undheim, Eivind A B; Fry, Bryan Grieg; Kalbacher, Hubert; Voelter, Wolfgang

    2016-02-01

    Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na⁺, K⁺, Ca⁺, Cl(-), etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7) has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae) venom. This peptide demonstrates 66% with chlorotoxin (ClTx) and 82% with CFTR channel inhibitor (GaTx1) sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca)/dinitrophenyl (Dnp) as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM), indicating the importance of this toxin in diseases associated with decreased MMP2 activity. PMID:26848686

  12. Structure-activity relationship of immunostimulatory effects of phthalates

    OpenAIRE

    Nielsen Gunnar D; Larsen Søren T

    2008-01-01

    Abstract Background Some chemicals, including some phthalate plasticizers, have been shown to have an adjuvant effect in mice. However, an adjuvant effect, defined as an inherent ability to stimulate the humoral immune response, was only observed after exposure to a limited number of the phthalates. An adjuvant effect may be due to the structure or physicochemical characteristics of the molecule. The scope of this study was to investigate which molecular characteristics that determine the obs...

  13. Structure-activity relationship of immunostimulatory effects of phthalates

    Directory of Open Access Journals (Sweden)

    Nielsen Gunnar D

    2008-10-01

    Full Text Available Abstract Background Some chemicals, including some phthalate plasticizers, have been shown to have an adjuvant effect in mice. However, an adjuvant effect, defined as an inherent ability to stimulate the humoral immune response, was only observed after exposure to a limited number of the phthalates. An adjuvant effect may be due to the structure or physicochemical characteristics of the molecule. The scope of this study was to investigate which molecular characteristics that determine the observed adjuvant effect of the most widely used phthalate plasticizer, the di-(2-ethylhexyl phthalate (DEHP, which is documented as having a strong adjuvant effect. To do so, a series of nine lipophilic compounds with structural and physicochemical relations to DEHP were investigated. Results Adjuvant effect of phthalates and related compounds were restricted to the IgG1 antibody formation. No effect was seen on IgE. It appears that lipophilicity plays a crucial role, but lipophilicity does not per se cause an adjuvant effect. In addition to lipophilicity, a phthalate must also possess specific stereochemical characteristics in order for it to have adjuvant effect. Conclusion The adjuvant effect of phthalates are highly influenced by both stereochemical and physico-chemical properties. This knowledge may be used in the rational development of plasticizers without adjuvant effect as well as in the design of new immunological adjuvants.

  14. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    Energy Technology Data Exchange (ETDEWEB)

    Rajagopal, Appavu; Deepa, Mohan [Molecular Biophysics Unit, Indian Institute of Sciences-Bangalore, Karnataka (India); Govindaraju, Munisamy [Bio-Spatial Technology Research Unit, Department of Environmental Biotechnology, School of Environmental Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu (India)

    2016-02-26

    While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”.

  15. Structure-activity-relationships (SAR) in pyrimidine nucleoside transport

    International Nuclear Information System (INIS)

    Several series of pyrimidine nucleosides were evaluated as part of a larger program to develop non-invasive brain imaging agents. The interaction of these antitumor/antiviral nucleosides with an NBMPR-sensitive murine erythroctye nucleoside transporter was evaluated by determining their inhibitory effect (Ki) on zero-trans influx of thymidine. Within each series of compounds, which had F, Cl, Br or I as halogen substituents, an increase in size of the halogen atom or a decrease in electronegativity decreased affinity for the transporter. Partition coefficients (P) of these pyrimidine nucleosides were measured to determine their potential to diffuse across the blood-brain-barrier (BBB). Most of the pyrimidine nucleosides had lower P values (log P i for nucleosides with a particular sugar moiety. Within a nucleoside series with a given sugar component, the binding affinity for the transporter was inversely proportional to lipophilicity. 25 refs., 2 tabs., 4 figs

  16. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    International Nuclear Information System (INIS)

    While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”

  17. Current trends in the structure-activity relationships of sialyltransferases.

    Science.gov (United States)

    Audry, Magali; Jeanneau, Charlotte; Imberty, Anne; Harduin-Lepers, Anne; Delannoy, Philippe; Breton, Christelle

    2011-06-01

    Sialyltransferases (STs) represent an important group of enzymes that transfer N-acetylneuraminic acid (Neu5Ac) from cytidine monophosphate-Neu5Ac to various acceptor substrates. In higher animals, sialylated oligosaccharide structures play crucial roles in many biological processes but also in diseases, notably in microbial infection and cancer. Cell surface sialic acids have also been found in a few microorganisms, mainly pathogenic bacteria, and their presence is often associated with virulence. STs are distributed into five different families in the CAZy database (http://www.cazy.org/). On the basis of crystallographic data available for three ST families and fold recognition analysis for the two other families, STs can be grouped into two structural superfamilies that represent variations of the canonical glycosyltransferase (GT-A and GT-B) folds. These two superfamilies differ in the nature of their active site residues, notably the catalytic base (a histidine or an aspartate residue). The observed structural and functional differences strongly suggest that these two structural superfamilies have evolved independently. PMID:21098518

  18. Structure-Activity Relationship of Chlorotoxin-Like Peptides

    Directory of Open Access Journals (Sweden)

    Syed Abid Ali

    2016-02-01

    Full Text Available Animal venom (e.g., scorpion is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na+, K+, Ca+, Cl−, etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7 has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae venom. This peptide demonstrates 66% with chlorotoxin (ClTx and 82% with CFTR channel inhibitor (GaTx1 sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca/dinitrophenyl (Dnp as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM, indicating the importance of this toxin in diseases associated with decreased MMP2 activity.

  19. Structure-activity relationships of new antiviral compounds.

    OpenAIRE

    Bonina, L; Orzalesi, G; Merendino, R; Arena, A; Mastroeni, P

    1982-01-01

    In preliminary experiments, the compound 2-amino-5-(2-sulfamoylphenyl)-1,3,4-thiadiazole (G413) was shown to possess high activity against DNA viruses (herpes simplex viruses 1 and 2 and adenovirus 17) and RNA viruses (poliovirus 1, echovirus 2, and coxsackievirus B4). Experiments on the replicative cycle of poliovirus 1 and production of infectious RNA viruses demonstrate that this compound probably prevents assembly of virus particles by acting on structural proteins. In the present experim...

  20. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    Directory of Open Access Journals (Sweden)

    Rajagopal Appavu

    2016-03-01

    Full Text Available While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”.

  1. Thapsigargin, origin, chemistry, structure-activity relationships and prodrug development

    DEFF Research Database (Denmark)

    Doan, Thi Quynh Nhu; Christensen, Søren Brøgger

    2015-01-01

    ) targeted against prostate cancer. Conjugation to a peptide, which only is a substrate for prostate specific membrane antigen enabled development of a prodrug (G202), which is targeted towards a number of cancer diseases including hepatocellular carcinoma. G202 has under the name of mipsagargin in clinical...

  2. Olfactory Discrimination Ability and Odor Structure Activity Relationships in Honeybees

    OpenAIRE

    Laska, Matthias; Galizia, Cosmas Giovanni; Giurfa, Martin; Menzel, Randolf

    1999-01-01

    Using the training procedure introduced by von Frisch in 1919, we tested the ability of free-flying honeybees to discriminate a conditioning odor from an array of 44 simultaneously presented substances. The stimuli included homologous series of aliphatic alcohols, aldehydes and ketones, isomeric forms of some of these substances, as well as several terpenes and odor mixtures, and thus comprised stimuli of varying degrees of structural similarity to any conditioning odor. We found (i) that the...

  3. Distributing Correlation Coefficients of Linear Structure-Activity/Property Models

    Directory of Open Access Journals (Sweden)

    Sorana D. BOLBOACA

    2011-12-01

    Full Text Available Quantitative structure-activity/property relationships are mathematical relationships linking chemical structure and activity/property in a quantitative manner. These in silico approaches are frequently used to reduce animal testing and risk-assessment, as well as to increase time- and cost-effectiveness in characterization and identification of active compounds. The aim of our study was to investigate the pattern of correlation coefficients distribution associated to simple linear relationships linking the compounds structure with their activities. A set of the most common ordnance compounds found at naval facilities with a limited data set with a range of toxicities on aquatic ecosystem and a set of seven properties was studied. Statistically significant models were selected and investigated. The probability density function of the correlation coefficients was investigated using a series of possible continuous distribution laws. Almost 48% of the correlation coefficients proved fit Beta distribution, 40% fit Generalized Pareto distribution, and 12% fit Pert distribution.

  4. Three-dimensional Quantitative Structure-activity Relationship of the Opioid Antagonist with Potent Anorectant Activity of 3,4-Dimethyl-4- (3-hydroxyphenyl)piperidine%类吗啡类拮抗物的结构与抑食活性的3D-QSAR研究

    Institute of Scientific and Technical Information of China (English)

    李华; 许禄; 苏锵

    2000-01-01

    A series of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated for their effect on food consumption in obese Zucker rats. In developing three-dimensional quantitative structure-activity relationship(3D-QSAR) studies for this series of opioid antagonists, different structure alignments have been tested to predict the anorectant activities.The interaction energies between molecules and the probe atom were then correlated with anorectant activity using partial least squares(PLS) method. The steric and electrostatic features of the 3D-QSAR were presented in the form of standard deviation coefficient contour maps of steric and electrostatic fields.The results showed that 3D-QSAR results are much better than the results obtained by 2D-QSAR.%用比较力场分析研究了3,4-二甲基-4-(3-羟基苯基)哌啶及其衍生物类吗啡拮抗物的结构与抑食活性的关系,考察了网格结构和探针原子的影响.结果表明,立体效应和静电作用场是描述其抑食活性和进行结构性能关系研究的最重要的结构参数.

  5. Categorical skew lattices

    CERN Document Server

    Kinyon, Michael

    2012-01-01

    Categorical skew lattices are a variety of skew lattices on which the natural partial order is especially well behaved. While most skew lattices of interest are categorical, not all are. They are characterized by a countable family of forbidden subalgebras. We also consider the subclass of strictly categorical skew lattices.

  6. Structure-activity relationships of lipopolysaccharide (LPS) in tumor necrosis factor-alpha (TNF-alpha) production and induction of macrophage cell death in the presence of cycloheximide (CHX) in a murine macrophage-like cell line, J774.1.

    Science.gov (United States)

    Karahashi, H; Amano, F

    1998-10-01

    The structure-activity relationships of lipopolysaccharide (LPS) in tumor necrosis factor-alpha (TNF-alpha) production and induction of macrophage cell death in the presence of cycloheximide (CHX) were examined in a murine macrophage-like cell line, J774.1. TNF-alpha production is one of the characteristic phenotypes of LPS-activated macrophages, and is observed upon incubation with LPS. On the contrary, macrophage cell death, which had been found in our laboratory (Amano F., Karahashi H., J. Endotoxin Res., 3, 415423 (1996)) and was examined as the release of lactate dehydrogenase (LDH) from cells into the culture supernatant, was observed 2.5 h after the addition of LPS in the presence of CHX. However, both TNF-alpha production and macrophage cell death were similarly dependent on the structures of LPS and lipid A. At more than 10 ng/ml, wild-type LPS from E.coli and S. minnesota exhibited the highest activity, and LPS as well as diphosphoryl lipid A from S. minnesota rough mutants also exhibited activity, but E. coli LPS detoxified by alkaline treatment or monophosphoryl lipid A from S. minnesota exhibited no activity even at 100 ng/ml. These results suggest that LPS-induced macrophage cell death in the presence of CHX shows similar requirements for LPS and/or lipid A structures as for the macrophage activation at higher doses than 10 ng/ml, although the former was not observed at 1 ng/ml LPS, while the latter was. However, TNF-alpha does not seem to be involved in the induction of macrophage cell death, because a neutralizing anti-TNF-alpha antibody failed to block the macrophage cell death and because recombinant TNF-alpha had little effect on the extent of LDH release in the presence or absence of LPS and/or CHX, and also because TNF-alpha production by LPS was abolished in the presence of CHX. PMID:9821819

  7. Categorization = Decision Making + Generalization

    OpenAIRE

    Seger, Carol A; Peterson, Erik J.

    2013-01-01

    We rarely, if ever, repeatedly encounter exactly the same situation. This makes generalization crucial for real world decision making. We argue that categorization, the study of generalizable representations, is a type of decision making, and that categorization learning research would benefit from approaches developed to study the neuroscience of decision making. Similarly, methods developed to examine generalization and learning within the field of categorization may enhance decision making...

  8. Categorizing Video Game Audio

    DEFF Research Database (Denmark)

    Westerberg, Andreas Rytter; Schoenau-Fog, Henrik

    2015-01-01

    This paper dives into the subject of video game audio and how it can be categorized in order to deliver a message to a player in the most precise way. A new categorization, with a new take on the diegetic spaces, can be used a tool of inspiration for sound- and game-designers to rethink how...... they can use audio in video games. The conclusion of this study is that the current models' view of the diegetic spaces, used to categorize video game audio, is not t to categorize all sounds. This can however possibly be changed though a rethinking of how the player interprets audio....

  9. Estudo da relação estrutura-atividade de saponinas hemolíticas e/ou imunoadjuvantes mediante uso de análise multivariada Study of the structure-activity relationship of adjuvant and/or hemolytic saponins by use of multivariate analysis

    Directory of Open Access Journals (Sweden)

    Samuel Kaiser

    2010-07-01

    Full Text Available Entre as diversas atividades biológicas relatadas para as saponinas, merecem destaque aquelas relacionadas ao aumento da resposta imune e a ruptura das membranas dos eritrócitos. No desenvolvimento de vacinas, ambas as propriedades exercem atividades antagônicas, contudo, as informações sobre as relações estrutura-atividade são relativamente escassas e, às vezes, conflitantes. O presente trabalho visa contribuir no estabelecimento das relações estruturais envolvidas com as atividades imunoadjuvante e hemolítica de saponinas triterpênicas. Para isso, foram selecionadas vinte saponinas de estrutura triterpênica, isoladas das espécies Aesculus hippocastanum, Dolichos lablab e Glycine max. A relação entre grupamentos substituintes do anel triterpênico e as atividades biológicas foi estudada mediante análise de agrupamentos e análise de componentes principais. Os resultados confirmam a importância da presença de açúcares em C-3 para a atividade hemolítica. Porém o efeito causado pela presença de uma hidroxila em C-16, de CH2OH em C-17, de uma acetila em C-22 e de um grupamento acila em C-21 sobre essa atividade parece ser mais acentuado. Já a presença de uma hidroxila em C-21, de uma metila em C-17 e de dois açúcares ligados à aglicona parece ser determinante para a atividade imunoadjuvante. Além disso, observa-se a existência de uma relação inversa entre as atividades hemolítica e imunoadjuvante.Among the various biological activities reported for saponins, those related with increase immune response and the destruction of the membrane of red blood cells deserve attention. In the development of vaccines, these properties exert antagonistic activities. However, the information about the structure-activity relationships is relatively scarce and sometimes contradictory. This paper aims to contribute to the establishment of structural relations involved with the hemolytic and adjuvant activities of triterpenic

  10. Categorical Pairs and the Indicative Shift

    OpenAIRE

    Kauffman, Louis H.

    2011-01-01

    This paper introduces the notion of a categorical pair, a pair of categories (C,C') such that every morphism in C is an object in C'. Categorical pairs are precursors to 2-categories. Arrows in C' can express relationships among the morphisms of C. In particular we show that by using a model of the linguistic process of naming, we can ensure that every morphism in C has an indirect self-reference of the form a -----> Fa where this arrow occurs in the category C'. This result is shown to gener...

  11. Learning Context for Text Categorization

    CERN Document Server

    Haribhakta, Y V

    2011-01-01

    This paper describes our work which is based on discovering context for text document categorization. The document categorization approach is derived from a combination of a learning paradigm known as relation extraction and an technique known as context discovery. We demonstrate the effectiveness of our categorization approach using reuters 21578 dataset and synthetic real world data from sports domain. Our experimental results indicate that the learned context greatly improves the categorization performance as compared to traditional categorization approaches.

  12. Ignorability for categorical data

    DEFF Research Database (Denmark)

    Jaeger, Manfred

    2005-01-01

    We study the problem of ignorability in likelihood-based inference from incomplete categorical data. Two versions of the coarsened at random assumption (car) are distinguished, their compatibility with the parameter distinctness assumption is investigated and several conditions for ignorability...

  13. Structure-Activity Association of Flavonoids in Lung Diseases

    Directory of Open Access Journals (Sweden)

    João Henrique G. Lago

    2014-03-01

    Full Text Available Flavonoids are polyphenolic compounds classified into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones according to their chemical structures. They are abundantly found in Nature and over 8,000 flavonoids have from different sources, mainly plant materials, have been described. Recently reports have shown the valuable effects of flavonoids as antiviral, anti-allergic, antiplatelet, antitumor, antioxidant, and anti-inflammatory agents and interest in these compounds has been increasing since they can be helpful to human health. Several mechanisms of action are involved in the biological properties of flavonoids such as free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and modulation of inflammatory responses. The anti-inflammatory effects of flavonoids have been described in a number of studies in the literature, but not frequently associated to respiratory disease. Thus, this review aims to discuss the effects of different flavonoids in the control of lung inflammation in some disorders such as asthma, lung emphysema and acute respiratory distress syndrome and the possible mechanisms of action, as well as establish some structure-activity relationships between this biological potential and chemical profile of these compounds.

  14. Categorical Database Generalization

    Institute of Scientific and Technical Information of China (English)

    LIU Yaolin; Martin Molenaar; AI Tinghua; LIU Yanfang

    2003-01-01

    This paper focuses on the issues of categorical database gen-eralization and emphasizes the roles ofsupporting data model, integrated datamodel, spatial analysis and semanticanalysis in database generalization.The framework contents of categoricaldatabase generalization transformationare defined. This paper presents an in-tegrated spatial supporting data struc-ture, a semantic supporting model andsimilarity model for the categorical da-tabase generalization. The concept oftransformation unit is proposed in generalization.

  15. Speech perception as categorization

    OpenAIRE

    Holt, Lori L.; Lotto, Andrew J.

    2010-01-01

    Speech perception (SP) most commonly refers to the perceptual mapping from the highly variable acoustic speech signal to a linguistic representation, whether it be phonemes, diphones, syllables, or words. This is an example of categorization, in that potentially discriminable speech sounds are assigned to functionally equivalent classes. In this tutorial, we present some of the main challenges to our understanding of the categorization of speech sounds and the conceptualization of SP that has...

  16. Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Wender A.; Andrade, Carlos Kleber Z.; Napolitano, Hamilton B., E-mail: wender@unb.br, E-mail: ckleber@unb.br [Universidade de Brasilia (LaQMOS/UnB), DF (Brazil). Inst. de Quimica; Vencato, Ivo; Castro, Miriam R.C. de; Camargo, Ademir J. [Universidade Estadual de Goias (UEG), Anapolis, GO (Brazil). Ciencias Exatas e Tecnologicas; Lariucci, Carlito [Universidade Estadual de Goias (UEG), Goiania, GO (Brazil). Inst. de Fisica

    2013-01-15

    The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structure activity relationship. (author)

  17. Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

    International Nuclear Information System (INIS)

    The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structure activity relationship. (author)

  18. Research of Web Pages Categorization

    Institute of Scientific and Technical Information of China (English)

    Zhongda Lin; Kun Deng; Yanfen Hong

    2006-01-01

    In this paper, we discuss several issues related to automated classification of web pages, especially text classification of web pages. We analyze features selection and categorization algorithms of web pages and give some suggestions for web pages categorization.

  19. Categorization of radiation sources

    International Nuclear Information System (INIS)

    The objective of this report is to develop a categorization scheme for radiation sources that could be relevant to decisions both in a retrospective application to bring sources under control and in a prospective sense to guide the application of the regulatory infrastructure. The Action Plan envisages that the preparation of guidance on national strategies and programmes for the detection and location of orphan sources and their subsequent management should commence after the categorization of sources has been carried out. In the prospective application of the system of notification, registration, and licensing, the categorization is relevant to prioritize a regulatory authority's resources and training activities; to guide the degree of detail necessary for a safety assessment; and to serve as a measure of the intensity of effort which a regulatory authority should apply to the safety and security of a particular type of source

  20. Categorical Pairs and the Indicative Shift

    CERN Document Server

    Kauffman, Louis H

    2011-01-01

    This paper introduces the notion of a categorical pair, a pair of categories (C,C') such that every morphism in C is an object in C'. Categorical pairs are precursors to 2-categories. Arrows in C' can express relationships among the morphisms of C. In particular we show that by using a model of the linguistic process of naming, we can ensure that every morphism in C has an indirect self-reference of the form a -----> Fa where this arrow occurs in the category C'. This result is shown to generalize and clarify known fixed point theorems in logic and categories, and is applied to Goedel's Incompleteness Theorem, the Cantor Diagonal Process and the Lawvere Fixed Point Theorem. In particular we show that the indirect self-reference that is central to Goedel's Theorem is an instance of a general pattern here called the indicative shift.

