WorldWideScience

Sample records for categorical structure-activity relationship

  1. Categorical differentiation and intergroup relationships.

    Science.gov (United States)

    Capozza, D; Volpato, C

    1990-03-01

    In this study we attempted to replicate the well-known Doise & Sinclair (1973) procedure for manipulating category salience, in a different social context. We considered the relationship between two groups of professionals: doctors and nurses, as perceived by 40 members of the superior group. The results did not confirm those obtained by Doise & Sinclair since they showed reduced categorical differentiation when the out-group was evoked in advance of the intergroup evaluations. The implications of these findings for theories of social categorization and social identity are discussed.

  2. Structure-activity relationships of insect defensins

    Science.gov (United States)

    Koehbach, Johannes

    2017-07-01

    Insects make up the largest and most diverse group of organisms on earth with several million species to exist in total. Considering the sheer number of insect species and the vast variety of ways they interact with their environment through chemistry, it is clear that they have significant potential as a source of new lead molecules. They have adapted to a range of ecological habitats and exhibit a symbiotic lifestyle with various microbes such as bacteria and fungi. Accordingly, numerous antimicrobial compounds have been identified including for example defensin peptides. Insect defensins were found to have broad-spectrum activity against various gram-positive/negative bacteria as well as fungi. They exhibit a unique structural topology involving the complex arrangement of three disulfide bonds as well as an alpha helix and beta sheets, which is known as cysteine-stabilized αβ motif. Their stability and amenability to peptide engineering make them promising candidates for the development of novel antibiotics lead molecules. This review highlights the current knowledge regarding the structure-activity relationships of insect defensin peptides and provides basis for future studies focusing on the rational design of novel cysteine-rich antimicrobial peptides.

  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...

  4. 3-alkyl fentanyl analogues: Structure-activity-relationship study

    OpenAIRE

    Vučković, Sonja; Savić-Vujović, Katarina; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Stojanović, Radan; Prostran, Milica

    2012-01-01

    Introduction. Fentanyl belongs to 4-anilidopiperidine class of synthetic opioid analgesics. It is characterized by high potency, rapid onset and short duration of action. A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful analgesic drugs. Objective. In this study, newly synthesized 3-alkyl fentanyl analogues were examined for analgesic activity and compared with fentanyl. Methods. ...

  5. (Quantitative structure-activity relationships in environmental toxicology)

    Energy Technology Data Exchange (ETDEWEB)

    Turner, J.E.

    1990-10-04

    The traveler attended the Fourth International Workshop on QSAR (Quantitative Structure-Activity Relationships) in Environmental Toxicology. He was an author or co-author on one platform and two poster presentations. The subject of the workshop offers a framework for analyzing and predicting the fate of chemical pollutants in organisms and the environment. QSAR is highly relevant to the ORNL program on the physicochemical characterization of chemical pollutants for health protection.

  6. Structure-activity relationship of crustacean peptide hormones.

    Science.gov (United States)

    Katayama, Hidekazu

    2016-01-01

    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.

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

    DEFF Research Database (Denmark)

    Doan, Thi Quynh Nhu; Christensen, Søren Brøgger

    2015-01-01

    inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of a peptide, which only is a substrate for prostate specific antigen enabled design of a prodrug (G115......) 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...

  8. Capturing structure-activity relationships from chemogenomic spaces.

    Science.gov (United States)

    Wendt, Bernd; Uhrig, Ulrike; Bös, Fabian

    2011-04-25

    Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery.

  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......-activity relationship study revealed a di-methyl citalopram, which binds to the S1 site with an affinity of 6.4 [4.7;8.8] μM (mean[SEM interval]) and shows an allosteric potency of 3.6 [3.3;3.8] μM, thus bearing ~2-fold selectivity for the allosteric site relative to the S1 site in SERT. CONCLUSIONS AND IMPLICATIONS...... 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...

  10. Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

    Science.gov (United States)

    Xue, Chao-Bin; Luo, Wan-Chun; Ding, Qi; Liu, Shou-Zhu; Gao, Xing-Xiang

    2008-05-01

    Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA ( q 2 = 0.855, r 2 = 0.978) and CoMSIA ( q 2 = 0.841, r 2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett σ), hydrophobic (π), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable ( I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that π, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe

  11. A structure-activity relationship study of ABCC2 inhibitors.

    Science.gov (United States)

    Wissel, Gloria; Deng, Feng; Kudryavtsev, Pavel; Ghemtio, Leo; Wipf, Peter; Xhaard, Henri; Kidron, Heidi