  1. Visual Search and the Collapse of Categorization

    Science.gov (United States)

    David, Smith, J.; Redford, Joshua S.; Gent, Lauren C.; Washburn, David A.

    2005-01-01

    Categorization researchers typically present single objects to be categorized. But real-world categorization often involves object recognition within complex scenes. It is unknown how the processes of categorization stand up to visual complexity or why they fail facing it. The authors filled this research gap by blending the categorization and…

  2. Learning Context for Text Categorization

    OpenAIRE

    Haribhakta, Y. V.; Parag Kulkarni

    2011-01-01

    This paper describes our work which is based on discovering context for text document categorization. The document categorization approach is derived from a combination of a learning paradigm known as relation extraction and an technique known as context discovery. We demonstrate the effectiveness of our categorization approach using reuters 21578 dataset and synthetic real world data from sports domain. Our experimental results indicate that the learned context greatly improves t...

  3. Humanizing Outgroups Through Multiple Categorization

    OpenAIRE

    Prati, Francesca; Crisp, Richard J.; Meleady, Rose; Rubini, Monica

    2016-01-01

    In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the o...

  4. Statistical Scaling of Categorical Data

    OpenAIRE

    Läuter, Henning; Ramadan, Ayad

    2011-01-01

    Estimation and testing of distributions in metric spaces are well known. R.A. Fisher, J. Neyman, W. Cochran and M. Bartlett achieved essential results on the statistical analysis of categorical data. In the last 40 years many other statisticians found important results in this field. Often data sets contain categorical data, e.g. levels of factors or names. There does not exist any ordering or any distance between these categories. At each level there are measured some metric or categorical v...

  5. Analysis of Ordinal Categorical Data

    CERN Document Server

    Agresti, Alan

    2012-01-01

    Statistical science's first coordinated manual of methods for analyzing ordered categorical data, now fully revised and updated, continues to present applications and case studies in fields as diverse as sociology, public health, ecology, marketing, and pharmacy. Analysis of Ordinal Categorical Data, Second Edition provides an introduction to basic descriptive and inferential methods for categorical data, giving thorough coverage of new developments and recent methods. Special emphasis is placed on interpretation and application of methods including an integrated comparison of the available st

  6. Students' Categorizations of Organic Compounds

    Science.gov (United States)

    Domin, Daniel S.; Al-Masum, Mohammad; Mensah, John

    2008-01-01

    Categorization is a fundamental psychological ability necessary for problem solving and many other higher-level cognitive tasks. In organic chemistry, students must establish groupings of different chemical compounds in order not only to solve problems, but also to understand course content. Classic models of categorization emphasize similarity as…

  7. The Chinese Text Categorization System with Category Priorities

    Directory of Open Access Journals (Sweden)

    Huan-Chao Keh

    2010-10-01

    Full Text Available The process of text categorization involves some understanding of the content of the documents and/or some previous knowledge of the categories. For the content of the documents, we use a filtering measure for feature selection in our Chinese text categorization system. We modify the formula of Term Frequency-Inverse Document Frequency (TF-IDF to strengthen important keywords’ weights and weaken unimportant keywords’ weights. For the knowledge of the categories, we use category priority to represent the relationship between two different categories. Consequently, the experimental results show that our method can effectively not only decrease noise text but also increase the accuracy rate and recall rate of text categorization.

  8. Categorization of Radioxenon

    Energy Technology Data Exchange (ETDEWEB)

    Keller, Paul E.

    2012-04-26

    This report summarizes a study into some false positive issues in the use of radioxenon as a method to verify a clandestine nuclear weapons explosion. False positives arise due to similarities between the radioxenon signature generated in medical isotope production and that generated in a nuclear weapon explosion. This report also discusses how to categorize the radioxenon by levels of urgency for manual analysis and interpretation and recommends applying machine learning and time series analysis techniques in the automation of radioxenon characterization. The literature indicates that medical isotope production is a major contributor to atmospheric radioxenon and is the main source of confusion in determining the source of radioxenon. While radioxenon emissions from nuclear power plants can be distinguished from that from nuclear weapon explosions, emissions from medical isotope production generate signatures similar to certain nuclide ratios found in nuclear weapons explosions. Different techniques for analyzing nuclide concentrations and ratios as well as including other sensing modalities via sensor fusion are discussed.

  9. Chlorotoxin: Structure, activity, and potential uses in cancer therapy.

    Science.gov (United States)

    Ojeda, Paola G; Wang, Conan K; Craik, David J

    2016-01-01

    Chlorotoxin is a disulfide-rich stable peptide from the venom of the Israeli scorpion Leiurus quinquestriatus, which has potential therapeutic applications in the treatment of cancer. Its ability to preferentially bind to tumor cells has been harnessed to develop an imaging agent to help visualize tumors during surgical resection. In addition, chlorotoxin has attracted interest as a vehicle to deliver anti-cancer drugs specifically to cancer cells. Given its interesting structural and biological properties, chlorotoxin also has the potential to be used in a variety of other biotechnology and biomedical applications. Here, we review the structure, activity and potential applications of chlorotoxin as a drug design scaffold. PMID:26418522

  10. Humanizing Outgroups Through Multiple Categorization

    Science.gov (United States)

    Prati, Francesca; Crisp, Richard J.; Meleady, Rose; Rubini, Monica

    2016-01-01

    In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the outgroup and reduced outgroup threat. Study 3 replicated this sequential mediation model and introduced a novel way of measuring humanization in which participants generated attributes corresponding to the outgroup in a free response format. Participants generated more uniquely human traits in the multiple versus simple categorization conditions. We discuss the theoretical implications of these findings and consider their role in informing and improving efforts to ameliorate contemporary forms of intergroup discrimination. PMID:26984016

  11. Categorization in the Affective Domain

    DEFF Research Database (Denmark)

    Sauciuc, Gabriela-Alina

    2011-01-01

    Data collected in Romance and Scandinavian languages (N=474) in a superordinate category name production task indicate that a multiple-strategy approach would be more suitable for accounting of categorization in the affective domain instead of a prototype approach as suggested by previous studies....... This paper will highlight performance aspects which appear to be consistent with such an interpretation, as well as an important layman- expert knowledge asymmetry in affective categorization....

  12. Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies.

    Science.gov (United States)

    Bach, Anders; Pizzirani, Daniela; Realini, Natalia; Vozella, Valentina; Russo, Debora; Penna, Ilaria; Melzig, Laurin; Scarpelli, Rita; Piomelli, Daniele

    2015-12-10

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads. PMID:26560855

  13. Quantitative structure activity relationship and risk analysis of some pesticides in the goat milk

    OpenAIRE

    Faqir Muhammad; Mian Muhammad Awais; Masood Akhtar; Muhammad Irfan Anwar

    2013-01-01

    The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean+/-SEM levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34+/-0.007, 0.063+/-0.002, 0.034+/-0.002 and 0.092+/-0.002, respectively; whereas, methyl parathion was not detected in an...

  14. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    International Nuclear Information System (INIS)

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

  15. Chemistry and Structure-Activity Relationship of the Styrylquinoline-Type HIV Integrase Inhibitors

    OpenAIRE

    Didier Desmaële; Jean-François Mouscadet

    2010-01-01

    In spite of significant progress in anti-HIV-1 therapy, current antiviral chemo-therapy still suffers from deleterious side effects and emerging drug resistance. Therefore, the development of novel antiviral drugs remains a crucial issue for the fight against AIDS. HIV-1 integrase is a key enzyme in the replication cycle of the retrovirus since it catalyzes the integration of the reverse transcribed viral DNA into the chromosomal DNA. Efforts to develop anti-integrase drugs started during the...

  16. Synthesis and structure-activity relationship of vicenistatin, a cytotoxic 20-membered macrolactam glycoside.

    Science.gov (United States)

    Fukuda, Hayato; Nishiyama, Yuko; Nakamura, Shiina; Ohno, Yutaro; Eguchi, Tadashi; Iwabuchi, Yoshiharu; Usui, Takeo; Kanoh, Naoki

    2012-12-01

    We have developed two syntheses of vicenistatin and its analogues. Our first-generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner-Wadsworth-Emmons reaction between the C3-C13 fragment and the C1-C2, C14-C19 fragment, followed by an intramolecular Stille coupling reaction. The second-generation strategy utilized a ring-closing metathesis of a hexaene intermediate to generate the desired 20-membered macrolactam. This second-generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20- and/or C23-demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins. PMID:23015368

  17. Inactivation of leukocyte elastase by aryl azolides and sulfonate salts. Structure-activity relationship studies.

    Science.gov (United States)

    Groutas, W C; Brubaker, M J; Zandler, M E; Mazo-Gray, V; Rude, S A; Crowley, J P; Castrisos, J C; Dunshee, D A; Giri, P K

    1986-07-01

    The inhibitory activity of a series of aryl azolides and sulfonate salts toward human leukocyte elastase is reported. Several of the compounds were found to be potent inhibitors of the enzyme. Active compounds were obtained only when the specificity group and the reactive moiety were separated by a two-carbon chain. The introduction of hydrophobic groups enhanced the inhibitory activity of these compounds, with the exception of the sulfonate salts. The nature of the leaving group had a profound effect on inhibitory activity, with compounds 23 and 26 being the most active (kobsd/[I] = 11,722 and 13,500 M-1 s-1, respectively). PMID:3643283

  18. Structure-activity relationship of aliphatic mono- and di-N-oxides: their radical scavenging abilities

    Czech Academy of Sciences Publication Activity Database

    Krasowska, A.; Murzyn, A.; Piasecki, A.; Sigler, Karel

    Poland: Polish Biochemical Society, 2006, s. 130-130. [Meeting of the Polish Biochemical Society /41./. Bialystok (PL), 12.09.2006-15.09.2006] R&D Projects: GA MŠk 1M0570 Grant ostatní: Polsko(PL) 3T09B 075 27 Institutional research plan: CEZ:AV0Z50200510 Keywords : plasma membrane * peroxyl radicals Subject RIV: EE - Microbiology, Virology

  19. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

    DEFF Research Database (Denmark)

    Bach, Anders

    2015-01-01

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may...... be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We...... administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads....

  20. Structure-Activity Relationships for DNA Damage by Alkenylbenzenes in Turkey Egg Fetal Liver.

    Science.gov (United States)

    Kobets, Tetyana; Duan, Jian-Dong; Brunnemann, Klaus D; Etter, Sylvain; Smith, Benjamin; Williams, Gary M

    2016-04-01

    Certain alkenylbenzenes (AB), flavoring chemicals naturally occurring in spices and herbs, are established to be cytotoxic and hepatocarcinogenic in rodents. The purpose of the present study was to determine the DNA damaging potential of key representatives of this class using the Turkey Egg Genotoxicity Assay. Medium white turkey eggs with 22- to 24-day-old fetuses received three injections of nine AB with different carcinogenic potentials: safrole (1, 2 mg/egg), methyl eugenol (2, 4 mg/egg), estragole (20, 40 mg/egg), myristicin (25, 50 mg/egg), elemicin (20, 50 mg/egg), anethole (5, 10 mg/egg), methyl isoeugenol (40, 80 mg/egg), eugenol (1, 2.5 mg/egg), and isoeugenol (1, 4 mg/egg). Three hours after the last injection, fetal livers were harvested for measurement of DNA strand breaks, using the comet assay and DNA adducts formation, using the nucleotide(3) (2)P-postlabeling assay. Estragole, myristicin, and elemicin induced DNA stand breaks. These compounds as well as safrole, methyl eugenol and anethole, at the highest doses tested, induced DNA adduct formation. Methyl isoeugenol, eugenol, and isoeugenol did not induce genotoxicity. The genotoxic AB all had the structural features of either a double bond in the alkenyl side chain at the terminal 2',3'-position, favorable to formation of proximate carcinogenic 1'-hydroxymetabolite or terminal epoxide, or the absence of a free phenolic hydroxyl group crucial for formation of a nontoxic glucuronide conjugate. In contrast, methyl isoeugenol, eugenol and isoeugenol, which were nongenotoxic, possessed chemical features, unfavorable to activation. PMID:26719370

  1. Diversity, Antimicrobial Action and Structure-Activity Relationship of Buffalo Cathelicidins.

    Directory of Open Access Journals (Sweden)

    Biswajit Brahma

    Full Text Available Cathelicidins are an ancient class of antimicrobial peptides (AMPs with broad spectrum bactericidal activities. In this study, we investigated the diversity and biological activity of cathelicidins of buffalo, a species known for its disease resistance. A series of new homologs of cathelicidin4 (CATHL4, which were structurally diverse in their antimicrobial domain, was identified in buffalo. AMPs of newly identified buffalo CATHL4s (buCATHL4s displayed potent antimicrobial activity against selected Gram positive (G+ and Gram negative (G- bacteria. These peptides were prompt to disrupt the membrane integrity of bacteria and induced specific changes such as blebing, budding, and pore like structure formation on bacterial membrane. The peptides assumed different secondary structure conformations in aqueous and membrane-mimicking environments. Simulation studies suggested that the amphipathic design of buCATHL4 was crucial for water permeation following membrane disruption. A great diversity, broad-spectrum antimicrobial action, and ability to induce an inflammatory response indicated the pleiotropic role of cathelicidins in innate immunity of buffalo. This study suggests short buffalo cathelicidin peptides with potent bactericidal properties and low cytotoxicity have potential translational applications for the development of novel antibiotics and antimicrobial peptidomimetics.

  2. Perovskite-supported palladium for methane oxidation - structure-activity relationships.

    Science.gov (United States)

    Eyssler, Arnim; Lu, Ye; Matam, Santhosh Kumar; Weidenkaff, Anke; Ferri, Davide

    2012-01-01

    Palladium is the precious metal of choice for methane oxidation and perovskite-type oxides offer the possibility to stabilize it as PdO, considered crucial for catalytic activity. Pd can adopt different oxidation and coordination states when associated with perovskite-type oxides. Here, we review our work on the effect of perovskite composition on the oxidation and coordination states of Pd and its influence on catalytic activity for methane oxidation in the case of typical Mn, Fe and Co perovskite-based oxidation catalysts. Especially X-ray absorption near edge structure (XANES) spectroscopy is shown to be crucial to fingerprint the different coordination states of Pd. Pd substitutes Fe and Co in the octahedral sites but without modifying catalytic activity with respect to the Pd-free perovskite. On LaMnO(3) palladium is predominantly exposed at the surface thus bestowing catalytic activity for methane oxidation. However, the occupancy of B-cation sites of the perovskite structure by Pd can be exploited to cyclically activate Pd and to protect it from particle growth. This is explicitly demonstrated for La(Fe, Pd)O(3), where catalytic activity for methane oxidation is enhanced under oscillating redox conditions at 500 °C, therefore paving the way to the practical application in three-way catalysts for stoichiometric natural gas engines. PMID:23211725

  3. Structure-Activity Relationship Investigation of Some New Tetracyclines by Electronic Index Methodology

    CERN Document Server

    Sato, Fernando; Santos, Helio F dos; Galvao, Douglas S

    2007-01-01

    Tetracyclines are an old class of molecules that constitute a broad-spectrum antibiotics. Since the first member of tetracycline family were isolated, the clinical importance of these compounds as therapeutic and prophylactic agents against a wide range of infections has stimulated efforts to define their mode of action as inhibitors of bacterial reproduction. We used three SAR methodologies for the analysis of biological activity of a set of 104 tetracycline compounds. Our calculation were carried out using the semi-empirical Austin Method One (AM1) and Parametric Method 3 (PM3). Electronic Indices Methodology (EIM), Principal Component Analysis (PCA) and Artificial Neural Networks (ANN) were applied to the classification of 14 old and 90 new proposed derivatives of tetracyclines. Our results make evident the importance of EIM descriptors in pattern recognition and also show that the EIM can be effectively used to predict the biological activity of Tetracyclines.

  4. Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.

    Science.gov (United States)

    Kawatkar, S P; Gagnon, M; Hoesch, V; Tiong-Yip, C; Johnson, K; Ek, M; Nilsson, E; Lister, T; Olsson, L; Patel, J; Yu, Q

    2016-07-15

    Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections. PMID:27265257

  5. The Role of the Protein Corona in Fiber Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Melanie Kucki

    2014-06-01

    Full Text Available When nanomaterials enter biological fluids, they are immediately covered by biomolecules, particularly proteins, forming the so-called protein corona. The dynamic nature and complexity of the protein corona can impact upon the biological effects and distribution of nanomaterials with an organism. Therefore, the protein corona is an important factor in determining the biological impact of any nanomaterials. The protein adsorption pattern is determined by various factors, including the bio-fluids’ protein composition, the nanomaterials’ physicochemical properties, as well as the time and type of exposure. Predominantly, research has focused upon spherical nano-objects, however, due to their ever-increasing potential use within human based applications, and, therefore, heightening and inevitable exposure to the human body, little is known regarding how proteins interact with nanofibers. Therefore, the present review focuses on the current knowledge as to how the geometry of man-made (nanofibers, carbon nanotubes (in comparison with asbestos fibers, affects their interaction with proteins within biological fluids. Summarizing state-of the art methodologies applied to dissect protein-binding signatures, it is further discussed whether the protein corona composition of fibrous and non-fibrous materials differ, as well as what impact the protein corona has on (nanofiber uptake, intracellular distribution and their subsequent toxicity.

  6. Hemoglobin binding of arylamines and nitroarenes: molecular dosimetry and quantitative structure-activity relationships.

    OpenAIRE

    Sabbioni, G

    1994-01-01

    N-Oxidation and nitroreduction to yield N-hydroxyarylamines are metabolic steps that are crucial for the genotoxic properties of aromatic amines and nitroarenes, respectively. N-Hydroxyarylamines can form adducts with DNA, tissue proteins, and the blood proteins albumin and hemoglobin in a dose-dependent manner. The determination of hemoglobin adducts is a useful tool for biomonitoring exposed populations. We have established the hemoglobin binding index (HBI) [(mmole compound/mole Hb)/(mmole...

  7. Antiviral and Quantitative Structure Activity Relationship Study for Dihydropyridones Derived from Curcumin

    Directory of Open Access Journals (Sweden)

    Bahjat A. Saeed

    2010-01-01

    Full Text Available Problem statement: Pyridones are known to have variety of biological activities like antitumor, antibacterial, anti-inflammatory and antimalarial activities. This study presents antiviral evaluation of dihydropyridones derived from curcumin, as well as curcumin for comparison. Approach: The compounds evaluated for their in vitro antiviral activities against the viruses: HIV-1, Bovin viral Diarrhea, Yellow Fever, Reovirus 1, Herpesvirus 1, Vaccinia, Vescular Stomatitis, Coxackie virus B2, Poliovirus 1 and Respiratory Syncytial viruses by using Microculture Tetrazolium assay (MTT method. The method was based on the metabolic reduction of 3-(4,5-dimethylthiazol-2- yl-2,5-diphenyltetrazolium bromide. Results: Antiviral biological activities represented as CC50 were within the range >100-26 for BHK-21, while they were within the range >90-≥13 against Respiratory Syncytial Virus when represented as EC50 for example. Both CC50 and EC50 values were found to increase with increasing chain length of the substituent on the nitrogen atom. Conclusion: The in vitro antiviral activities of the tested dihydropyridones can be enhanced by increasing chain length of the substituent on the nitrogen atom.

  8. Studies on the Quantitative Structure-activity Relationship of Substituted Biphenyls by Density Function Theory (DFT)

    Institute of Scientific and Technical Information of China (English)

    HAN Xiang-Yun; ZHENG Qing

    2007-01-01

    Geometrical configurations of 16 substituted biphenyls were computed at the B3LYP/6-311G** level with Gaussian 98 program. Based on linear solvation energy theory, lgKow as well as the structural and thermodynamic parameters obtained at this level was taken as theoretical descriptors, and corresponding equation predicting the toxicity of Daphnia magna (-lgEC50)was thus obtained, in which three parameters were contained, i.e., n-octanol/water partition coefficients (lgKow), dipole moment of the molecules (μ) and entropy (S°). For this equation, R2 =0.9582, q2 = 0.8921 and SD = 0.102. The absolute t-scores of three variables are larger than the standard one in the confidence range of 95%, which confirms the creditability and stability of this model.

  9. The Structure-Activity Relationship of an Ozonide Carboxylic Acid (OZ78) Against Fasciola hepatica

    OpenAIRE

    Zhao, Qingjie; Vargas, Mireille; Dong, Yuxiang; ZHOU, Lin; Wang, Xiaofang; Sriraghavan, Kamaraj; Keiser, Jennifer; Vennerstrom, Jonathan L.

    2010-01-01

    In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of twenty-six new compounds administered at single 100 mg/kg oral doses to F. hepatica-in...

  10. Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

    Science.gov (United States)

    Zhao, Qingjie; Vargas, Mireille; Dong, Yuxiang; Zhou, Lin; Wang, Xiaofang; Sriraghavan, Kamaraj; Keiser, Jennifer; Vennerstrom, Jonathan L

    2010-05-27

    In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatica. PMID:20423101

  11. Structure-activity relationships in the hydrolysis of substrates by the phosphotriesterase from Pseudomonas diminuta

    International Nuclear Information System (INIS)

    The mechanism and substrate specificity of the phosphotriesterase from Pseudomonas diminuta have been examined. The enzyme hydrolyzes a large number of phosphotriester substrates in addition to paraoxon (diethyl p-nitrophenyl phosphate) and its thiophosphate analogue, parathion. The two ethyl groups in paraoxon can be changed to propyl and butyl groups, but the maximal velocity and Km values decrease substantially. The enzyme will not hydrolyze phosphomonoesters or -diesters. There is a linear correlation between enzymatic activity and the pKa of the phenolic leaving group for 16 paraoxon analogues. The beta value in the corresponding Bronsted plot is -0.8. No effect on either Vmax or Vmax/Km is observed when sucrose is used to increase the relative solvent viscosity by 3-fold. These results are consistent with rate-limiting phosphorus-oxygen bond cleavage. A plot of log V versus pH for the hydrolysis of paraoxon shows one enzymatic group that must be unprotonated for activity with a pKa of 6.1. The deuterium isotope effect by D2O on Vmax and Vmax/Km is 2.4 and 1.2, respectively, and the proton inventory is linear, which indicates that only one proton is in flight during the transition state. The inhibition patterns by the products are consistent with a random kinetic mechanism

  12. Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship

    Czech Academy of Sciences Publication Activity Database

    Agarwal, Ch.; Wadhwa, R.; Deep, G.; Biedermann, David; Gažák, Radek; Křen, Vladimír; Agarwal, R.

    2013-01-01

    Roč. 8, č. 3 (2013), e00074. E-ISSN 1932-6203 R&D Projects: GA MŠk(CZ) ME10027 Institutional support: RVO:61388971 Keywords : Silybin * silibinin * anti-cancer efficacy Subject RIV: CE - Biochemistry Impact factor: 3.534, year: 2013

  13. Synthesis, biological activities and structure-activity relationships for new avermectin analogues.

    Science.gov (United States)

    Zhang, Jian; Nan, Xiang; Yu, Hai-Tao; Cheng, Pi-Le; Zhang, Yan; Liu, Ying-Qian; Zhang, Shao-Yong; Hu, Guan-Fang; Liu, Huanxiang; Chen, An-Liang

    2016-10-01

    In an effort to discover new molecules with good insecticidal activities, more than 40 new avermectin derivatives were synthesized and evaluated for their biological activities against three species of arachnids, insects and nematodes, namely, Tetranychus Cinnabarinus, Aphis craccivora and Bursaphelenchus xylophilus. All the tested compounds showed potent inhibitory activities against three insect species. Notably, the majority of compounds exhibited high selectivity against T. cinnabarinus, some of which were much better in comparison with avermectin. Especially compounds 9j (LC50: 0.005 μM) and 16d (LC50: 0.002 μM) were 2.5- and 4.7-fold more active than avermectin (LC50: 0.013 μM), respectively, against T. cinnabarinus. Moreover, compounds 9b, 9d-f, 9h, 9j, 9l, 9n, 9p, 9r, 9v and 17d showed superior activities with LC50 values of 2.959-5.013 μM compared to that of 1 (LC50: 6.746 μM) against B. xylophilus. Meanwhile, the insecticidal activities of compounds 9f, 9g, 9h, and 9m against A. craccivora were 7-8 times better than that of avermectin, with LC50 values of 7.744, 5.634, 6.809, 7.939 and 52.234 μM, respectively. Furthermore, QSAR analysis showed that the molecular shape, size, connectivity degree and electronic distribution of avermectin analogues had substantial effects on insecticidal potency. These preliminary results provided useful insight in guiding further modifications of avermectin in the development of potential new insecticides. PMID:27318119

  14. Quantitative structure-activity relationship of estrogen activities of bisphenol A analogs

    Institute of Scientific and Technical Information of China (English)

    CUI Shihai; LIU Shushen; YANG Jing; WANG Xiaodong; WANG Liansheng

    2006-01-01

    The molecular electronegativity-distance vector (MEDV) is employed to describe the chemical structure of bisphenol A analogs and their correlated estrogen activities. The result shows that the constructed models have good predictability and indicates substructures that may influence estrogen activities of chemicals.

  15. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    OpenAIRE

    Ligia Guerrero; Julián Castillo; Mar Quiñones; Santiago Garcia-Vallvé; Lluis Arola; Gerard Pujadas; Begoña Muguerza

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric metho...

  16. Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.

    Science.gov (United States)

    Arias, Hugo R; Feuerbach, Dominik; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof

    2011-09-01

    The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca²⁺ influx in human embryonic muscle AChRs with the following potency sequence (IC(50) in μM): (±)-18-methylaminocoronaridine (5.9±0.3)∼(±)-18-methoxycoronaridine (18-MC) (6.8±0.8)>(-)-ibogaine (17±3)∼(+)-catharanthine (20±1)>(±)-albifloranine (46±13), (b) bind to the [³H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [³H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [³H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC₅₀) that correlate very well with the pK(i) values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 ų for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization. PMID:21642011

  17. Structure-activity relationships in aminosterol antibiotics: the effect of stereochemistry at the 7-OH group.

    Science.gov (United States)

    Tessema, Tsemre-Dingel; Gassler, Frank; Shu, Youheng; Jones, Stephen; Selinsky, Barry S

    2013-06-01

    Squalamine and three aminosterol analogs have been shown to inhibit bacterial cell growth and induce lysis of large unilamellar phospholipid vesicles. The analogs differ in the identity of the polyamine attached at C3 of the sterol, and the stereochemistry of a hydroxyl substituent at C7. Analogs with a tetraammonium spermine polyamine are somewhat more active than analogs with a shorter trisammonium spermidine polyamine, and analogs with an axial (α) hydroxyl substituent at C7 are more active than analogs with the corresponding equatorial (β) hydroxyl group. There is some variability noted; the 7β-OH spermine analog is the most active compound against Escherichia coli, but the least effective against Pseudomonas aeruginosa. Lytic activity correlates well with antimicrobial activity of the compounds, but the lytic activity varies with the phospholipid composition of the vesicles. PMID:23618624

  18. A Class of Promising Acaricidal Tetrahydroisoquinoline Derivatives: Synthesis, Biological Evaluation and Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Rui Yang

    2014-06-01

    Full Text Available As part of our continuing research on isoquinoline acaricidal drugs, this paper reports the preparation of a series of the 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines with various substituents on the N-phenyl ring, their in vitro acaricidal activities against Psoroptes cuniculi, a mange mite, and discusses their SAR as well. The structures of all compounds, including 12 new ones, were elucidated by analysis of UV, IR, NMR, ESI-MS, HR-MS spectra and X-ray diffraction experiments. All target compounds showed varying degrees of activity at 0.4 mg/mL. Compound 1 showed the strongest activity, with a 50% lethal concentration value (LC50 of 0.2421 μg/mL and 50% lethal time value (LT50 of 7.79 h, comparable to the standard drug ivermectin (LC50 = 0.2474 μg/mL; LT50 = 20.9 h. The SAR showed that the substitution pattern on the N-aromatic ring exerted a significant effect on the activity. The substituents 2'-F, 3'-F, 2'-Cl, 2'-Br and 2'-CF3 remarkably enhanced the activity. Generally, for the isomers with the same substituents at different positions, the order of the activity was ortho > meta > para. It was concluded that the target compounds represent a class of novel promising candidates or lead compounds for the development of new tetrahydroisoquinoline acaricidal agents.

  19. Application of PCA and HCA to the Structure-Activity Relationship Study of Fluoroquinolones

    Science.gov (United States)

    Li, Xiao-hong; Zhang, Xian-zhou; Cheng, Xin-lu; Yang, Xiang-dong; Zhu, Zun-lue

    2006-04-01

    Density functional theory (DFT) was used to calculate molecular descriptors (properties) for 12 fluoroquinolone with anti-S.pneumoniae activity. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to reduce dimensionality and investigate in which variables should be more effective for classifying fluoroquinolones according to their degree of an-S.pneumoniae activity. The PCA results showed that the variables ELUMO, Q3, Q5, QA, logP, MR, VOL and ΔEHL of these compounds were responsible for the anti-S.pneumoniae activity. The HCA results were similar to those obtained with PCA. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-S.pneumoniae activity. By using the chemometric results, 6 synthetic compounds were analyzed through the PCA and HCA and two of them are proposed as active molecules with anti-S.pneumoniae, which is consistent with the results of clinic experiments.

  20. Application of PCA and HCA to the Structure-activity Relationship (SAR) Study of Fluoroquinolones

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; ZHANG Rui-hou; CHENG Xin-Lu; YANG Xiang-Dong

    2006-01-01

    Density functional theory (DFT) was used to calculate a set of molecular descriptors (properties) for 14 fluoroquinolones with anti-B.fragilis activity. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed in order to reduce dimensionality and investigate which subset of variables should be more effective for classifying fluoroquinolones according to their an-B.fragilis activity degree. The PCA shows that the variables of ELUMO, △EHL, μ, Q2, Q3, Q5, Q6, QB, LogP, MR and MP are responsible for the separation between compounds with higher and lower anti-B.fragilis activities. The HCA results are similar to those obtained with PCA. By using the chemometric results, 4 synthetic compounds were analyzed through PCA and HCA, and 2 of them are proposed as active molecules against B.fragilis, which is consistent with the results of clinic experiments. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-B.fragilis activity.

  1. Structure-activity relationship of CART (cocaine- and amphetamine-regulated transcript) peptide fragments

    Czech Academy of Sciences Publication Activity Database

    Maixnerová, Jana; Hlaváček, Jan; Blokešová, Darja; Kowalczyk, W.; Elbert, Tomáš; Šanda, Miloslav; Blechová, Miroslava; Železná, Blanka; Slaninová, Jiřina; Maletínská, Lenka

    2007-01-01

    Roč. 28, č. 10 (2007), s. 1945-1953. ISSN 0196-9781 R&D Projects: GA ČR GA303/05/0614 Institutional research plan: CEZ:AV0Z40550506 Keywords : CART peptide * fragments * binding * PC12 cells Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.368, year: 2007

  2. Structure-Activity Relationships of Synthetic Coumarins as HIV-1 Inhibitors

    OpenAIRE

    I. Kostova; S. Raleva; Genova, P.; R. Argirova

    2006-01-01

    HIV/AIDS pandemics is a serious threat to health and development of mankind, and searching for effective anti-HIV agents remains actual. Considerable progress has been made in recent years in the field of drug development against HIV. A lot of structurally different coumarins were found to display potent anti-HIV activity. The current review demonstrates the variety of synthetic coumarins having unique mechanism of action referring to the different stages of HIV replication. Recent studies ba...

  3. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    Science.gov (United States)

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  4. Structure-activity relationships to estimate the effective Henry's law coefficients of organics of atmospheric interest

    OpenAIRE

    Raventos-Duran, T.; M. Camredon; R. Valorso; B. Aumont

    2010-01-01

    The Henry's law coefficient is a key property needed to address the multiphase behaviour of organics in the atmosphere. Methods that can reliably predict the values for the vast number of organic compounds of atmospheric interest are therefore required. The effective Henry's law coefficient H* in air-water systems at 298 K was compiled from literature for 488 organic compounds bearing functional groups of atmospheric relevance. This data set was used to assess the reliabili...

  5. Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.

    Science.gov (United States)

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

    2011-10-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

  6. Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis

    DEFF Research Database (Denmark)

    Nielsen, S F; Christensen, S B; Cruciani, G;

    1998-01-01

    of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots...... for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes....

  7. A parallel semisynthetic approach for structure-activity relationship studies of peptide YY

    DEFF Research Database (Denmark)

    Albertsen, Louise; Østergaard, Søren; Paulsson, Johan F; Norrild, Jens Chr.; Strømgaard, Kristian

    2013-01-01

    . In the plate format, an array of [Ala30]PYY(3-36) analogues were generated by ligation, desulfurization, and subsequent solid-phase extraction. The generated analogues, in which either Arg33, Gln34, Arg35, or Tyr36 had been substituted with proteinogenic or non-proteinogenic amino acids, were tested...

  8. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

  9. Structure-activity relationship study of twelve compounds from Paris polyphylla Smith var. pubescens

    OpenAIRE

    Huang, Xianxiao; Gao, Wenyuan; Man, Shuli; Gao, Ying; Huang, Luqi; Liu, Changxiao

    2010-01-01

    Twelve compounds were isolated from the rhizoma of Paris polyphylla Smith var. pubescens Handel-Mazzetti. Based on spectral data, the isolated compounds were identified as stigmasterol (1), β- Ecdysterone (2), Diosgenin (3), Ophiopogonin C’ (4), Diosgenin-3-O-α-L-arabinofuranosyl(1→4)-β-D-glucoside (5), Dioscin (6), Paris saponin I (7), Paris saponin II (8), Pennogenin-3-O-α-L- arabinofuranosyl (1→4)- β- D-glucoside (9), Paris saponin VI (10), Pennog...

  10. Solvents for CO2 capture. Structure-activity relationships combined with vapour-liquid-equilibrium measurements

    NARCIS (Netherlands)

    Mergler, Y.L.; Rumley-Van Gurp, R.; Brasser, P.; Koning, M.C. de; Goetheer, E.L.V.

    2011-01-01

    In this study a systematic approach was chosen to test and characterize amine systems for CO2 capture. Vapour-liquid-equilibrium measurements were performed on a homologue series of amines, with ethylene amine as base structure. Various functional groups were used that ranged in chemical and physica

  11. Three-dimensional Quantitative Structure-activity Relationship Models of HIV-1 Integrase Inhibitors of DKAs

    Institute of Scientific and Technical Information of China (English)

    ZHANG Mei-Qing; ZHAO Wen-Na; LU Shao-Yong

    2012-01-01

    As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds (DKAs) are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques (CoMFA and CoMSIA) were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search (AOS) and all-placement search (APS) were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.

  12. Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay

    Science.gov (United States)

    Many Fusarium species produce trichothecenes, sesquiterpene epoxides that differ in patterns of oxygenation and esterification at carbon positions C-3, C-4, C-7, C-8, and C-15. For the first comprehensive and quantitative comparison of the effects of oxygenation and esterification on trichothecene ...

  13. Predicting the adsorption properties of carbon dioxide corrosion inhibitors using a structure-activity relationship

    Energy Technology Data Exchange (ETDEWEB)

    Kinsella, B.; De Marco, R.; Jefferson, A.; Pejcic, B. [Western Australian Corrosion Research Group, Department of Applied Chemistry, Curtin University of Technology, GPO Box U1987, Perth, 6845, WA (Australia); Durnie, W. [Nalco/Exxon Energy Chemicals Ltd, Hardley, Hythe, Southampton (Australia)

    2004-07-01

    This paper presents a study of the influence of various chemical inhibitors on the corrosion rate of mild steel in brine electrolyte under carbon dioxide conditions. The performances as corrosion inhibitors were fitted to a Temkin adsorption isotherm, and various constants of adsorption (i.e., adsorption equilibrium constants and molecular interaction constants) have been obtained. The inhibitor adsorption mechanism has been discussed in terms of thermodynamics (i.e., {delta}H, {delta}G and {delta}S) and this revealed that some compounds chemisorbed onto the steel electrode. In addition, molecular modelling was undertaken using PCSPARTAN Plus and HyperChem Professional, and the various molecular parameters have been correlated with the thermodynamic adsorption properties of the inhibitors. A four-parameter fit for both negative and positive charged molecules is discussed. (authors)

  14. Structure-Activity Relationships of Retro-dihydrochalcones Isolated from Tacca sp

    OpenAIRE

    Peng, Jiangnan; Risinger, April L.; Da, Chenxiao; Fest, Gary A.; Kellogg, Glen E.; Mooberry, Susan L.

    2013-01-01

    Several biologically active compounds have been identified from Tacca species, including glycosides, diarylheptanoids, saponins, withanolides, and the taccalonolide class of microtubule stabilizers. More recently, two cytotoxic retro-dihydrochalcones named evelynin A (7) and taccabulin A (6) were isolated and their biological activities characterized, including the finding that taccabulin has microtubule destabilizing effects. Here we describe the identification and characterization of five n...

  15. Effects of Irradiation on the Structure-activity Relationship of Konjac Glucomannan Molecular Chain Membrane

    Institute of Scientific and Technical Information of China (English)

    WU Chun-Hua; PENG Shu-Hui; WEN Cheng-Rong; WANG Li-Xia; XIONG Bo; LIU Ya-Nan; FAN Lin-Lin; YAO Min-Na; PANG Jie

    2012-01-01

    To know the effects of irradiation on the konjac glucomannan (KGM) molecular chain membrane, KGM membrane solution was treated with the irradiation dose of 0-20 kGy in this study, and the structure and properties of KGM membrane were analyzed with Infrared spectrum, Raman spectrum, X-ray, SEM scanning and so on. The results revealed that the effects of different irradiation doses on the KGM molecular chain structure were different. Higher irradiation dose (20 kGy) resulted in partial damage against KGM membrane crystal structure, and there was no obvious change for the amorphous structure; with membrane property test, the tensile strength of KGM membrane gradually increased with the increase of irradiation dose and its elongation at break reduced, but these changes were not significant, WVP value reduced; with SEM, the membrane surface treated with irradiation was smoother even than the membrane without treatment. In addition, when increasing the irradiation dose, membrane surface became more even, and arrangement was more orderly and compact. KGM membrane nrooerties, and it is an ideal Irradiation modification could effectively improve the modification method.

  16. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

    DEFF Research Database (Denmark)

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian;

    2013-01-01

    class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information...... showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but...

  17. Anti-cancer efficacy of silybin derivatives -- a structure-activity relationship.

    Directory of Open Access Journals (Sweden)

    Chapla Agarwal

    Full Text Available Silybin or silibinin, a flavonolignan isolated from Milk thistle seeds, is one of the popular dietary supplements and has been extensively studied for its antioxidant, hepatoprotective and anti-cancer properties. We have envisioned that potency of silybin could be further enhanced through suitable modification/s in its chemical structure. Accordingly, here, we synthesized and characterized a series of silybin derivatives namely 2,3-dehydrosilybin (DHS, 7-O-methylsilybin (7OM, 7-O-galloylsilybin (7OG, 7,23-disulphatesilybin (DSS, 7-O-palmitoylsilybin (7OP, and 23-O-palmitoylsilybin (23OP; and compared their anti-cancer efficacy using human bladder cancer HTB9, colon cancer HCT116 and prostate carcinoma PC3 cells. In all the 3 cell lines, DHS, 7OM and 7OG demonstrated better growth inhibitory effects and compared to silybin, while other silybin derivatives showed lesser or no efficacy. Next, we prepared the optical isomers (A and B of silybin, DHS, 7OM and 7OG, and compared their anti-cancer efficacy. Isomers of these three silybin derivatives also showed better efficacy compared with respective silybin isomers, but in each, there was no clear cut silybin A versus B isomer activity preference. Further studies in HTB cells found that DHS, 7OM and 7OG exert better apoptotic activity than silibinin. Clonogenic assays in HTB9 cells further confirmed that both the racemic mixtures as well as pure optical isomers of DHS, 7OM and 7OG were more effective than silybin. Overall, these results clearly suggest that the anti-cancer efficacy of silybin could be significantly enhanced through structural modifications, and identify strong anti-cancer efficacy of silybin derivatives, namely DHS, 7OM, and 7OG, signifying that their efficacy and toxicity should be evaluated in relevant pre-clinical cancer models in rodents.

  18. Translation of Structure-Activity Relationships from Cyclic Mixed Efficacy Opioid Peptides to Linear Analogues

    OpenAIRE

    Anand, Jessica P.; Porter-Barrus, Vanessa R.; Waldschmidt, Helen V.; Yeomans, Larisa; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

    2014-01-01

    Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the co-administration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR-related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we descri...