    2017-05-30

    Multidrug resistance associated protein 2 (MRP2/ABCC2) is a membrane transport protein that can potentially affect the disposition of many substrate drugs and their metabolites. Recently, we studied the interaction of a library of 432 compounds with ABCC2, and the structure-activity relationship (SAR) of a subset of 64 compounds divided into four scaffolds (Wissel, G. et al., 2015. Bioorg Med Chem., 23(13), pp.3513-25). We have now expanded this test set by investigating 114 new compounds, of which 71 are representative of the previous four scaffolds and 43 compounds belong to a new scaffold. Interaction with ABCC2 was assessed by measuring the compounds effect on 5(6)-carboxy-2',7'-dichlorofluorescein transport in the vesicular transport assay. In line with our previous study, we observed that anionic charge is not essential for inhibition of ABCC2 transport, even though it often increases the inhibitory activity within the analogue series. Additionally, we found that halogen substitutions often increase the inhibitory activity. The results confirm the importance of structural features such as aromaticity and lipophilicity for ABCC2 inhibitory activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. 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.

  13. Quantitative structure-activity relationship study of amide mosquito repellents.

    Science.gov (United States)

    Wang, P; Xu, X; Liao, S; Song, J; Fan, G; Chen, S; Wang, Z

    2017-04-01

    A quantitative structure-activity relationship (QSAR) study on 43 amide repellents was carried out by the heuristic method in order to reveal the correlations between molecular parameters of these amides and their repellency against Aedes aegypti. Sketches and optimizations of molecular structures were achieved by the Gaussian software package. Generation and screening of molecular parameters were accomplished using CODESSA 2.7.10 software. The leave-one-out method was applied for the model validation. The results showed that a four-descriptor QSAR model with r 2 of 0.897 was obtained. The average r 2 values of the training set and test set of the QSAR model were 0.901 and 0.863, respectively, which suggested that the stability and predictability of the model were confirmed. Analysis of the implications of the descriptors that constitute the QSAR model indicated that all the descriptors were related to the charge distribution over the molecule and affect the dipole moment of the repellents.

  14. Quantum mechanical quantitative structure-activity relationships to avoid mutagenicity.

    Science.gov (United States)

    Holder, Andrew J; Ye, Lin

    2009-01-01

    The purpose of this work is to develop a quantum mechanically based quantitative structure-activity relationship (QMQSAR or QSAR hereafter) adequate to predict and explain Ames TA100-derived mutagenicities for a number of organic molecules. A set of 35 structurally similar molecules with epoxide (oxirane) functionalities and systematic, reliable experimental data were selected to construct a QSAR model. The SAM1 quantum mechanical method was used to perform conformational analysis and properties calculations. This QM information was used to compute a variety of descriptors. From this a two-descriptor regression model was constructed. The two descriptors are ESP-HACA-1/TMSA and HOMO-LUMO energy gap. Statistical results for the model: R(2)=0.857, R(adj)(2)=0.818,R(cv)(2)=0.848,s(2)=0.0618. The variance inflation factor and significance for both descriptors were 1.082 and design of non-mutagenic monomers that may be useful for dental restorative composites. The model also serves as a screening tool for rating the mutagenicity of new candidate materials.

  15. Structure-activity relationship of nerve-highlighting fluorophores.

    Directory of Open Access Journals (Sweden)

    Summer L Gibbs

    Full Text Available Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.

  16. 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

  17. Quantitative Structure Activity Relationships of Aquatic Narcosis: A Review.

    Science.gov (United States)

    Adhikari, Chandana; Mishra, Bijay Kumar

    2017-07-11

    Prior estimation of toxicity of each and every, existing and yet to be synthesized chemicals is a must to elude their adverse effect on the environment. Experimental determination of such parameters is time consuming, cost effective and above all it demands the sacrifice of many vertebrates. At this end the REACH regulations advocate for the use of non-testing predictive methods such as read-across, weight-of-evidence and QSAR (quantitative structure-activity relationship) techniques. Among these methods, QSAR is found to be the best as it is based on molecular structure only. The descriptors used in deriving the model in QSAR vary according to the nature of the narcotics as well as the species used for. The success of a model in predicting the toxicity of a narcotic purely depends on the type of descriptors selected that explains the structural features closely related to the property under study. In this review we focused on the different types of descriptors and QSAR models used to explain the narcosis phenomenon. Literature was scanned for acute toxicity of chemicals on species like tadpoles, protozoa, planktonic crustaceans, and small fishes like million fish, rainbow fish etc. from different sources. The toxicity and toxicants were classified considering their polarity and specific interactions of the compounds. Due to complex nature of the substrate, the mechanism of action of toxicant is uncertain. However, the overall results obtained from the biological study have been subjected to QSAR studies to obtain various models, which can provide some ideas on the mode of toxicological action. Different types of molecular descriptors derived both experimentally and theoretically have been used in the QSAR studies. Mostly biochemicals have a specific signature on oil/water partition (Ko/w, P), which is the crux in biological activity. Accordingly, the toxicological activities have a good correlations with log P. Addition of some more structural descriptors improves

  18. Gastric cytoprotective activity of ilicic aldehyde: structure-activity relationships.

    Science.gov (United States)

    Donadel, Osvaldo J; Guerreiro, Eduardo; María, Alejandra O; Wendel, Graciela; Enriz, Ricardo D; Giordano, Oscar S; Tonn, Carlos E

    2005-08-01

    A series of sesquiterpene compounds possessing both eudesmane and eremophilane skeletons were tested as gastric cytoprotective agents on male Wistar rats. The presence of an alpha,beta-unsaturated aldehyde on the C-7 side chain together with a hydroxyl group at C-4 is the requirement for the observed antiulcerogenic activity. In an attempt to establish new molecular structural requirements for this gastric cytoprotective activity, a structure-activity study was performed.