  19. N4-amino-acid derivatives of 6-azacytidine: structure-activity relationship.

    Science.gov (United States)

    Alexeeva, I; Palchikovskaya, L; Shalamay, A; Nosach, L; Zhovnovataya, V; Povnitsa, O; Dyachenko, N

    2000-01-01

    Several N4-derivatives of 6-azacytidine were synthesized using of Vorbrüggen's condensation method. Their antiviral activity with respect to the adenovirus serotypes 2 and 5 in Hep-2 cells culture was studied and primary specific activity was determined. Correlation between chemical structure of new 6-azacytidine derivatives and their biological properties is discussed. PMID:10961682

  20. Structure Activity Relationships of N-linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids

    Directory of Open Access Journals (Sweden)

    Makanjuola Ogunsina

    2013-12-01

    Full Text Available 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (1 was previously reported to show potent in vitro antitumor activity on a range of cancer cell lines derived from breast, pancreas and prostate cancer. This compound was not toxic to mice and was inactive against breast tumor xenografts in mice. This inactivity was attributed to hydrolysis of the glycosidic linkage by glycosidases. Here three N-linked (glycosylamide analogs 2–4, one triazole-linked analog 5 of 1 as well as two diglycosylated analogs 6 and 7 with different stereochemistry at the C2-position of the glycerol moiety were synthesized and their antitumor activity against breast (JIMT-1, BT-474, MDA-MB-231, pancreas (MiaPaCa2 and prostrate (DU145, PC3 cancer cell lines was determined. The diglycosylated analogs 1-O-hexadecyl-2(R-, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (7 and the 1:1 diastereomeric mixture of 1-O-hexadecyl-2(R/S, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (6 showed the most potent cytotoxic activity at CC50 values of 17.5 µM against PC3 cell lines. The replacement of the O-glycosidic linkage by a glycosylamide or a glycosyltriazole linkage showed little or no activity at highest concentration tested (30 µM, whereas the replacement of the glycerol moiety by triazole resulted in CC50 values in the range of 20 to 30 µM. In conclusion, the replacement of the O-glycosidic linkage by an N-glycosidic linkage or triazole-linkage resulted in about a two to three fold loss in activity, whereas the replacement of the methoxy group on the glycerol backbone by a second glucosamine moiety did not improve the activity. The stereochemistry at the C2-position of the glycero backbone has minimal effect on the anticancer activities of these diglycosylated analogs.

  1. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    Science.gov (United States)

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

  2. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship

    Science.gov (United States)

    Akhtar, Muhammad Nadeem; Sakeh, Nurshafika M.; Zareen, Seema; Gul, Sana; Lo, Kong Mun; Ul-Haq, Zaheer; Shah, Syed Adnan Ali; Ahmad, Syahida

    2015-04-01

    Browning of fruits and vegetables is a serious issue in the food industry, as it damages the organoleptic properties of the final products. Overproduction of melanin causes aesthetic problems such as melisma, freckles and lentigo. In this study, a series of chalcones (1-10) have been synthesized and examined for their tryrosinase inhibitory activity. The results showed that flavokawain B (1), flavokawain A (2) and compound 3 were found to be potential tyrosinase inhibitors, indicating IC50 14.20-14.38 μM values. This demonstrates that 4-substituted phenolic compound especially at ring A exhibited significant tyrosinase inhibition. Additionally, molecular docking results showed a strong binding affinity for compounds 1-3 through chelation between copper metal and ligands. The detailed molecular docking and SARs studies correlate well with the tyrosinase inhibition studies in vitro. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and single X-ray crystallographic techniques. These findings could lead to design and discover of new tyrosinase inhibitors to control the melanine overproduction and overcome the economic loss of food industry.

  3. Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

    OpenAIRE

    Hao Wang; Shuang-Xi Ren; Ze-Yu He; De-Long Wang; Xiao-Nan Yan; Jun-Tao Feng; Xing Zhang

    2014-01-01

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which l...

  4. Synthesis and structure-activity relationship of liposomal substrates for phospholipase A(2)

    DEFF Research Database (Denmark)

    Viart, Helene Marie-France; Clausen, Mads Hartvig

    2011-01-01

    A recent innovation in the use of liposomes as drug delivery systems consists of covalently attaching an anticancer drug at the sn-2 position of phospholipids. However, some of those lipids could not be hydrolyzed by sPLA2. Steric bulk in the vicinity of the sn-2 position appears to prevent hydro...... hydrolysis of the substrate. Structurally different lipids have been synthesized and formulated as liposomes, subjected to sPLA2 and the hydrolysis rates have been compared to Molecular Dynamics simulations of the enzyme/substrate complexes....

  5. Structure-activity relationships to estimate the effective Henry's law constants of organics of atmospheric interest

    OpenAIRE

    Raventos-Duran, T.; M. Camredon; R. Valorso; C. Mouchel-Vallon; Aumont, B.

    2010-01-01

    The Henry's law constant is a key property needed to address the multiphase behaviour of organics in the atmosphere. Methods that can reliably predict the values for the vast number of organic compounds of atmospheric interest are therefore required. The effective Henry's law constant H* in air-water systems at 298 K was compiled from literature for 488 organic compounds bearing functional groups of atmospheric relevance. This data set was used to ass...

  6. Long-acting contraceptive agents: structure activity relationships in a series of norethisterone and levonorgestrel esters.

    Science.gov (United States)

    Bialy, G; Blye, R P; Enever, R P; Naqvi, R H; Lindberg, M C

    1983-03-01

    A large number of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling mature rats. In the norethisterone series several esters exhibited duration of activity comparable to that of norethisterone enanthate. In the levonorgestrel series the butanoic, cyclobutylcarboxylic and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methylpregn-4-ene-3,20-dione) when prepared as aqueous microcrystalline suspensions. PMID:6419411

  7. Applying quantitative structure-activity relationship approaches to nanotoxicology: Current status and future potential

    OpenAIRE

    Winkler, David; Mombelli, Enrico; Pietroiusti, Antonio; TRAN C. Lang; Worth, Andrew; Fadeel, Bengt; MCCALL Maxine

    2013-01-01

    The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the enviro...

  8. Synthesis and Structure-Activity Relationships of Imidazole-Coumarin Conjugates against Hepatitis C Virus

    Directory of Open Access Journals (Sweden)

    Shwu-Chen Tsay

    2016-02-01

    Full Text Available A series of new conjugated compounds with a –SCH2– linkage were synthesized by chemical methods from imidazole and coumarin derivatives. The experimental results indicate that of the twenty newly synthesized imidazole–coumarin conjugates, three of them exhibited appealing EC50 values (5.1–8.4 μM and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1 position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents.

  9. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    Energy Technology Data Exchange (ETDEWEB)

    Prouillac, Caroline, E-mail: c.prouillac@vetagro-sup.fr [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Rodriguez, Frédéric; Baltas, Michel [Université Paul Sabatier, SPCMIB-UMR5068, Laboratoire de Synthèse et de Physicochimie des Molécules d' Intérêt Biologique, 118 route de Narbonne, 31062 TOULOUSE cedex 9 (France); Lecoeur, Sylvaine [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France)

    2012-03-15

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

  10. Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study.

    Science.gov (United States)

    Lepri, Susan; Buonerba, Federica; Goracci, Laura; Velilla, Irene; Ruzziconi, Renzo; Schindler, Bryan D; Seo, Susan M; Kaatz, Glenn W; Cruciani, Gabriele

    2016-02-11

    Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported. PMID:26757340

  11. Anticancer activity of natural cytokinins: A structure-activity relationship study

    Czech Academy of Sciences Publication Activity Database

    Voller, Jiří; Zatloukal, Marek; Lenobel, René; Doležal, Karel; Béres, Tibor; Kryštof, Vladimír; Spíchal, Lukáš; Niemann, P.; Džubák, P.; Hajdúch, M.; Strnad, Miroslav

    2010-01-01

    Roč. 41, 11-12 (2010), s. 1350-1359. ISSN 0031-9422 R&D Projects: GA ČR GA301/08/1649; GA ČR GA206/09/1284 Institutional research plan: CEZ:AV0Z50380511 Keywords : SAR * Cytokinins * Cancer Subject RIV: FD - Oncology ; Hematology Impact factor: 3.150, year: 2010

  12. In vitro structure-activity relationship of Re-cyclized octreotide analogues

    International Nuclear Information System (INIS)

    Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods: Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS3 and N2S2 coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of 99mTc-cyclized analogue 4.

  13. Single Metal Ions in Host Zeolite Matrices. Structure-Activity-Selectivity-Relationships

    Czech Academy of Sciences Publication Activity Database

    Wichterlová, Blanka; Dědeček, Jiří; Sobalík, Zdeněk

    Dordrecht : Kluwer, 2001 - (Centi, G.; Wichterlová, B.; Bell, A.), s. 31-53 - (NATO Science Series. Mathematics, Physics and Chemistry. 13). [Workshop on Catalysis by Unique Metal Ion Structures in Solid Matrices. Praha-Průhonice (CZ), 04.07.2000-07.07.2000] R&D Projects: GA ČR GA104/00/0640; GA AV ČR IAA4040007; GA AV ČR IBS4040016; GA MŠk OC D15.20 Institutional research plan: CEZ:AV0Z4040901 Keywords : coordination of Co ions * faujasite and chabasite structures * sixt member rings Subject RIV: CF - Physical ; Theoretical Chemistry

  14. Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues

    Science.gov (United States)

    Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

    2014-03-01

    A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

  15. New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.

    Science.gov (United States)

    Roy, Pierre-Philippe; D'Souza, Kenneth; Cuperlovic-Culf, Miroslava; Kienesberger, Petra C; Touaibia, Mohamed

    2016-08-01

    Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities. PMID:27155760

  16. In-silico structure activity relationship study of toxicity endpoints by QSAR modeling (SOT)

    Science.gov (United States)

    Several thousand chemicals were tested in 700 toxicity-related in-vitro HTS bioassays through the EPA’s ToxCast and Tox21 projects. This chemical set only covers a portion of the chemical space of interest for environmental exposure, leading to a need to fill data gaps with alter...

  17. In vitro structure-activity relationship of Re-cyclized octreotide analogues

    Energy Technology Data Exchange (ETDEWEB)

    Dannoon, Shorouk F. [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Bigott-Hennkens, Heather M. [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Ma Lixin [Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); International Institute of Nano and Molecular Medicine, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Gallazzi, Fabio [Structural Biology Core, University of Missouri, Columbia, MO 65211 (United States); Lewis, Michael R., E-mail: lewismic@missouri.ed [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Jurisson, Silvia S., E-mail: jurissons@missouri.ed [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States)

    2010-07-15

    Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods: Various octreotide analogue sequences and coordination systems (e.g., S{sub 2}N{sub 2} and S{sub 3}N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with {sup 111}In-DOTA-Tyr{sup 3}-octreotide in AR42J rat pancreatic tumor cells yielded IC{sub 50} values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr{sup 3}-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr{sup 3}-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS{sub 3} and N{sub 2}S{sub 2} coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of {sup 99m}Tc-cyclized analogue 4.

  18. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  19. Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12

    DEFF Research Database (Denmark)

    Nielsen, S F; Thastrup, Ole; Pedersen, R; Olsen, C E; Christensen, S B

    1995-01-01

    A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant ...

  20. Investigation of the structure / activity relationship of VOx nanoparticles (B2)

    OpenAIRE

    Hävecker, Michael; Pinna, Nicola; Zhu, Zhen Ping; Swoboda, Manfred; Kleimenov, Evgueni; Weiß, Klaus; Sack-Kongehl, Hilde; Niederberger, Markus; Urban, Joachim; Su, Dang Sheng; Schlögl, Robert

    2004-01-01

    The influence of the geometric and the electronic structure on the catalytic properties has been studied. A micro reactor set-up has been developed that allows to study the reactivity of microscopically small samples. The new set-up is equipped with a proton transfer mass spectrometer that is suitable to detect and identify small quantities of volatile hydrocarbons down to the sub-ppb range. VOx nanoparticles prepared by different methods have been studied. The redox properties of the c...

  1. Discovery and structure activity relationships of 2-pyrazolines derived from chalcones from a pest management perspective

    Science.gov (United States)

    Synthesis of chalcones and 2-pyrazoline derivatives has been an active field of research due to the established pharmacological effects of these compounds. In this study, a series of chalcone (1a-i), 2-pyrazoline-1-carbothioamides (2a-i) and 2-pyrazoline-1-carboxamide derivatives (3a-g) were synthes...

  2. CLE Peptides in Plants: Proteolytic Processing,Structure-Activity Relationship, and Ligand-Receptor Interaction

    Institute of Scientific and Technical Information of China (English)

    Xiaoming Gao; Yongfeng Guo

    2012-01-01

    Ligand-receptor signaling initiated by the CLAVATA3/ENDOSPERM SURROUNDING REGION (CLE) family peptides is critical in regulating cell division and differentiation in meristematic tissues in plants.Biologically active CLE peptides are released from precursor proteins via proteolytic processing.The mature form of CLE ligands consists of 12-13 amino acids with several post-translational modifications.This review summarizes recent progress toward understanding the proteolytic activities that cleave precursor proteins to release CLE peptides,the molecular structure and function of mature CLE ligands,and interactions between CLE ligands and corresponding leucine-rich repeat (LRR) receptor-like kinases (RLKs).

  3. Structure-activity relationships in the hydrophobic interactions of polyphenols with cellulose and collagen.

    Science.gov (United States)

    Tang, H R; Covington, A D; Hancock, R A

    2003-10-01

    Polyphenol interactions with both cellulose and collagen in the solid state have been studied by using chromatography on cellulose and by evaluating the hydrothermal stability of the polyphenol treated sheepskin collagen. Twenty-four polyphenolic compounds were studied, including seven glucose-based gallotannins, five polyalcohol-based gallotannins, and twelve ellagitannins. In the cellulose-polyphenols systems, the polyphenol's affinity to cellulose is positively correlated with their molecular masses, the number of galloyl groups, and their hydrophobicity (logP). The polyphenol treatment increased the hydrothermal stability of collagen samples, and such effects are also positively correlated with the molecular masses, total number of galloyl groups and the hydrophobicity of polyphenols. Ellagitannins showed much weaker interactions with both biopolymers than gallotannins having similar molecular mass, the same number of galloyl groups, and the same number of phenolic hydroxyl groups. It is concluded that, for the polyphenol interactions with both cellulose and collagen, (1) the galloyl group of polyphenols is the functional group; (2) the strength of interactions are positively correlated with molecular size, the number of galloyl groups and the hydrophobicity of polyphenols; (3) the hydrophobic interactions are of great significance; and (4) the interactions are strongly dependent on the flexibility of galloyl groups. PMID:14579312

  4. Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals

    International Nuclear Information System (INIS)

    Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to identify alternative toxicity measures that may be used as surrogates for carcinogenic potency. Alternative toxicity measures for carcinogenic potency currently being used in the literature include lethal dose (dose that kills 50% of a study population [LD50]), lowest-observed-adverse-effect-level (LOAEL) and maximum tolerated dose (MTD). The purpose of this study was to investigate the correlation between tumor dose (TD50) and three alternative toxicity measures as an estimator of carcinogenic potency. A second aim of this study was to develop a Classification and Regression Tree (CART) between TD50 and estimated/experimental predictor variables to predict the carcinogenic potency of new chemicals. Rat TD50s of 590 structurally diverse chemicals were obtained from the Cancer Potency Database, and the three alternative toxicity measures considered in this study were estimated using TOPKAT, a toxicity estimation software. Though poor correlations were obtained between carcinogenic potency and the three alternative toxicity (both experimental and TOPKAT) measures for the CPDB chemicals, a CART developed using experimental data with no missing values as predictor variables provided reasonable estimates of TD50 for nine chemicals that were part of an external validation set. However, if experimental values for the three alternative measures, mutagenicity and logP are not available in the literature, then either the CART developed using missing experimental values or estimated values may be used for making a prediction

  5. Peptidomimetics Based On Dehydroepiandrosterone Scaffold: Synthesis, Antiproliferation Activity, Structure-Activity Relationship, and Mechanisms.

    Science.gov (United States)

    Wang, Xiaohui; Su, Haihuan; Wang, Wenda; Chen, Changshui; Cao, Xiufang

    2016-01-01

    A series of novel peptidomimetics bearing dehydroepiandrosterone moiety were designed, synthesized, and evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on inhibitory activities, some of the newly prepared compounds indicated significantly inhibition activities against human hepatoma cancer (HepG2), human lung cancer (A549), human melanoma (A875) cell lines compared with the control 5-fluorouracil. Especially, compounds Ii (IC50 cell lines. The highly potential compound Ik induced apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compound Ik were further evaluated using Annexin V-FITC/propidium iodide dual staining assay, which revealed these highly potential compounds induced cell death in HepG2 cells at least partly by apoptosis. PMID:27585479

  6. Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies.

    Science.gov (United States)

    Lourenço, André Luiz; Saito, Max Seidy; Dorneles, Luís Eduardo Gomes; Viana, Gil Mendes; Sathler, Plínio Cunha; Aguiar, Lúcia Cruz de Sequeira; de Pádula, Marcelo; Domingos, Thaisa Francielle Souza; Fraga, Aline Guerra Manssour; Rodrigues, Carlos Rangel; de Sousa, Valeria Pereira; Castro, Helena Carla; Cabral, Lucio Mendes

    2015-01-01

    The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations. PMID:25903367

  7. Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

    OpenAIRE

    André Luiz Lourenço; Max Seidy Saito; Luís Eduardo Gomes Dorneles; Gil Mendes Viana; Plínio Cunha Sathler; Lúcia Cruz de Sequeira Aguiar; Marcelo de Pádula; Thaisa Francielle Souza Domingos; Aline Guerra Manssour Fraga; Carlos Rangel Rodrigues; Valeria Pereira de Sousa; Helena Carla Castro; Lucio Mendes Cabral

    2015-01-01

    The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approache...

  8. Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

    Directory of Open Access Journals (Sweden)

    André Luiz Lourenço

    2015-04-01

    Full Text Available The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.

  9. Observing behaviour categorically

    DEFF Research Database (Denmark)

    Nielsen, Mogens; Cheng, Allan

    1995-01-01

    In an attempt to understand the relationships and differences between the extensive amount of research within the field of bisimulation equivalences, Joyal, Nielsen, and Winskel recently proposed an abstract category-theoretic definition of bisimulation. They identify spans of morphisms satisfyin......, in fact, captures not only bisimulations but many other behavioural equivalences. We also briefly present presheaf models as an abstract model of computation....

  10. Unstructured Documents Categorization: A Study

    Directory of Open Access Journals (Sweden)

    Debnath Bhattacharyya

    2008-12-01

    Full Text Available The main purpose of communication is to transfer information from onecorner to another of the world. The information is basically stored in forms of documents or files created on the basis of requirements. So, the randomness of creation and storage makes them unstructured in nature. As a consequence, data retrieval and modification become hard nut to crack. The data, that is required frequently, should maintain certain pattern. Otherwise, problems like retrievingerroneous data or anomalies in modification or time consumption in retrieving process may hike. As every problem has its own solution, these unstructured documents have also given the solution named unstructured document categorization. That means, the collected unstructured documents will be categorized based on some given constraints. This paper is a review which deals with different techniques like text and data mining, genetic algorithm, lexicalchaining, binarization method to reach the fulfillment of desired unstructured document categorization appeared in the literature.

  11. Web Page Categorization Using Artificial Neural Networks

    OpenAIRE

    S. M. Kamruzzaman

    2010-01-01

    Web page categorization is one of the challenging tasks in the world of ever increasing web technologies. There are many ways of categorization of web pages based on different approach and features. This paper proposes a new dimension in the way of categorization of web pages using artificial neural network (ANN) through extracting the features automatically. Here eight major categories of web pages have been selected for categorization; these are business & economy, education, government, en...

  12. Sensitivity method for integrated structure/active control law design

    Science.gov (United States)

    Gilbert, Michael G.

    1987-01-01

    The development is described of an integrated structure/active control law design methodology for aeroelastic aircraft applications. A short motivating introduction to aeroservoelasticity is given along with the need for integrated structures/controls design algorithms. Three alternative approaches to development of an integrated design method are briefly discussed with regards to complexity, coordination and tradeoff strategies, and the nature of the resulting solutions. This leads to the formulation of the proposed approach which is based on the concepts of sensitivity of optimum solutions and multi-level decompositions. The concept of sensitivity of optimum is explained in more detail and compared with traditional sensitivity concepts of classical control theory. The analytical sensitivity expressions for the solution of the linear, quadratic cost, Gaussian (LQG) control problem are summarized in terms of the linear regulator solution and the Kalman Filter solution. Numerical results for a state space aeroelastic model of the DAST ARW-II vehicle are given, showing the changes in aircraft responses to variations of a structural parameter, in this case first wing bending natural frequency.

  13. A Categorical Construction of Ultrafilters

    CERN Document Server

    Litt, Daniel; Kominers, Scott D

    2007-01-01

    We provide a brief exposition of ultrafilters and offer a categorical construction for them in terms of the inverse limit of an inverse family of finite partitions. From this construction, we derive a result which answers the conjecture of E. Rosinger posed in arXiv:0709.0084v2 in the negative.

  14. Comparison of Text Categorization Algorithms

    Institute of Scientific and Technical Information of China (English)

    SHI Yong-feng; ZHAO Yan-ping

    2004-01-01

    This paper summarizes several automatic text categorization algorithms in common use recently, analyzes and compares their advantages and disadvantages.It provides clues for making use of appropriate automatic classifying algorithms in different fields.Finally some evaluations and summaries of these algorithms are discussed, and directions to further research have been pointed out.

  15. Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469.

    Science.gov (United States)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian; Merten, Nicole; Pfleiderer, Michael; Karlsen, Kasper K; Rasmussen, Sanne S; Steensgaard, Mette; Hamacher, Alexandra; Schmidt, Johannes; Drewke, Christel; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Ullrich, Susanne; Kostenis, Evi; Kassack, Matthias U; Ulven, Trond

    2010-10-14

    The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29). PMID:24900217

  16. Categorization of exchange fluxes explains the four relational models

    CERN Document Server

    Favre, Maroussia

    2013-01-01

    The theory of Relational Models (RMs) posits four elementary models of relationships governing all human interactions, singly or in combination: Communal Sharing, Authority Ranking, Equality Matching, and Market Pricing. By considering two agents that can act in one out of three ways towards one another: give resource A, give resource B, or give nothing, we find four discrete categories of exchange fluxes that map unequivocally to the four RMs. This categorization shows that the RMs form an exhaustive set of all possible elementary exchanges. Hence, the fluxes categorization answers why there are just four RMs and explains their discreteness. By considering the costs associated with extracting resources, storing them and implementing each flux category, we are able to propose conditions under which each RM should evolve. We also logically deduce the singular nature of the Authority Ranking model. Our propositions are compatible with anthropological, ethnological and historical observations and can be tested a...

  17. The influence of landscape variation on landform categorization

    Directory of Open Access Journals (Sweden)

    Maia Williams

    2012-12-01

    Full Text Available This paper compares the landform vocabularies of residents from two regions in Portugal. Participants described both their own and the other, less familiar landscapes in response to video footage of the regions. The results indicate that participants used more detailed vocabularies to describe the known landscape compared to the less familiar study site, with detail triggered by individual place recognition. A relationship between landform lexica content and landscape type was observed in the relative placement of detail within each vocabulary. The observed drivers of categorization were the salient features of the landscape (elevation and land cover and utilitarian motivations (land use, context, and familiarity. The results offer support to the notion of non-universality in geographic object categorization.

  18. A Route Confidence Evaluation Method for Reliable Hierarchical Text Categorization

    CERN Document Server

    Hatami, Nima; Armano, Giuliano

    2012-01-01

    Hierarchical Text Categorization (HTC) is becoming increasingly important with the rapidly growing amount of text data available in the World Wide Web. Among the different strategies proposed to cope with HTC, the Local Classifier per Node (LCN) approach attains good performance by mirroring the underlying class hierarchy while enforcing a top-down strategy in the testing step. However, the problem of embedding hierarchical information (parent-child relationship) to improve the performance of HTC systems still remains open. A confidence evaluation method for a selected route in the hierarchy is proposed to evaluate the reliability of the final candidate labels in an HTC system. In order to take into account the information embedded in the hierarchy, weight factors are used to take into account the importance of each level. An acceptance/rejection strategy in the top-down decision making process is proposed, which improves the overall categorization accuracy by rejecting a few percentage of samples, i.e., thos...

  19. Categorical perception of animal patterns

    OpenAIRE

    Goldstein, Julie; Davidoff, Jules B.

    2010-01-01

    As part of the more general issue of whether culture can affect perception, the present paper addresses the Whorfian question of whether the language available to describe perceptual experience can influence the experience itself. It investigated the effect of vocabulary on perceptual classification by the study of a remote culture (Himba) which possesses a poor colour vocabulary but a rich vocabulary of animal pattern terms. Thus, the present study examined Categorical Perception (CP) with a...

  20. Categorizing Muslims in Postcolonial Indonesia

    OpenAIRE

    Ali, Muhamad

    2013-01-01

    This paper categorizes Muslim beliefs and practices in postcolonial Indonesia—santri-abangan-priyayi, traditionalist-modernist, political-cultural, fundamentalist-liberal, great-little tradition, and global-local—and argues that, far from being fixed, they must be situated in context. Such a typology must consider contingency, diversity, and complexity, shaped by various factors. The terms santri and abangan are useful to identify fractions of the Muslim population in Java, but are not releva...

  1. Categorical Algebra and its Applications

    CERN Document Server

    1988-01-01

    Categorical algebra and its applications contain several fundamental papers on general category theory, by the top specialists in the field, and many interesting papers on the applications of category theory in functional analysis, algebraic topology, algebraic geometry, general topology, ring theory, cohomology, differential geometry, group theory, mathematical logic and computer sciences. The volume contains 28 carefully selected and refereed papers, out of 96 talks delivered, and illustrates the usefulness of category theory today as a powerful tool of investigation in many other areas.

  2. Semantic information influences race categorization from faces.

    Science.gov (United States)

    Tskhay, Konstantin O; Rule, Nicholas O

    2015-06-01

    It is well established that low-level visual features affect person categorization in a bottom-up fashion. Few studies have examined top-down influences, however, and have largely focused on how information recalled from memory or from motivation influences categorization. Here, we investigated how race categorizations are affected by the context in which targets are perceived by manipulating semantic information associated with the faces being categorized. We found that presenting faces that systematically varied in racial ambiguity with race-congruent (vs. incongruent) semantic labels shifted the threshold at which perceivers distinguished between racial groups. The semantic information offered by the labels therefore appeared to influence the categorization of race. These findings suggest that semantic information creates a context for the interpretation of perceptual cues during social categorization, highlighting an active role of top-down information in race perception. PMID:25810414

  3. Modeling and Scaling of Categorical Data

    OpenAIRE

    Läuter, Henning; Ramadan, Ayad

    2011-01-01

    Estimation and testing of distributions in metric spaces are well known. R.A. Fisher, J. Neyman, W. Cochran and M. Bartlett achieved essential results on the statistical analysis of categorical data. In the last 40 years many other statisticians found important results in this field. Often data sets contain categorical data, e.g. levels of factors or names. There does not exist any ordering or any distance between these categories. At each level there are measured some metric or categorical v...

  4. Categorical Data Analysis in Experimental Biology

    OpenAIRE

    Xu, Bo; Feng, Xuyan; Rebecca D Burdine

    2010-01-01

    The categorical data set is an important data class in experimental biology and contains data separable into several mutually exclusive categories. Unlike measurement of a continuous variable, categorical data can not be analyzed with methods such as the student’s t-test. Thus, these data require a different method of analysis to aid in interpretation. In this article, we will review issues related to categorical data, such as how to plot them in a graph, how to integrate results from differe...

  5. Categorization: The View from Animal Cognition.

    Science.gov (United States)

    Smith, J David; Zakrzewski, Alexandria C; Johnson, Jennifer M; Valleau, Jeanette C; Church, Barbara A

    2016-01-01

    Exemplar, prototype, and rule theory have organized much of the enormous literature on categorization. From this theoretical foundation have arisen the two primary debates in the literature-the prototype-exemplar debate and the single system-multiple systems debate. We review these theories and debates. Then, we examine the contribution that animal-cognition studies have made to them. Animals have been crucial behavioral ambassadors to the literature on categorization. They reveal the roots of human categorization, the basic assumptions of vertebrates entering category tasks, the surprising weakness of exemplar memory as a category-learning strategy. They show that a unitary exemplar theory of categorization is insufficient to explain human and animal categorization. They show that a multiple-systems theoretical account-encompassing exemplars, prototypes, and rules-will be required for a complete explanation. They show the value of a fitness perspective in understanding categorization, and the value of giving categorization an evolutionary depth and phylogenetic breadth. They raise important questions about the internal similarity structure of natural kinds and categories. They demonstrate strong continuities with humans in categorization, but discontinuities, too. Categorization's great debates are resolving themselves, and to these resolutions animals have made crucial contributions. PMID:27314392

  6. Combining dimensional and categorical representation of psychosis: the way forward for DSM-V and ICD-11?

    LENUS (Irish Health Repository)

    Demjaha, A

    2009-12-01

    There is good evidence that psychotic symptoms segregate into symptom dimensions. However, it is still unclear how these dimensions are associated with risk indicators and other clinical variables, and whether they have advantages over categorical diagnosis in clinical practice. We investigated symptom dimensions in a first-onset psychosis sample and examined their associations with risk indicators and clinical variables. We then examined the relationship of categorical diagnoses to the same variables.

  7. Individual Differences in Categorical Perception Are Related to Sublexical/Phonological Processing in Reading

    Science.gov (United States)

    Lopez-Zamora, Miguel; Luque, Juan L.; Alvarez, Carlos J.; Cobos, Pedro L.

    2012-01-01

    This article examines the relationship between individual differences in speech perception and sublexical/phonological processing in reading. We used an auditory phoneme identification task in which a /ba/-/pa/ syllable continuum measured sensitivity to classify participants into three performance groups: poor, medium, and good categorizers. A…

  8. From Sound to Syntax: Phonological Constraints on Children's Lexical Categorization of New Words

    Science.gov (United States)

    Fitneva, Stanka A.; Christiansen, Morten H.; Monaghan, Padraic

    2009-01-01

    Two studies examined the role of phonological cues in the lexical categorization of new words when children could also rely on learning by exclusion and whether the role of phonology depends on extensive experience with a language. Phonological cues were assessed via phonological typicality--an aggregate measure of the relationship between the…

  9. Cholinergic control of visual categorization in macaques.

    Science.gov (United States)

    Aggelopoulos, Nikolaos C; Liebe, Stefanie; Logothetis, Nikos K; Rainer, Gregor

    2011-01-01

    Acetylcholine (ACh) is a neurotransmitter acting via muscarinic and nicotinic receptors that is implicated in several cognitive functions and impairments, such as Alzheimer's disease. It is believed to especially affect the acquisition of new information, which is particularly important when behavior needs to be adapted to new situations and to novel sensory events. Categorization, the process of assigning stimuli to a category, is a cognitive function that also involves information acquisition. The role of ACh on categorization has not been previously studied. We have examined the effects of scopolamine, an antagonist of muscarinic ACh receptors, on visual categorization in macaque monkeys using familiar and novel stimuli. When the peripheral effects of scopolamine on the parasympathetic nervous system were controlled for, categorization performance was disrupted following systemic injections of scopolamine. This impairment was observed only when the stimuli that needed to be categorized had not been seen before. In other words, the monkeys were not impaired by the central action of scopolamine in categorizing a set of familiar stimuli (stimuli which they had categorized successfully in previous sessions). Categorization performance also deteriorated as the stimulus became less salient by an increase in the level of visual noise. However, scopolamine did not cause additional performance disruptions for difficult categorization judgments at lower coherence levels. Scopolamine, therefore, specifically affects the assignment of new exemplars to established cognitive categories, presumably by impairing the processing of novel information. Since we did not find an effect of scopolamine in the categorization of familiar stimuli, scopolamine had no significant central action on other cognitive functions such as perception, attention, memory, or executive control within the context of our categorization task. PMID:22110428

  10. Categorical aspects of polar decomposition

    CERN Document Server

    Heunen, Chris

    2010-01-01

    Polar decomposition unquestionably provides a notion of factorization in the category of Hilbert spaces. But it does not fit existing categorical notions, mainly because its factors are not closed under composition. We observe that the factors are images of functors. This leads us to consider notions of factorization that emphasize reconstruction of the composite category from the factors. We find that the category of Hilbert spaces is a composition of a totally disconnected abelian groupoid and a finitely accessible category. This separates probabilistic and complementarity aspects in quantum mechanics.

  11. Categorization: The View from Animal Cognition

    Science.gov (United States)

    Smith, J. David; Zakrzewski, Alexandria C.; Johnson, Jennifer M.; Valleau, Jeanette C.; Church, Barbara A.

    2016-01-01

    Exemplar, prototype, and rule theory have organized much of the enormous literature on categorization. From this theoretical foundation have arisen the two primary debates in the literature—the prototype-exemplar debate and the single system-multiple systems debate. We review these theories and debates. Then, we examine the contribution that animal-cognition studies have made to them. Animals have been crucial behavioral ambassadors to the literature on categorization. They reveal the roots of human categorization, the basic assumptions of vertebrates entering category tasks, the surprising weakness of exemplar memory as a category-learning strategy. They show that a unitary exemplar theory of categorization is insufficient to explain human and animal categorization. They show that a multiple-systems theoretical account—encompassing exemplars, prototypes, and rules—will be required for a complete explanation. They show the value of a fitness perspective in understanding categorization, and the value of giving categorization an evolutionary depth and phylogenetic breadth. They raise important questions about the internal similarity structure of natural kinds and categories. They demonstrate strong continuities with humans in categorization, but discontinuities, too. Categorization’s great debates are resolving themselves, and to these resolutions animals have made crucial contributions. PMID:27314392

  12. Categorization: The View from Animal Cognition

    Directory of Open Access Journals (Sweden)

    J. David Smith

    2016-06-01

    Full Text Available Exemplar, prototype, and rule theory have organized much of the enormous literature on categorization. From this theoretical foundation have arisen the two primary debates in the literature—the prototype-exemplar debate and the single system-multiple systems debate. We review these theories and debates. Then, we examine the contribution that animal-cognition studies have made to them. Animals have been crucial behavioral ambassadors to the literature on categorization. They reveal the roots of human categorization, the basic assumptions of vertebrates entering category tasks, the surprising weakness of exemplar memory as a category-learning strategy. They show that a unitary exemplar theory of categorization is insufficient to explain human and animal categorization. They show that a multiple-systems theoretical account—encompassing exemplars, prototypes, and rules—will be required for a complete explanation. They show the value of a fitness perspective in understanding categorization, and the value of giving categorization an evolutionary depth and phylogenetic breadth. They raise important questions about the internal similarity structure of natural kinds and categories. They demonstrate strong continuities with humans in categorization, but discontinuities, too. Categorization’s great debates are resolving themselves, and to these resolutions animals have made crucial contributions.

  13. Hierarchical document categorization using associative networks

    NARCIS (Netherlands)

    Bloom, Niels; Theune, Mariët; Jong, de Franciska; Klement, E.P.; Borutzky, W.; Fahringer, T.; Hamza, M.H.; Uskov, V.

    2013-01-01

    Associative networks are a connectionist language model with the ability to handle dynamic data. We used two associative networks to categorize random sets of related Wikipedia articles with only their raw text as input. We then compared the resulting categorization to a gold standard: the manual ca

  14. 39 CFR 775.6 - Categorical exclusions.

    Science.gov (United States)

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Categorical exclusions. 775.6 Section 775.6 Postal... PROCEDURES § 775.6 Categorical exclusions. (a) The classes of actions in this section are those that the... “reference actions” documented under § 775.6(b)(17). (9) Acquisition and disposal through sale,...

  15. Unsupervised image categorization by hypergraph partition.

    Science.gov (United States)

    Huang, Yuchi; Liu, Qingshan; Lv, Fengjun; Gong, Yihong; Metaxas, Dimitris N

    2011-06-01

    We present a framework for unsupervised image categorization in which images containing specific objects are taken as vertices in a hypergraph and the task of image clustering is formulated as the problem of hypergraph partition. First, a novel method is proposed to select the region of interest (ROI) of each image, and then hyperedges are constructed based on shape and appearance features extracted from the ROIs. Each vertex (image) and its k-nearest neighbors (based on shape or appearance descriptors) form two kinds of hyperedges. The weight of a hyperedge is computed as the sum of the pairwise affinities within the hyperedge. Through all of the hyperedges, not only the local grouping relationships among the images are described, but also the merits of the shape and appearance characteristics are integrated together to enhance the clustering performance. Finally, a generalized spectral clustering technique is used to solve the hypergraph partition problem. We compare the proposed method to several methods and its effectiveness is demonstrated by extensive experiments on three image databases. PMID:21282850

  16. Text Categorization with Latent Dirichlet Allocation

    Directory of Open Access Journals (Sweden)

    ZLACKÝ Daniel

    2014-05-01

    Full Text Available This paper focuses on the text categorization of Slovak text corpora using latent Dirichlet allocation. Our goal is to build text subcorpora that contain similar text documents. We want to use these better organized text subcorpora to build more robust language models that can be used in the area of speech recognition systems. Our previous research in the area of text categorization showed that we can achieve better results with categorized text corpora. In this paper we used latent Dirichlet allocation for text categorization. We divided initial text corpus into 2, 5, 10, 20 or 100 subcorpora with various iterations and save steps. Language models were built on these subcorpora and adapted with linear interpolation to judicial domain. The experiment results showed that text categorization using latent Dirichlet allocation can improve the system for automatic speech recognition by creating the language models from organized text corpora.

  17. Decision Making Under Uncertain Categorization

    Directory of Open Access Journals (Sweden)

    Stephanie Ying-Fen Chen

    2014-09-01

    Full Text Available Two experiments investigated how category information is used in decision making under uncertainty and whether the framing of category information influences how it is used. Subjects were presented with vignettes in which the categorization of a critical item was ambiguous and were asked to choose among a set of actions with the goal of attaining the desired outcome for the main character in the story. The normative decision making strategy was to base the decision on all possible categories; however, research on a related topic, category-based induction, has found that people often only consider a single category when making predictions when categorization is uncertain. These experiments found that subjects tend to consider multiple categories when making decisions, but do so both when it is and is not appropriate, suggesting that use of multiple categories is not driven by an understanding of what categories are and are not relevant to the decision. Similarly, although a framing manipulation increased the rate of multiple-category use, it did so in situations in which multiple-category use was and was not appropriate.

  18. Categorical Perception of Lexical Tones in Mandarin-speaking Congenital Amusics

    Directory of Open Access Journals (Sweden)

    Wan Ting Huang

    2015-06-01

    Full Text Available Previous research suggests that within Mandarin-speaking congenital amusics, only a subgroup has behavioral lexical tone perception impairments (tone agnosia, whereas the rest of amusics do not. The purpose of the current study was to investigate the categorical nature of lexical tone perception in Mandarin-speaking amusics with and without behavioral lexical tone deficits. Three groups of listeners (controls, pure amusics and amusics with tone agnosia participated in tone identification and discrimination tasks. Indexes of the categorical perception of a physical continuum of fundamental frequencies ranging from a rising to level tone were measured. Specifically, the stimulus durations were manipulated at 100 and 200 ms. For both stimulus durations, all groups exhibited similar categorical boundaries. The pure amusics showed sharp identification slopes and significantly peaked discrimination functions similar to those of normal controls. However, such essential characteristics for the categorical perception of lexical tones were not observed in amusics with tone agnosia. An enlarged step-size from 20 Hz to 35 Hz was not able to produce any discrimination peaks in tone agnosics either. The current study revealed that only amusics with tone agnosia showed a lack of categorical tone perception, while the pure amusics demonstrated typical categorical perception of lexical tones, indicating that the deficit of pitch processing in music does not necessarily result in the deficit in the categorical perception of lexical tones. The different performance between congenital amusics with and without tone agnosia provides a new perspective on the proposition of the relationship between music and speech perception.

  19. Categorical apparatus of individual marketing

    OpenAIRE

    I.L. Reshetnikova; Yu.A. Eremenko

    2013-01-01

    The aim of the article. The aim of the article is to clarify the essence of individual marketing and its interconnection with relationship marketing, CRM, direct marketing and database marketing based on a study of the marketing genesis and the evolution of the process of individual communication between buyer and seller. We consider relationship marketing as the most general notion that involves individual marketing, CRM, direct marketing and database marketing. Relationship marketing is to ...

  20. Analysis of categorical data with R

    CERN Document Server

    Bilder, Christopher R

    2014-01-01

    Learn How to Properly Analyze Categorical DataAnalysis of Categorical Data with R presents a modern account of categorical data analysis using the popular R software. It covers recent techniques of model building and assessment for binary, multicategory, and count response variables and discusses fundamentals, such as odds ratio and probability estimation. The authors give detailed advice and guidelines on which procedures to use and why to use them.The Use of R as Both a Data Analysis Method and a Learning ToolRequiring no prior experience with R, the text offers an introduction to the essent

  1. Relationship of Personality Traits to Student Retention

    Science.gov (United States)

    Liang, John Paul

    2010-01-01

    Carl Jung's theory of psychological types has been the basis for the development of personality categorization, including tests such as Myers-Briggs Type Indicator (MBTI). This study analyzed the extent of the relationship between MBTI and Tinto (1993) retention factors that influence Oriental medicine students' choice of staying or dropping out…

  2. Random matrix approach to categorical data analysis

    Science.gov (United States)

    Patil, Aashay; Santhanam, M. S.

    2015-09-01

    Correlation and similarity measures are widely used in all the areas of sciences and social sciences. Often the variables are not numbers but are instead qualitative descriptors called categorical data. We define and study similarity matrix, as a measure of similarity, for the case of categorical data. This is of interest due to a deluge of categorical data, such as movie ratings, top-10 rankings, and data from social media, in the public domain that require analysis. We show that the statistical properties of the spectra of similarity matrices, constructed from categorical data, follow random matrix predictions with the dominant eigenvalue being an exception. We demonstrate this approach by applying it to the data for Indian general elections and sea level pressures in the North Atlantic ocean.

  3. EFFECTS OF TALKER GENDER ON DIALECT CATEGORIZATION

    Science.gov (United States)

    CLOPPER, CYNTHIA G.; CONREY, BRIANNA; PISONI, DAVID B.

    2011-01-01

    The identification of the gender of an unfamiliar talker is an easy and automatic process for naïve adult listeners. Sociolinguistic research has consistently revealed gender differences in the production of linguistic variables. Research on the perception of dialect variation, however, has been limited almost exclusively to male talkers. In the present study, naïve participants were asked to categorize unfamiliar talkers by dialect using sentence-length utterances under three presentation conditions: male talkers only, female talkers only, and a mixed gender condition. The results revealed no significant differences in categorization performance across the three presentation conditions. However, a clustering analysis of the listeners’ categorization errors revealed significant effects of talker gender on the underlying perceptual similarity spaces. The present findings suggest that naïve listeners are sensitive to gender differences in speech production and are able to use those differences to reliably categorize unfamiliar male and female talkers by dialect. PMID:21423866

  4. Web Page Categorization Using Artificial Neural Networks

    CERN Document Server

    Kamruzzaman, S M

    2010-01-01

    Web page categorization is one of the challenging tasks in the world of ever increasing web technologies. There are many ways of categorization of web pages based on different approach and features. This paper proposes a new dimension in the way of categorization of web pages using artificial neural network (ANN) through extracting the features automatically. Here eight major categories of web pages have been selected for categorization; these are business & economy, education, government, entertainment, sports, news & media, job search, and science. The whole process of the proposed system is done in three successive stages. In the first stage, the features are automatically extracted through analyzing the source of the web pages. The second stage includes fixing the input values of the neural network; all the values remain between 0 and 1. The variations in those values affect the output. Finally the third stage determines the class of a certain web page out of eight predefined classes. This stage i...

  5. Computably Categorical Fields via Fermat's Last Theorem

    OpenAIRE

    Miller, Russell; Schoutens, Hans

    2012-01-01

    We construct a computable, computably categorical field of infinite transcendence degree over the rational numbers, using the Fermat polynomials and assorted results from algebraic geometry. We also show that this field has an intrinsically computable (infinite) transcendence basis.

  6. Theory-based categorization under speeded conditions

    Science.gov (United States)

    Luhmann, Christian C.; Ahn, Woo-Kyoung; Palmeri, Thomas J.

    2009-01-01

    It is widely accepted that similarity influences rapid categorization, whereas theories can influence only more leisurely category judgments. In contrast, we argue that it is not the type of knowledge used that determines categorization speed, but rather the complexity of the categorization processes. In two experiments, participants learned four categories of items, each consisting of three causally related features. Participants gave more weight to cause features than to effect features, even under speeded response conditions. Furthermore, the time required to make judgments was equivalent, regardless of whether participants were using causal knowledge or base-rate information. We argue that both causal knowledge and base-rate information, once precompiled during learning, can be used at roughly the same speeds during categorization, thus demonstrating an important parallel between these two types of knowledge. PMID:17128608

  7. Categorization: The View from Animal Cognition

    OpenAIRE

    J. David Smith; Alexandria C. Zakrzewski; Johnson, Jennifer M.; Valleau, Jeanette C.; Church, Barbara A.

    2016-01-01

    Exemplar, prototype, and rule theory have organized much of the enormous literature on categorization. From this theoretical foundation have arisen the two primary debates in the literature—the prototype-exemplar debate and the single system-multiple systems debate. We review these theories and debates. Then, we examine the contribution that animal-cognition studies have made to them. Animals have been crucial behavioral ambassadors to the literature on categorization. They reveal the roots o...

  8. Outlier Analysis of Categorical Data using NAVF

    OpenAIRE

    D. LAKSHMI SREENIVASA REDDY; B. Raveendra Babu; A. Govardhan

    2013-01-01

    Outlier mining is an important task to discover the data records which have an exceptional behavior comparing with other records in the remaining dataset. Outliers do not follow with other data objects in the dataset. There are many effective approaches to detect outliers in numerical data. But for categorical dataset there are limited approaches. We propose an al-gorithm NAVF (Normally distributed attribute value frequency) to detect outliers in categorical data. This algorithm utilizes the ...

  9. Skin-color Based Videos Categorization

    OpenAIRE

    Rehanullah Khan; Asad Maqsood; Zeeshan Khan; Muhammad Ishaq; Arsalan Arif

    2012-01-01

    On dedicated websites, people can upload videos and share it with the rest of the world. Currently these videos are cat- egorized manually by the help of the user community. In this paper, we propose a combination of color spaces with the Bayesian network approach for robust detection of skin color followed by an automated video categorization. Exper- imental results show that our method can achieve satisfactory performance for categorizing videos based on skin color.

  10. Skin-color based videos categorization

    CERN Document Server

    Khan, Rehanullah; Khan, Zeeshan; Ishaq, Muhammad; Arif, Arsalan

    2012-01-01

    On dedicated websites, people can upload videos and share it with the rest of the world. Currently these videos are cat- egorized manually by the help of the user community. In this paper, we propose a combination of color spaces with the Bayesian network approach for robust detection of skin color followed by an automated video categorization. Exper- imental results show that our method can achieve satisfactory performance for categorizing videos based on skin color.

  11. PageRank in Malware Categorization

    OpenAIRE

    Kang, BooJoong; Yerima, Suleiman Y.; McLaughlin, Kieran; Sezer, Sakir

    2016-01-01

    In this paper, we propose a malware categorization method that models malware behavior in terms of instructions using PageRank. PageRank computes ranks of web pages based on structural information and can also compute ranks of instructions that represent the structural information of the instructions in malware analysis methods. Our malware categorization method uses the computed ranks as features in machine learning algorithms. In the evaluation, we compare the effectiveness of different Pag...

  12. Maximally Informative Observables and Categorical Perception

    OpenAIRE

    Tsiang, Elaine

    2012-01-01

    We formulate the problem of perception in the framework of information theory, and prove that categorical perception is equivalent to the existence of an observable that has the maximum possible information on the target of perception. We call such an observable maximally informative. Regardless whether categorical perception is real, maximally informative observables can form the basis of a theory of perception. We conclude with the implications of such a theory for the problem of speech per...

  13. Interference effects of categorization on decision making.

    Science.gov (United States)

    Wang, Zheng; Busemeyer, Jerome R

    2016-05-01

    Many decision making tasks in life involve a categorization process, but the effects of categorization on subsequent decision making has rarely been studied. This issue was explored in three experiments (N=721), in which participants were shown a face stimulus on each trial and performed variations of categorization-decision tasks. On C-D trials, they categorized the stimulus and then made an action decision; on X-D trials, they were told the category and then made an action decision; on D-alone trials, they only made an action decision. An interference effect emerged in some of the conditions, such that the probability of an action on the D-alone trials (i.e., when there was no explicit categorization before the decision) differed from the total probability of the same action on the C-D or X-D trials (i.e., when there was explicit categorization before the decision). Interference effects are important because they indicate a violation of the classical law of total probability, which is assumed by many cognitive models. Across all three experiments, a complex pattern of interference effects systematically occurred for different types of stimuli and for different types of categorization-decision tasks. These interference effects present a challenge for traditional cognitive models, such as Markov and signal detection models, but a quantum cognition model, called the belief-action entanglement (BAE) model, predicted that these results could occur. The BAE model employs the quantum principles of superposition and entanglement to explain the psychological mechanisms underlying the puzzling interference effects. The model can be applied to many important and practical categorization-decision situations in life. PMID:26896726

  14. Granitic pluton inner structural activities partition and its concomitant dykes mass activities of northern Guangdong province

    International Nuclear Information System (INIS)

    The granite mass inner structural activities distributed with agminate and the high frequency of directions and phases, in northern Guangdong province. The granite mass inner uranous mineralization are manipulatived with structure. Based on the geological characteristics of the Zhuguang and Guidong granite mass, interrelated information of numerous uranium field,and isotope ages, the text mark off ternary phases about the granite mass inner structural activities--the anterior, corresponding and posterior period of neutral-basic dykes activities. And go with these structural activities, it came into being activities about multi-phases dykess mass. The uranium ore brought at the volitant date of dykes and silicic dykesal mass, after the appearance of neutral-basic dykes. (authors)

  15. Mimesis in the Relationship between Art and Reality

    Institute of Scientific and Technical Information of China (English)

    李翠翠

    2010-01-01

    The relationship between art and reality is broadly categorized according to mimesis.This paper attempts to examine the relationship among mimesis,art and reality in discussing criticisms of several representative classical literature theorists.Their concepts of mimesis lead them to take an important position regarding artistic creation.

  16. Relative cue encoding in the context of sophisticated models of categorization: Separating information from categorization

    Science.gov (United States)

    McMurray, Bob

    2014-01-01

    Traditional studies of human categorization often treat the processes of encoding features and cues as peripheral to the question of how stimuli are categorized. However, in domains where the features and cues are less transparent, how information is encoded prior to categorization may constrain our understanding of the architecture of categorization. This is particularly true in speech perception, where acoustic cues to phonological categories are ambiguous and influenced by multiple factors. Here, it is crucial to consider the joint contributions of the information in the input and the categorization architecture. We contrasted accounts that argue for raw acoustic information encoding with accounts that posit that cues are encoded relative to expectations, and investigated how two categorization architectures—exemplar models and back-propagation parallel distributed processing models—deal with each kind of information. Relative encoding, akin to predictive coding, is a form of noise reduction, so it can be expected to improve model accuracy; however, like predictive coding, the use of relative encoding in speech perception by humans is controversial, so results are compared to patterns of human performance, rather than on the basis of overall accuracy. We found that, for both classes of models, in the vast majority of parameter settings, relative cues greatly helped the models approximate human performance. This suggests that expectation-relative processing is a crucial precursor step in phoneme categorization, and that understanding the information content is essential to understanding categorization processes. PMID:25475048

  17. Relative cue encoding in the context of sophisticated models of categorization: Separating information from categorization.

    Science.gov (United States)

    Apfelbaum, Keith S; McMurray, Bob

    2015-08-01

    Traditional studies of human categorization often treat the processes of encoding features and cues as peripheral to the question of how stimuli are categorized. However, in domains where the features and cues are less transparent, how information is encoded prior to categorization may constrain our understanding of the architecture of categorization. This is particularly true in speech perception, where acoustic cues to phonological categories are ambiguous and influenced by multiple factors. Here, it is crucial to consider the joint contributions of the information in the input and the categorization architecture. We contrasted accounts that argue for raw acoustic information encoding with accounts that posit that cues are encoded relative to expectations, and investigated how two categorization architectures-exemplar models and back-propagation parallel distributed processing models-deal with each kind of information. Relative encoding, akin to predictive coding, is a form of noise reduction, so it can be expected to improve model accuracy; however, like predictive coding, the use of relative encoding in speech perception by humans is controversial, so results are compared to patterns of human performance, rather than on the basis of overall accuracy. We found that, for both classes of models, in the vast majority of parameter settings, relative cues greatly helped the models approximate human performance. This suggests that expectation-relative processing is a crucial precursor step in phoneme categorization, and that understanding the information content is essential to understanding categorization processes. PMID:25475048

  18. Assessing Expertise in Quantum Mechanics using Categorization Task

    CERN Document Server

    Lin, Shih-Yin

    2016-01-01

    We discuss the categorization of 20 quantum mechanics problems by 6 physics professors and 22 undergraduate students from two honors-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty members' categorizations were overall rated better than those of students by three faculty members who evaluated all of the categorizations. But the categories created by faculty members were more diverse compared to the uniformity of the categories they created when asked to categorize introductory mechanics problems.

  19. Asian Dust Weather Categorization with Satellite and Surface Observations

    Science.gov (United States)

    Lin, Tang-Huang; Hsu, N. Christina; Tsay, Si-Chee; Huang, Shih-Jen

    2011-01-01

    This study categorizes various dust weather types by means of satellite remote sensing over central Asia. Airborne dust particles can be identified by satellite remote sensing because of the different optical properties exhibited by coarse and fine particles (i.e. varying particle sizes). If a correlation can be established between the retrieved aerosol optical properties and surface visibility, the intensity of dust weather can be more effectively and consistently discerned using satellite rather than surface observations. In this article, datasets consisting of collocated products from Moderate Resolution Imaging Spectroradiometer Aqua and surface measurements are analysed. The results indicate an exponential relationship between the surface visibility and the satellite-retrieved aerosol optical depth, which is subsequently used to categorize the dust weather. The satellite-derived spatial frequency distributions in the dust weather types are consistent with China s weather station reports during 2003, indicating that dust weather classification using satellite data is highly feasible. Although the period during the springtime from 2004 to 2007 may be not sufficient for statistical significance, our results reveal an increasing tendency in both intensity and frequency of dust weather over central Asia during this time period.

  20. Residual abilities in age-related macular degeneration to process spatial frequencies during natural scene categorization.

    Science.gov (United States)

    Musel, Benoit; Hera, Ruxandra; Chokron, Sylvie; Alleysson, David; Chiquet, Christophe; Romanet, Jean-Paul; Guyader, Nathalie; Peyrin, Carole

    2011-11-01

    Age-related macular degeneration (AMD) is characterized by a central vision loss. We explored the relationship between the retinal lesions in AMD patients and the processing of spatial frequencies in natural scene categorization. Since the lesion on the retina is central, we expected preservation of low spatial frequency (LSF) processing and the impairment of high spatial frequency (HSF) processing. We conducted two experiments that differed in the set of scene stimuli used and their exposure duration. Twelve AMD patients and 12 healthy age-matched participants in Experiment 1 and 10 different AMD patients and 10 healthy age-matched participants in Experiment 2 performed categorization tasks of natural scenes (Indoors vs. Outdoors) filtered in LSF and HSF. Experiment 1 revealed that AMD patients made more no-responses to categorize HSF than LSF scenes, irrespective of the scene category. In addition, AMD patients had longer reaction times to categorize HSF than LSF scenes only for indoors. Healthy participants' performance was not differentially affected by spatial frequency content of the scenes. In Experiment 2, AMD patients demonstrated the same pattern of errors as in Experiment 1. Furthermore, AMD patients had longer reaction times to categorize HSF than LSF scenes, irrespective of the scene category. Again, spatial frequency processing was equivalent for healthy participants. The present findings point to a specific deficit in the processing of HSF information contained in photographs of natural scenes in AMD patients. The processing of LSF information is relatively preserved. Moreover, the fact that the deficit is more important when categorizing HSF indoors, may lead to new perspectives for rehabilitation procedures in AMD. PMID:22192508

  1. Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: structure-activity relationships for betulinic acid analogues.

    Science.gov (United States)

    Ziegler, Hanne L; Franzyk, Henrik; Sairafianpour, Majid; Tabatabai, Mehrnoush; Tehrani, Mahboubeh D; Bagherzadeh, Karim; Hägerstrand, Henry; Staerk, Dan; Jaroszewski, Jerzy W

    2004-01-01

    The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH(2)OH, CONH(2)) caused formation of echinocytes, whereas those lacking this ability (CH(3), CHO, COOCH(3)) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC(50) values in the range 7-28 microM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs. PMID:14697777

  2. State of affairs: Design and structure-activity relationships of reversible P2Y12 receptor antagonists.

    Science.gov (United States)

    Zetterberg, Fredrik; Svensson, Peder

    2016-06-15

    Myocardial infarction and stroke are the most common causes of mortality and morbidity in the developed world. Therefore the search for antiplatelet therapy has been in focus for the last decades, in particular the search for new P2Y12R antagonists. The first P2Y12R drug developed, clopidogrel, is a major success but there is still room for improvement with respect to bleeding profile and non-responders. These liabilities could be due to the fact that clopidogrel is a pro-drug and upon activation binds covalently to the receptor. Therefore a lot of effort has gone into identifying reversible inhibitors. One recent example is ticagrelor, which in clinical studies have been shown to be safer and even reduce rate of death from vascular events as compared head to head with clopidogrel. We here review the medicinal chemistry strategies used in the design of new reversible P2Y12R antagonists. In addition, we also present structure based design studies based on the recently published agonist and antagonist X-ray structures of P2Y12R. PMID:27133596

  3. Leishmanicidal activity of plants from the Peruvian traditional pharmacopeia and molecules of synthesis; study structure-activity relationship.

    OpenAIRE

    Estevez, Yannick

    2009-01-01

    New world Leishmaniasis are parasitosis with heavy socio-economic consequences. Nowadays the commercially available treatments require parenteral administrations and are not affordable for the concerned populations. The search for new active molecules is thus urgently needed. To contribute to the research effort of therapeutic alternative, we were interested in traditional pharmacopeia of populations living in endemic zone (two ethnic groups of Peruvian Amazonia: the Chayahuita and the Yanesh...

  4. Synthesis and Structure-Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells

    DEFF Research Database (Denmark)

    Rønnest, Mads Holger; Rebacz, Blanka; Markworth, Lene;

    2009-01-01

    Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34 griseoful......Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34...

  5. Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships.

    NARCIS (Netherlands)

    Seyberth, T.; Voss, S.; Brock, R.E.; Wiesmuller, K.H.; Jung, G.

    2006-01-01

    Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines

  6. Structure-activity relationships for the fluorescence of ochratoxin A: Insight for detection of ochratoxin A metabolites

    International Nuclear Information System (INIS)

    Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium that is widely found as a contaminant of food products. The toxin is a renal carcinogen in male rats, the cause of mycotoxicoses in pigs and has been associated with chronic human kidney diseases. Bioactivation has been implicated in OTA-mediated toxicity, although inconsistent results have been reported, due, in part, to the difficulty in detecting OTA metabolites in vivo. Liquid chromatography (LC) coupled with fluorescence detection (FLD) is the most widely used analytical detection method for OTA. Under acidic conditions the toxin generates blue fluorescence (465 nm) that is due to an excited state intramolecular proton transfer (ESIPT) process that generates an emissive keto tautomer. Disruption of this ESIPT process quenches fluorescence intensity and causes a blue shift in emission maxima. The aim of the present study was to determine the impact of the C5-chlorine atom, the lactone moiety and the amide bond on OTA fluorescence and derive optical parameters for OTA metabolites that have been detected in vitro. Our results highlight the limitations of LC/FLD for OTA metabolites that do not undergo ESIPT. For emissive derivatives, our absorption and emission data improves the sensitivity of LC/FLD (3-4-fold increase in the limit of detection (LOD)) for OTA analogues bearing a C5-OH group, such as the hydroquinone (OTHQ) metabolite and the glutathione conjugate of OTA (OTA-GSH). This increased sensitivity may facilitate the detection of OTA metabolites bearing a C5-OH group in biological fluids and enhance our understanding of OTA-mediated toxicity

  7. Structure-activity relationship of polyphenols on inhibition of chemical mediator release from rat peritoneal exudate cells.

    Science.gov (United States)

    Yamada, K; Shoji, K; Mori, M; Ueyama, T; Matsuo, N; Oka, S; Nishiyama, K; Sugano, M

    1999-03-01

    The effect of phenolic compounds in foodstuffs on histamine and leukotriene B4 (LTB4) release from rat peritoneal exudate cells and their antioxidative activity were examined to assess their antiallergenic activities. Among them, triphenols such as pyrogallol and gallic acid inhibited histamine release from the cells, but diphenols did not. On the other hand, o- and p-diphenols such as catechol and hydroquinone with strong antioxidative activity inhibited LTB4 release as strongly as pyrogallol, but an m-derivative resorcinol with weak antioxidative activity did not. Though carboxylated compounds and their noncarboxylated counterparts were antioxidative, the former exerted a much weaker inhibitory effect on the LTB4 release than the latter. In flavonols, only myricetin with a triphenolic B ring strongly inhibited histamine release, but all flavonols strongly suppressed LTB4 release irrespective of the number of OH groups in the B ring. Among flavonoids with an o-diphenolic B ring, flavonol and flavone with a C4-carbonyl group strongly inhibited LTB4 release, whereas the activity of anthocyan without C4-carbonyl was much weaker than the above compounds. These results suggest that triphenolic structure is essential for the inhibition of histamine release. On the other hand, antioxidative activity and membrane permeability of phenolic compounds seemed to be essential for the inhibition of LTB4 release. In addition, the C4-carbonyl group seemed to be important for strongly inhibiting LTB4 release. PMID:10476914

  8. STRUCTURE-ACTIVITY RELATIONSHIP AMONG ORGANOTINS IN AN IN VITRO MODEL OF NEURONAL DIFFERENTIATION AND PROGRAMMED CELL DEATH.

    Science.gov (United States)

    The organotins are used as heat stabilizers in PVC pipes and as marine biocides. Human exposure to monomethyltin (MMT) and dimethyltin (DMT) can occur in the water supply as a result of leaching from PVC pipes. Developmental exposure of rats to MMT and the known neurotoxicant t...

  9. Synthesis and structure-activity relationship studies of polysubstituted pyrimidines as inhibitors of immune-activated nitric oxide production

    Czech Academy of Sciences Publication Activity Database

    Jansa, Petr; Holý, Antonín; Dračínský, Martin; Kolman, Viktor; Janeba, Zlatko; Kmoníčková, Eva; Zídek, Zdeněk

    2015-01-01

    Roč. 24, č. 5 (2015), s. 2154-2166. ISSN 1054-2523 R&D Projects: GA ČR(CZ) GAP303/12/0172; GA MV VG20102015046 Institutional support: RVO:61388963 ; RVO:68378041 Keywords : pyrimidine * nitric oxide * NO * anti-inflammatory Subject RIV: CC - Organic Chemistry Impact factor: 1.402, year: 2014

  10. Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials.

    Science.gov (United States)

    Lai, David Y

    2015-11-01

    With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials. PMID:26111809

  11. Structure-activity relationships of seco-prezizaane and picrotoxane/picrodendrane terpenoids by Quasar receptor-surface modeling.

    Science.gov (United States)

    Schmidt, Thomas J; Gurrath, Marion; Ozoe, Yoshihisa

    2004-08-01

    The seco-prezizaane-type sesquiterpenes pseudoanisatin and parviflorolide from Illicium are noncompetitive antagonists at housefly (Musca domestica) gamma-aminobutyric acid (GABA) receptors. They show selectivity toward the insect receptor and thus represent new leads toward selective insecticides. Based on the binding data for 13 seco-prezizaane terpenoids and 17 picrotoxane and picrodendrane-type terpenoids to housefly and rat GABA receptors, a QSAR study was conducted by quasi-atomistic receptor-surface modeling (Quasar). The resulting models provide insight into the structural basis of selectivity and properties of the binding sites at GABA receptor-coupled chloride channels of insects and mammals. PMID:15246092

  12. The use of protein structure/activity relationships in the rational design of stable particulate delivery systems

    Directory of Open Access Journals (Sweden)

    M.H.B. Costa

    2002-06-01

    Full Text Available The recombinant heat shock protein (18 kDa-hsp from Mycobacterium leprae was studied as a T-epitope model for vaccine development. We present a structural analysis of the stability of recombinant 18 kDa-hsp during different processing steps. Circular dichroism and ELISA were used to monitor protein structure after thermal stress, lyophilization and chemical modification. We observed that the 18 kDa-hsp is extremely resistant to a wide range of temperatures (60% of activity is retained at 80ºC for 20 min. N-Acylation increased its ordered structure by 4% and decreased its ß-T1 structure by 2%. ELISA demonstrated that the native conformation of the 18 kDa-hsp was preserved after hydrophobic modification by acylation. The recombinant 18 kDa-hsp resists to a wide range of temperatures and chemical modifications without loss of its main characteristic, which is to be a source of T epitopes. This resistance is probably directly related to its lack of organization at the level of tertiary and secondary structures.

  13. Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships.

    Science.gov (United States)

    Thysiadis, Savvas; Mpousis, Spyros; Avramidis, Nicolaos; Katsamakas, Sotirios; Balomenos, Athanasios; Remelli, Rosaria; Efthimiopoulos, Spyros; Sarli, Vasiliki

    2016-03-01

    Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396. PMID:26819000

  14. Biosynthesis, Chemical Structure, and Structure-Activity Relationship of Orfamide Lipopeptides Produced by Pseudomonas protegens and Related Species

    OpenAIRE

    Ma, Zongwang; Geudens, Niels; Kieu, Nam P.; Sinnaeve, Davy; Ongena, Marc; Martins, José C.; Höfte, Monica

    2016-01-01

    Orfamide type cyclic lipopeptides (CLPs) are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study, we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudornonas species. Genetic characterization together with chemical identification revealed that the main orfamide com...

  15. Biosynthesis, Chemical Structure, and Structure-Activity Relationship of Orfamide Lipopeptides Produced by Pseudomonas protegens and Related Species.

    Science.gov (United States)

    Ma, Zongwang; Geudens, Niels; Kieu, Nam P; Sinnaeve, Davy; Ongena, Marc; Martins, José C; Höfte, Monica

    2016-01-01

    Orfamide-type cyclic lipopeptides (CLPs) are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study, we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudomonas species. Genetic characterization together with chemical identification revealed that the main orfamide compound produced by the P. protegens group is orfamide A, while the related strains Pseudomonas sp. CMR5c and CMR12a produce orfamide B. Comparison of orfamide fingerprints led to the discovery of two new orfamide homologs (orfamide F and orfamide G) in Pseudomonas sp. CMR5c. The structures of these two CLPs were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. Mutagenesis and complementation showed that orfamides determine the swarming motility of parental Pseudomonas sp. strain CMR5c and their production was regulated by luxR type regulators. Orfamide A and orfamide B differ only in the identity of a single amino acid, while orfamide B and orfamide G share the same amino acid sequence but differ in length of the fatty acid part. The biological activities of orfamide A, orfamide B, and orfamide G were compared in further bioassays. The three compounds were equally active against Magnaporthe oryzae on rice, against Rhizoctonia solani AG 4-HGI in in vitro assays, and caused zoospore lysis of Phytophthora and Pythium. Furthermore, we could show that orfamides decrease blast severity in rice plants by blocking appressorium formation in M. oryzae. Taken all together, our study shows that orfamides produced by P. protegens and related species have potential in biological control of a broad spectrum of fungal plant pathogens. PMID:27065956

  16. Biosynthesis, chemical structure and structure-activity relationship of orfamide lipopeptides produced by Pseudomonas protegens and related species

    Directory of Open Access Journals (Sweden)

    Zongwang eMa

    2016-03-01

    Full Text Available Orfamide-type cyclic lipopeptides (CLPs are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudomonas species. Genetic characterization together with chemical identification revealed that the main orfamide compound produced by the P. protegens group is orfamide A, while the related strains Pseudomonas sp. CMR5c and CMR12a produce orfamide B. Comparison of orfamide fingerprints led to the discovery of two new orfamide homologues (orfamide F and orfamide G in Pseudomonas sp. CMR5c. The structures of these two CLPs were determined by nuclear magnetic resonance (NMR and mass spectrometry (MS analysis. Mutagenesis and complementation showed that orfamides determine the swarming motility of parental Pseudomonas sp. strain CMR5c and their production was regulated by luxR type regulators. Orfamide A and orfamide B differ only in the identity of a single amino acid, while orfamide B and orfamide G share the same amino acid sequence but differ in length of the fatty acid part. The biological activities of orfamide A, orfamide B and orfamide G were compared in further bioassays. The three compounds were equally active against Magnaporthe oryzae on rice, against Rhizoctonia solani AG 4-HGI in in vitro assays, and caused zoospore lysis of Phytophthora and Pythium. Furthermore we could show that orfamides decrease blast severity in rice plants by blocking appressorium formation in M. oryzae. Taken all together, our study shows that orfamides produced by P. protegens and related species have potential in biological control of a broad spectrum of fungal plant pathogens.

  17. Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: synthesis, structure-activity relationships, and X-ray crystallographic studies.

    Science.gov (United States)

    Wen, Xiaoan; Sun, Hongbin; Liu, Jun; Cheng, Keguang; Zhang, Pu; Zhang, Liying; Hao, Jia; Zhang, Luyong; Ni, Peizhou; Zographos, Spyros E; Leonidas, Demetres D; Alexacou, Kyra-Melinda; Gimisis, Thanasis; Hayes, Joseph M; Oikonomakos, Nikos G

    2008-06-26

    Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity ( 7, 18- 20) or no activity ( 21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition. PMID:18517260

  18. Structure-activity relationship study of steroidal 1,2,4,5-tetraoxane animalarials using computational procedures

    Directory of Open Access Journals (Sweden)

    APURBA K. BHATTACHARJEE

    2005-03-01

    Full Text Available A three-dimensional QSAR pharmacophore model for antimalarial activity of steroidal 1,2,4,5-tetraoxanes was developed from a set of 17 substituted antimalarial derivatives out of 27 analogues that exhibited remarkable in vitro activity (below 100 ng/mL against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid and one hydrophobic (aliphatic feature, was found to map well onto the potent analogues and many other well-known antimalarial trioxane drugs including artemisinin, arteether, artesunic acid, and tetraoxanes. The presence of at least one hydrogen bond acceptor in the trioxane or the tetraoxane moiety appears to be necessary for potent activity of this class of compounds. Docking calculations of some of these compounds with heme are consistent with the above observation as the proximity of the heme iron to the oxygen atom of the trioxane or the tetraoxane moiety favors potent activity of the compounds. Electron transfer from the oxygen of trioxane or the tetraoxane appears to be crucial for mechanism of action of the compounds. This information together with the pharmacophore should enable search for new peroxide containing antimalarial candidates from databases and custom designed synthesis of more efficacious and safer analogues.

  19. Quantitative structure-activity relationship (QSAR) prediction of (eco)toxicity of short aliphatic protic ionic liquids.

    Science.gov (United States)

    Peric, Brezana; Sierra, Jordi; Martí, Esther; Cruañas, Robert; Garau, Maria Antonia

    2015-05-01

    Ionic liquids (ILs) are considered as a group of very promising compounds due to their excellent properties (practical non-volatility, high thermal stability and very good and diverse solving capacity). The ILs have a good prospect of replacing traditional organic solvents in vast variety of applications. However, the complete information on their environmental impact is still not available. There is also an enormous number of possible combinations of anions and cations which can form ILs, the fact that requires a method allowing the prediction of toxicity of existing and potential ILs. In this study, a group contribution QSAR model has been used in order to predict the (eco)toxicity of protic and aprotic ILs for five tests (Microtox®, Pseudokirchneriella subcapitata and Lemna minor growth inhibition test, and Acetylcholinestherase inhibition and Cell viability assay with IPC-81 cells). The predicted and experimental toxicity are well correlated. A prediction of EC50 for these (eco)toxicity tests has also been made for eight representatives of the new family of short aliphatic protic ILs, whose toxicity has not been determined experimentally to date. The QSAR model applied in this study can allow the selection of potentially less toxic ILs amongst the existing ones (e.g. in the case of aprotic ILs), but it can also be very helpful in directing the synthesis efforts toward developing new "greener" ILs respectful with the environment (e.g. short aliphatic protic ILs). PMID:25728357

  20. Sesquiterpene esters from Celastrus orbiculatus and their structure-activity relationship on the modulation of multidrug resistance.

    Science.gov (United States)

    Kim, S E; Kim, H S; Hong, Y S; Kim, Y C; Lee, J J

    1999-05-01

    Six new (1-6) and three known (7-9) sesquiterpene esters were isolated from the roots of Celastrus orbiculatus. The structures of the new compounds were elucidated as 1beta-acetoxy-6alpha-furoyloxy-9alpha-benzoyl oxydihydro-beta-agarofur an (1), 1beta-acetoxy-6alpha-benzoyloxy-9alpha-furoyloxydih ydro-beta-agarofur an (2), 1beta-acetoxy-6alpha, 9alpha-difuroyloxydihydro-beta-agarofuran (3), 1beta, 2beta-diacetoxy-6alpha-furoyloxy-9alpha-benzo yloxydihydro-beta-agarof uran (4), 1beta-acetoxy-2beta, 6alpha-difuroyloxy-9alpha-benzoyloxydihydro-beta -agarofuran (5), and 1beta-acetoxy-2beta,6alpha, 9alpha-tribenzoyloxydihydro-beta-agarofuran (6). Compounds 4, 5, and 7-9 were shown to be more active than verapamil in reversing vinblastine resistance in multidrug-resistant KB-V1 cells. PMID:10346948

  1. Biosynthesis, Chemical Structure, and Structure-Activity Relationship of Orfamide Lipopeptides Produced by Pseudomonas protegens and Related Species

    Science.gov (United States)

    Ma, Zongwang; Geudens, Niels; Kieu, Nam P.; Sinnaeve, Davy; Ongena, Marc; Martins, José C.; Höfte, Monica

    2016-01-01

    Orfamide-type cyclic lipopeptides (CLPs) are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study, we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudomonas species. Genetic characterization together with chemical identification revealed that the main orfamide compound produced by the P. protegens group is orfamide A, while the related strains Pseudomonas sp. CMR5c and CMR12a produce orfamide B. Comparison of orfamide fingerprints led to the discovery of two new orfamide homologs (orfamide F and orfamide G) in Pseudomonas sp. CMR5c. The structures of these two CLPs were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. Mutagenesis and complementation showed that orfamides determine the swarming motility of parental Pseudomonas sp. strain CMR5c and their production was regulated by luxR type regulators. Orfamide A and orfamide B differ only in the identity of a single amino acid, while orfamide B and orfamide G share the same amino acid sequence but differ in length of the fatty acid part. The biological activities of orfamide A, orfamide B, and orfamide G were compared in further bioassays. The three compounds were equally active against Magnaporthe oryzae on rice, against Rhizoctonia solani AG 4-HGI in in vitro assays, and caused zoospore lysis of Phytophthora and Pythium. Furthermore, we could show that orfamides decrease blast severity in rice plants by blocking appressorium formation in M. oryzae. Taken all together, our study shows that orfamides produced by P. protegens and related species have potential in biological control of a broad spectrum of fungal plant pathogens. PMID:27065956

  2. Discovery of novel heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis, structure-activity relationship analysis and biological evaluation.

    Science.gov (United States)

    Li, Ying-Bo; Yan, Xu; Li, Ri-Dong; Liu, Peng; Sun, Shao-Qian; Wang, Xin; Cui, Jing-Rong; Zhou, De-Min; Ge, Ze-Mei; Li, Run-Tao

    2016-04-13

    A series of new analogs based on the structure of lead compound 10 were designed, synthesized and evaluated for their in vitro anti-cancer activities against four selected human cancer cell lines (HL-60, Bel-7402, SK-BR-3 and MDA-MB-468). Several synthesized compounds exhibited improved anti-cancer activities comparing with lead compound 10. Among them, 1,3,4-oxadiazole analogs 17o showed highest bioactivity with IC50 values of 1.23, 0.58 and 4.29 μM against Bel-7402, SK-BR-3 and MDA-MB-468 cells, respectively. It is noteworthy that 17o has potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cells. The further mechanistic study showed that it induced apoptosis and cell cycle arrest through disrupting spindle assembly in mitotic progression, indicating these synthesized dithiocarbamates represented a novel series of anti-cancer compounds targeting mitosis. PMID:26900655

  3. Structure-activity relationship studies of new rifamycins containing l-amino acid esters as inhibitors of bacterial RNA polymerases.

    Science.gov (United States)

    Czerwonka, Dominika; Domagalska, Joanna; Pyta, Krystian; Kubicka, Marcelina M; Pecyna, Paulina; Gajecka, Marzena; Przybylski, Piotr

    2016-06-30

    New rifamycins (1-12) combined with different l-amino acids, containing methyl, ethyl, tert-butyl and benzyl groups at the ester part, via amine linkage, were synthesized and their structures in solution were determined by spectroscopic FT-IR and 1D and 2D NMR methods as well as visualized by DFT calculations. Two types of rifamycin structures were detected in solution: a zwitterionic one with the transferred proton from O(8)H phenol to secondary N(38) atom and a pseudocyclic structure stabilized via formation of intramolecular H-bond within the protonated basic C(3)-substituent. The presence of these rifamycins' structures influenced physico-chemical (logP, solubility) parameters and antibacterial properties. The bulkiness at the ester substituent of new rifamycins containing aromatic l-amino acids was found to be an important factor, besides the solubility, to achieve relatively high antibacterial activity against reference S. epidermidis and reference S. aureus and MRSA strains (MICs 0.016-0.063 μg/mL), comparable to that of rifampicin. SAR for the novel derivatives was discussed in view of the calculated structures of rifamycin-RNAP complexes. PMID:27061985

  4. Structure-activity relationship of cocaine- and amphetamine-regulated transcript (CART) by peptide analogs: Importance of disulfide bridges

    Czech Academy of Sciences Publication Activity Database

    Blechová, Miroslava; Nagelová, Veronika; Demianova, Zuzana; Železná, Blanka; Maletínská, Lenka

    2012-01-01

    Roč. 18, S1 (2012), S89-S90. ISSN 1075-2617. [European Peptide Symposium /32./. 02.09.2012-07.09.2012, Athens] Institutional research plan: CEZ:AV0Z40550506 Keywords : CART * neuropeptides * cell line PC12 * anorexigenic effect Subject RIV: CE - Biochemistry

  5. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids.

    Science.gov (United States)

    Havrylyuk, Dmytro; Roman, Olexandra; Lesyk, Roman

    2016-05-01

    The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids. PMID:26922234

  6. Quantitative structure activity relationship model for predicting the depletion percentage of skin allergic chemical substances of glutathione.

    Science.gov (United States)

    Si, Hongzong; Wang, Tao; Zhang, Kejun; Duan, Yun-Bo; Yuan, Shuping; Fu, Aiping; Hu, Zhide

    2007-05-22

    A quantitative model was developed to predict the depletion percentage of glutathione (DPG) compounds by gene expression programming (GEP). Each kind of compound was represented by several calculated structural descriptors involving constitutional, topological, geometrical, electrostatic and quantum-chemical features of compounds. The GEP method produced a nonlinear and five-descriptor quantitative model with a mean error and a correlation coefficient of 10.52 and 0.94 for the training set, 22.80 and 0.85 for the test set, respectively. It is shown that the GEP predicted results are in good agreement with experimental ones, better than those of the heuristic method. PMID:17481417

  7. Hands-On Approach to Structure Activity Relationships: The Synthesis, Testing, and Hansch Analysis of a Series of Acetylcholineesterase Inhibitors

    Science.gov (United States)

    Locock, Katherine; Tran, Hue; Codd, Rachel; Allan, Robin

    2015-01-01

    This series of three practical sessions centers on drugs that inhibit the enzyme acetylcholineesterase. This enzyme is responsible for the inactivation of acetylcholine and has been the target of drugs to treat glaucoma and Alzheimer's disease and for a number of insecticides and warfare agents. These sessions relate to a series of carbamate…

  8. Structure-activity relationships for the fluorescence of ochratoxin A: Insight for detection of ochratoxin A metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Frenette, Christine; Paugh, Robert J. [Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Tozlovanu, Mariana; Juzio, Maud [ENSAT, UMR CNRS 5503, 1 Avenue Agrobiopole 31326 Auzeville-Tolosane (France); Pfohl-Leszkowicz, Annie [ENSAT, UMR CNRS 5503, 1 Avenue Agrobiopole 31326 Auzeville-Tolosane (France)], E-mail: leszkowicz@ensat.fr; Manderville, Richard A. [Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada)], E-mail: rmanderv@uoguelph.ca

    2008-06-09

    Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium that is widely found as a contaminant of food products. The toxin is a renal carcinogen in male rats, the cause of mycotoxicoses in pigs and has been associated with chronic human kidney diseases. Bioactivation has been implicated in OTA-mediated toxicity, although inconsistent results have been reported, due, in part, to the difficulty in detecting OTA metabolites in vivo. Liquid chromatography (LC) coupled with fluorescence detection (FLD) is the most widely used analytical detection method for OTA. Under acidic conditions the toxin generates blue fluorescence (465 nm) that is due to an excited state intramolecular proton transfer (ESIPT) process that generates an emissive keto tautomer. Disruption of this ESIPT process quenches fluorescence intensity and causes a blue shift in emission maxima. The aim of the present study was to determine the impact of the C5-chlorine atom, the lactone moiety and the amide bond on OTA fluorescence and derive optical parameters for OTA metabolites that have been detected in vitro. Our results highlight the limitations of LC/FLD for OTA metabolites that do not undergo ESIPT. For emissive derivatives, our absorption and emission data improves the sensitivity of LC/FLD (3-4-fold increase in the limit of detection (LOD)) for OTA analogues bearing a C5-OH group, such as the hydroquinone (OTHQ) metabolite and the glutathione conjugate of OTA (OTA-GSH). This increased sensitivity may facilitate the detection of OTA metabolites bearing a C5-OH group in biological fluids and enhance our understanding of OTA-mediated toxicity.

  9. Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae): Structure/Activity Relationships

    OpenAIRE

    Morais, Thiago R.; Thais A. da Costa-Silva; Tempone, Andre G.; Samanta Etel T. Borborema; Marcus T. Scotti; Raquel Maria F. de Sousa; Ana Carolina C. Araujo; Alberto de Oliveira; Sérgio Antônio L. de Morais; Patricia Sartorelli; Lago, João Henrique G.

    2014-01-01

    Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic deri...

  10. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    Science.gov (United States)

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents. PMID:27077228

  11. Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.

    Science.gov (United States)

    Fowler, C J; Tiger, G; Stenström, A

    1997-11-01

    The ability of rat brain (minus cerebellum) homogenates to deamidate arachidonyl ethanolamide (anandamide) was determined with a custom-synthesized substrate, arachidonyl ethanolamide-[1-3H] ([3H]anandamide). Conditions whereby initial velocities were measured were established. The homogenates deamidated anandamide with a Km value of 0.8 microM and a Vmax value of 1.73 nmol . (mg protein)-1 . min-1. The deamidation of 2 microM -3H-anandamide was inhibited by phenylmethylsulfonyl fluoride and arachidonyl trifluoromethyl ketone with IC50 values of 3.7 and 0.23 microM, respectively. Ibuprofen inhibited anandamide deamidation in a mixed fashion, with Ki and K'i values of 82 and 1420 microM. At an anandamide concentration of 2 microM, the IC50 values (in microM) of a series of compounds related in structure to ibuprofen were as follows: suprofen, 170; ibuprofen, 270; fenoprofen, 480; naproxen, 550; ketoprofen, 650; diclofenac, approximately 1000. Sulindac produced 27% inhibition at a concentration of 1000 microM, whereas isobutyric acid, hydrocinnamic acid, acetylsalicylic acid and acetaminophen were essentially inactive at concentrations

  12. Structure-Activity Relationship of 3-Substituted Pregnanolones Acting on the N-Methyl-D-Aspartate Receptors

    Czech Academy of Sciences Publication Activity Database

    Kudová, Eva; Chodounská, Hana; Slavíková, Barbora; Kapras, Vojtěch; Vyklický, Vojtěch; Borovská, Jiřina; Krausová, Barbora; Vyklický ml., Ladislav

    Kanazawa : -, 2012. [International Congress on Hormonal Steroids and Hormones and Cancer /15./. 15.11.2012-17.11.2012, Kanazawa] R&D Projects: GA ČR(CZ) GAP303/12/1464; GA TA ČR(CZ) TE01020028 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : N-methyl-D-aspartate receptors * NMDA Subject RIV: CC - Organic Chemistry

  13. Transformation of Organophosphorus Pesticides in the Presence of Aqueous Chlorine: Kinetics, Pathways, and Structure-Activity Relationships

    Science.gov (United States)

    The fate of organophosphorus (OP) pesticides in the presence of aqueous chlorine was investigated under simulated drinking water treatment conditions. Intrinsic rate coefficients were found for the reaction of hypochlorous acid (kHOCl,OP) and hypochlorite ion (kOCl,OP) for eight...

  14. Organophosphorus (OP) Pesticide Degradation in the Presence of Chlorinated Oxidants: Kinetics, Modeling, and Structure-Activity Relationships

    Science.gov (United States)

    The rates and pathways for pesticide transformation during drinking water treatment are known for only a few pesticides and under limited conditions. The resulting oxons are more toxic than the parent pesticides. The transformation rates and pathways for chlorpyrifos, an OP pest...

  15. Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

    DEFF Research Database (Denmark)

    Hansen, Martin; Phonekeo, Karina; Paine, James S; Leth-Petersen, Sebastian; Begtrup, Mikael; Bräuner-Osborne, Hans; Kristensen, Jesper Langgaard

    2014-01-01

    N-benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a...

  16. Cytotoxicity and structure activity relationship studies of maplexins A-I, gallotannins from red maple (Acer rubrum).

    Science.gov (United States)

    González-Sarrías, Antonio; Yuan, Tao; Seeram, Navindra P

    2012-05-01

    Maplexins A-I are a series of structurally related gallotannins recently isolated from the red maple (Acer rubrum) species. They differ in number and location of galloyl derivatives attached to 1,5-anhydro-glucitol. Here, maplexins A-I were evaluated for anticancer effects against human tumorigenic (colon, HCT-116; breast, MCF-7) and non-tumorigenic (colon, CCD-18Co) cell lines. The maplexins which contained two (maplexins C-D) or three (maplexins E-I) galloyl derivatives each, inhibited cancer cell growth while those with only one galloyl group (maplexins A-B) did not. Moreover, maplexins C-D showed greater antiproliferative effects than maplexins E-I (IC(50)=59.8-67.9 and 95.5-108.5 μM vs. 73.7-165.2 and 115.5-182.5 μM against HCT-116 and MCF-7 cells, respectively). Notably, the cancer cells were up to 2.5-fold more sensitive to the maplexins than the normal cells. In further mechanistic studies, maplexins C-D (at 75 μM concentrations) induced apoptosis and arrested cell cycle (in the S-phase) of the cancer cells. These results suggest that the number of galloyl groups attached to the 1,5-anhydro-glucitol moiety in these gallotannins are important for antiproliferative activity. Also, this is the first in vitro anticancer study of maplexins. PMID:22387705

  17. EF-Tu from the enacyloxin producing Frateuria W-315 strain: Structure/activity relationship and antibiotic resistance.

    Science.gov (United States)

    Créchet, Jean-Bernard; Malosse, Christian; Hountondji, Codjo

    2016-08-01

    In this report, we have demonstrated that the poly(U)-dependent poly(Phe) synthesis activity of elongator factor Tu (EF-Tu) from the enacyloxin producing strain Frateuria sp. W-315 is inhibited by the antibiotic similarly to that of Escherichia coli EF-Tu. The inhibitory effect of enacyloxin observed in a purified system was the same as that obtained with an S30 extract from E. coli or Frateuria sp. W-315, respectively, suggesting that antibiotic resistance of enacyloxin producing Frateuria sp. W-315 is not due neither to EF-Tu nor to other components of the translation machinery but to a still unknown mechanism. The EF-Tu gene, as PCR amplified from Frateuria W-315 genomic DNA and sequenced represented an ORF of 1191 nucleotides corresponding to 396 amino acids. This protein is larger than the product of tufA from E. coli by only two amino acid residues. Alignment of the amino acid sequence of EF-Tu from E. coli with those of Frateuria and Ralstonia solanacearum indicates on average 80% identical amino acid residues and 9.7% conservative replacements between EF-Tu Frateuria and EF-Tu E. coli, on one hand, and 97% identity and 1.7% conservative replacement between EF-Tu Frateuria and EF-Tu Ralstonia solanacearum, on the other hand. These strong primary structure similarities between EF-Tu from different origins are consistent with the fact that this factor is essential for the translation process in all kingdoms of life. Comparison of the effects of antibiotics on EF-Tu Frateuria and EF-Tu E. coli revealed that enacyloxin, kirromycin and pulvomycin exert a stronger stimulation of the GDP dissociation rate on EF-Tu Frateuria, while the effects of the antibiotics on the GDP association rate were comparable for the two EF-Tu species. Different mutants of EF-Tu E. coli were constructed with the help of site directed mutagenesis by changing one or several residues of EF-Tu E. coli by the corresponding residues of EF-Tu Frateuria. The single A45K substitution did not modify the intrinsic GTPase activity of EF-Tu E. coli. In contrast, a 2-3 fold stimulation of the intrinsic GTPase activity was observed with the single A42E, F46Y, Q48E and the double F46Y/Q48E substitution. Finally, up to a 7 fold stimulation was observed with the quadruple substitution (mutant A42E/A45K/F46Y/Q48E. PMID:27126073

  18. Synthesis, antimicrobial screening and structure-activity relationship of some novel 2-hydroxy-5-(nitro-substituted phenylazo benzylidine anilines

    Directory of Open Access Journals (Sweden)

    Halve A

    2006-01-01

    Full Text Available The title compounds were synthesized by the condensation of nitro-substituted 2-hydroxy-5- (nitro-substituted phenylazo benzaldehyde (3 with different aromatic amines in presence of ethanol in good yield. The chemical structures were confirmed by IR, 1H NMR and elemental analysis. All the synthesized compounds (4a-j have been evaluated for their in vitro antimicrobial activity against S. aureus , P. aeruginosa , E. coli , A. fumigatus , A. niger and C. neoformans .

  19. Mining Discriminative Patterns from Graph Data with Multiple Labels and Its Application to Quantitative Structure-Activity Relationship (QSAR) Models.

    Science.gov (United States)

    Shao, Zheng; Hirayama, Yuya; Yamanishi, Yoshihiro; Saigo, Hiroto

    2015-12-28

    Graph data are becoming increasingly common in machine learning and data mining, and its application field pervades to bioinformatics and cheminformatics. Accordingly, as a method to extract patterns from graph data, graph mining recently has been studied and developed rapidly. Since the number of patterns in graph data is huge, a central issue is how to efficiently collect informative patterns suitable for subsequent tasks such as classification or regression. In this paper, we consider mining discriminative subgraphs from graph data with multiple labels. The resulting task has important applications in cheminformatics, such as finding common functional groups that trigger multiple drug side effects, or identifying ligand functional groups that hit multiple targets. In computational experiments, we first verify the effectiveness of the proposed approach in synthetic data, then we apply it to drug adverse effect prediction problem. In the latter dataset, we compared the proposed method with L1-norm logistic regression in combination with the PubChem/Open Babel fingerprint, in that the proposed method showed superior performance with a much smaller number of subgraph patterns. Software is available from https://github.com/axot/GLP. PMID:26549421

  20. Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Quimica Fundamental]. E-mail: mramos@ufpe.br; Melo, Sebastiao Jose de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Antibioticos]. E-mail: melosebastiao@yahoo.com.br; Falcao, Emerson Peter da Silva [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Centro Academico de Vitoria de Santo Antao; Catanho, Maria Teresa J. de Almeida [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Biofisica e Radiobiologia

    2008-07-01

    The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

  1. 3-Dimensional quantitative structure-activity relationship and molecular docking studies of tetrasubstituted pyrazole derivatives as inhibitors of cyclooxygenase-2

    Directory of Open Access Journals (Sweden)

    Kulwinder Singh

    2014-04-01

    Conclusion: The present study shall help in rational drug design and synthesis of new selective COX-2 inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between COX-2 and the novel tetrasubstituted pyrazole derivative compounds. [Int J Res Med Sci 2014; 2(2.000: 612-619

  2. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study.

    Science.gov (United States)

    Pérez, Sheila; Vale, Carmen; Alonso, Eva; Fuwa, Haruhiko; Sasaki, Makoto; Konno, Yu; Goto, Tomomi; Suga, Yuto; Vieytes, Mercedes R; Botana, Luis M

    2012-09-17

    The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 μg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases. PMID:22894724

  3. Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Pecic, Stevan; Pakhomova, Svetlana; Newcomer, Marcia E.; Morisseau, Christophe; Hammock, Bruce D.; Zhu, Zhengxiang; Rinderspacher, Alison; Deng, Shi-Xian [UCD; (LSU); (Columbia)

    2013-09-27

    A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

  4. The law of cognitive structure activation: New directions in understanding depression and psychotherapy

    OpenAIRE

    Moretti, M. M.

    1991-01-01

    Comments on C. Sedikides and J. J. Skowronski's (see record 1992-00351-001) article on the law of cognitive structure activation (CSA) and disagrees with some of their statements regarding the implications of the CSA principle for psychotherapy. Alternative positions are offered regarding the applicability of the CSA principle for understanding depression and psychotherapy.

  5. CATEGORIZATION OF EVENT SEQUENCES FOR LICENSE APPLICATION

    Energy Technology Data Exchange (ETDEWEB)

    G.E. Ragan; P. Mecheret; D. Dexheimer

    2005-04-14

    The purposes of this analysis are: (1) Categorize (as Category 1, Category 2, or Beyond Category 2) internal event sequences that may occur before permanent closure of the repository at Yucca Mountain. (2) Categorize external event sequences that may occur before permanent closure of the repository at Yucca Mountain. This includes examining DBGM-1 seismic classifications and upgrading to DBGM-2, if appropriate, to ensure Beyond Category 2 categorization. (3) State the design and operational requirements that are invoked to make the categorization assignments valid. (4) Indicate the amount of material put at risk by Category 1 and Category 2 event sequences. (5) Estimate frequencies of Category 1 event sequences at the maximum capacity and receipt rate of the repository. (6) Distinguish occurrences associated with normal operations from event sequences. It is beyond the scope of the analysis to propose design requirements that may be required to control radiological exposure associated with normal operations. (7) Provide a convenient compilation of the results of the analysis in tabular form. The results of this analysis are used as inputs to the consequence analyses in an iterative design process that is depicted in Figure 1. Categorization of event sequences for permanent retrieval of waste from the repository is beyond the scope of this analysis. Cleanup activities that take place after an event sequence and other responses to abnormal events are also beyond the scope of the analysis.

  6. Structural Antitumoral Activity Relationships of Synthetic Chalcones

    OpenAIRE

    Cesar Echeverria; Juan Francisco Santibañez; Oscar Donoso-Tauda; Escobar, Carlos A.; Rodrigo Ramirez-Tagle

    2009-01-01

    Relationships between the structural characteristic of synthetic chalcones and their antitumoral activity were studied. Treatment of HepG2 cells for 24 h with synthetic 2’-hydroxychalcones resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities using the DFT method including solvent effects, suggest a structure-activity relationship between the Chalcones structure and the apoptosis in Hep...

  7. Outlier Analysis of Categorical Data using NAVF

    Directory of Open Access Journals (Sweden)

    D. LAKSHMI SREENIVASA REDDY

    2013-01-01

    Full Text Available Outlier mining is an important task to discover the data records which have an exceptional behavior comparing with other records in the remaining dataset. Outliers do not follow with other data objects in the dataset. There are many effective approaches to detect outliers in numerical data. But for categorical dataset there are limited approaches. We propose an al-gorithm NAVF (Normally distributed attribute value frequency to detect outliers in categorical data. This algorithm utilizes the frequent pattern data mining method. It avoids problem of giving k-outliers to get optimal accuracy in any classification models in previous work like Greedy, AVF, FPOF, and FDOD while finding outliers. The algorithm is applied on UCI ML Repository datasets like Nursery, Breast cancer mushroom and bank dataset by excluding numerical attributes. The experimental results show that it is efficient for outlier detection in categorical dataset.

  8. Clustering Categorical Data:A Cluster Ensemble Approach

    Institute of Scientific and Technical Information of China (English)

    He Zengyou(何增友); Xu Xiaofei; Deng Shengchun

    2003-01-01

    Clustering categorical data, an integral part of data mining,has attracted much attention recently. In this paper, the authors formally define the categorical data clustering problem as an optimization problem from the viewpoint of cluster ensemble, and apply cluster ensemble approach for clustering categorical data. Experimental results on real datasets show that better clustering accuracy can be obtained by comparing with existing categorical data clustering algorithms.

  9. An Improved Algorithm of Bayesian Text Categorization

    Directory of Open Access Journals (Sweden)

    Tao Dong

    2011-08-01

    Full Text Available Text categorization is a fundamental methodology of text mining and a hot topic of the research of data mining and web mining in recent years. It plays an important role in building traditional information retrieval, web indexing architecture, Web information retrieval, and so on. This paper presents an improved algorithm of text categorization that combines the feature weighting technique with Naïve Bayesian classifier. Experimental results show that using the improved Gini index algorithm to feature weight can improve the performance of Naïve Bayesian classifier effectively. This algorithm obtains good application in the sensitive information recognition system.

  10. Categorizing Pedagogical Patterns by Teaching Activities and Pedagogical Values

    Science.gov (United States)

    Bennedsen, Jens; Eriksen, Ole

    2006-01-01

    The main contribution of this paper is a proposal for a universal pedagogical pattern categorization based on teaching values and activities. This categorization would be more sustainable than the arbitrary categorization implied by pedagogical pattern language themes. Pedagogical patterns from two central patterns languages are analyzed and…

  11. Split extensions, semidirect product and holomorph of categorical groups

    OpenAIRE

    Kasangian, Stefano; Metere, Giuseppe; Vitale, Enrico

    2006-01-01

    Working in the context of categorical groups, we show that the semidirect product provides a biequivalence between actions and points. From this biequivalence, we deduce a two-dimensional classification of split extensions of categorical groups, as well as the universal property of the holomorph of a categorical group. We also discuss the link between the holomorph and inner autoequivalences.

  12. Categorization of Quantum Mechanics Problems by Professors and Students

    Science.gov (United States)

    Lin, Shih-Yin; Singh, Chandralekha

    2010-01-01

    We discuss the categorization of 20 quantum mechanics problems by physics professors and undergraduate students from two honours-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty…

  13. Categorical apparatus of individual marketing

    Directory of Open Access Journals (Sweden)

    I.L. Reshetnikova

    2013-12-01

    Full Text Available The aim of the article. The aim of the article is to clarify the essence of individual marketing and its interconnection with relationship marketing, CRM, direct marketing and database marketing based on a study of the marketing genesis and the evolution of the process of individual communication between buyer and seller. We consider relationship marketing as the most general notion that involves individual marketing, CRM, direct marketing and database marketing. Relationship marketing is to be viewed as establishing long-term relationships between seller and buyer on mutually beneficial basis. The emergence of information technologies and their widespread use in business has a significant impact on relationship marketing and led to the concept of CRM. The results of the analysis. We consider CRM as business strategy which is based on information technologies and designed to provide long-term, mutually beneficial relationships with customers through client-oriented approach and the creation of high customer value to the product and company. CRM and CRM-systems that are designed to work with customers' databases and are operating with huge volumes of information for marketing purposes have contributed to the realization of the principles of individual marketing. Conceptual approaches to the definition of the concepts of «individual marketing» and CRM allow us to identify common and distinctive features as well as the interdependency between them. It is appropriate to talk about CRM as the concept which is broader than individual marketing. CRM focuses on relationships with customers, and the main objective of it is to establish long-term relationships for mutual benefit, while individual marketing needs to be supported by resources and technologies to create a specific product that is able to meet the particular individual needs of customers. It should be noted that the practical implementation of the principles of CRM is possible when using an

  14. The Use of Aftereffects in the Study of Relationships among Emotion Categories

    Science.gov (United States)

    Rutherford, M. D.; Chattha, Harnimrat Monica; Krysko, Kristen M.

    2008-01-01

    The perception of visual aftereffects has been long recognized, and these aftereffects reveal a relationship between perceptual categories. Thus, emotional expression aftereffects can be used to map the categorical relationships among emotion percepts. One might expect a symmetric relationship among categories, but an evolutionary, functional…

  15. Same-Different Categorization in Rats

    Science.gov (United States)

    Wasserman, Edward A.; Castro, Leyre; Freeman, John H.

    2012-01-01

    Same-different categorization is a fundamental feat of human cognition. Although birds and nonhuman primates readily learn same-different discriminations and successfully transfer them to novel stimuli, no such demonstration exists for rats. Using a spatial discrimination learning task, we show that rats can both learn to discriminate arrays of…

  16. How Experimental Trial Context Affects Perceptual Categorization

    Directory of Open Access Journals (Sweden)

    Thomas J Palmeri

    2015-02-01

    Full Text Available To understand object categorization, participants are tested in experiments often quite different from how people experience object categories in the real world. Learning and knowledge of categories is measured in discrete experimental trials, those trials may or may not provide feedback, trials appear one after another, after some fixed inter-trial interval, with hundreds of trials in a row, within experimental blocks with some structure dictated by the experimental design. In the real world, outside of certain educational and vocational contexts, opportunities to learn and use categories are intermixed over time with a whole multitude of intervening experiences. It is clear from any elementary understanding of human cognition that sequential effects matter, yet this understanding is often ignored, and categorization trials are often instead treated as independent events, immune to local trial context. In this perspective, we use some of our work to illustrate some of the consequences of the fact that categorization experiments have a particular trial structure. Experimental trial context can affect performance in category learning and categorization experiments in ways that can profoundly affect theoretical conclusions.

  17. Categorizing Pedagogical Patterns by Teaching Activities and Pedagogical Value

    DEFF Research Database (Denmark)

    Eriksen, Ole

    2006-01-01

    The main contribution of this paper is a proposal for a universal pedagogical pattern categorization based on teaching values and activities. This categorization would be more sustainable than the arbitrary categorization implied by pedagogical pattern language themes. Pedagogical patterns from two......-based categorization, we have combined it with a categorization based on teaching activities. The catalogue could be seen as a tool for combining pedagogical theories and patterns and it is a proposal for a solution to the problem of organizing pedagogical patterns....

  18. Categorization of Quantum Mechanics Problems by Professors and Students

    CERN Document Server

    Lin, Shih-Yin

    2016-01-01

    We discuss the categorization of 20 quantum mechanics problems by physics professors and undergraduate students from two honors-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty members' categorizations were overall rated higher than those of students by three faculty members who evaluated all of the categorizations. The categories created by faculty members were more diverse compared to the categories they created for a set of introductory mechanics problems. Some faculty members noted that the categorization of introductory physics problems often involves identifying fundamental principles relevant for the problem, whereas in upper-level undergraduate quantum mechanics problems, it mainly involves identifying concepts and procedures required to solve the problem. Moreover, physics faculty members who evaluated others' categorizations express...

  19. Relationship between personality and metal disorders

    OpenAIRE

    Emil Benedik

    2000-01-01

    This article describes a relationship between personality, personality disorders and other mental disorders. We are also interested in possibility to include psychological methods and theory of personality in modern classifications of mental disorders, which represents classical medical model. This categorical model has lots of limitations, especially in field of personality disorders, which are psychological phenomenon in the first place. We are interested in alternative ways and model of de...

  20. Lexical familiarity and processing efficiency: individual differences in naming, lexical decision, and semantic categorization.

    Science.gov (United States)

    Lewellen, M J; Goldinger, S D; Pisoni, D B; Greene, B G

    1993-09-01

    College students were separated into 2 groups (high and low) on the basis of 3 measures: subjective familiarity ratings of words, self-reported language experiences, and a test of vocabulary knowledge. Three experiments were conducted to determine if the groups also differed in visual word naming, lexical decision, and semantic categorization. High Ss were consistently faster than low Ss in naming visually presented words. They were also faster and more accurate in making difficult lexical decisions and in rejecting homophone foils in semantic categorization. Taken together, the results demonstrate that Ss who differ in lexical familiarity also differ in processing efficiency. The relationship between processing efficiency and working memory accounts of individual differences in language processing is also discussed. PMID:8371087