  19. 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

    of 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...

  20. Activity Landscape Plotter: A Web-Based Application for the Analysis of Structure-Activity Relationships.

    Science.gov (United States)

    González-Medina, Mariana; Méndez-Lucio, Oscar; Medina-Franco, José L

    2017-03-27

    Activity landscape modeling is a powerful method for the quantitative analysis of structure-activity relationships. This cheminformatics area is in continuous growth, and several quantitative and visual approaches are constantly being developed. However, these approaches often fall into disuse due to their limited access. Herein, we present Activity Landscape Plotter as the first freely available web-based tool to automatically analyze structure-activity relationships of compound data sets. Based on the concept of activity landscape modeling, the online service performs pairwise structure and activity relationships from an input data set supplied by the user. For visual analysis, Activity Landscape Plotter generates Structure-Activity Similarity and Dual-Activity Difference maps. The user can interactively navigate through the maps and export all the pairwise structure-activity information as comma delimited files. Activity Landscape Plotter is freely accessible at https://unam-shiny-difacquim.shinyapps.io/ActLSmaps /.

  1. Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

    DEFF Research Database (Denmark)

    Mungalpara, Jignesh; Zachariassen, Zack G; Thiele, Stefanie

    2013-01-01

    The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-D-Tyr(5)-), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation......, and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i...... potent than 2, which means that the D-Tyr(5) side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure-activity data for the cyclopentapeptides suggest that appropriately designed Arg(2)-2-Nal(3) dipeptidomimetics have potential as CXCR4...

  2. A biology-based approach for quantitative structure-activity relationships (QSARs) in ecotoxicity.

    NARCIS (Netherlands)

    Jager, T.; Kooijman, S.A.L.M.

    2009-01-01

    Quantitative structure-activity relationships (QSARs) for ecotoxicity can be used to fill data gaps and limit toxicity testing on animals. QSAR development may additionally reveal mechanistic information based on observed patterns in the data. However, the use of descriptive summary statistics for

  3. Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.

    NARCIS (Netherlands)

    Nolte, Tom M; Peijnenburg, Willie J G M; Hendriks, A Jan; van de Meent, Dik

    After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural

  4. Phyto-fungicides: Structure activity relationships of the thymol derivatives against Rhizoctonia solani

    Science.gov (United States)

    Thymol, the key component of thyme oil and its derivatives were evaluated for their structure activity relationship as fungicide against Rhizoctonia solani. Since plant based chemicals are considered as “Generally Recognized as Safe” (GRAS) chemicals, there is a great potential to use phytochemicals...

  5. Quantitative structure activity relationship of benzoxazinone derivatives as neuropeptide Y Y5 receptor antagonists.

    Science.gov (United States)

    Deswal, S; Roy, N

    2006-04-01

    Quantitative structure activity relationship (QSAR) has been established for 30 benzoxazinone derivatives acting as neuropeptide Y Y5 receptor antagonists. The genetic algorithm and multiple linear regression were used to generate the relationship between biological activity and calculated descriptors. Model with good statistical qualities was developed using four descriptors from topological, thermodynamic, spatial and electrotopological class. The validation of the model was done by cross validation, randomization and external test set prediction.

  6. Structure-activity relationships of nucleoside analogues for inhibition of tick-borne encephalitis virus

    Czech Academy of Sciences Publication Activity Database

    Eyer, L.; Šmídková, Markéta; Nencka, Radim; Neča, J.; Kastl, T.; Palus, Martin; De Clercq, E.; Růžek, Daniel

    2016-01-01

    Roč. 133, Sep (2016), s. 119-129 ISSN 0166-3542 R&D Projects: GA MZd(CZ) NV16-34238A; GA ČR(CZ) GA16-20054S Institutional support: RVO:61388963 ; RVO:60077344 Keywords : structure-activity relationship * tick-borne encephalitis * nucleoside inhibitor * antiviral activity * cytotoxicity Subject RIV: CC - Organic Chemistry; EE - Microbiology, Virology (BC-A) Impact factor: 4.271, year: 2016

  7. Modifiers in rhodium catalysts for carbon monoxide hydrogenation: Structure-activity relationships

    Energy Technology Data Exchange (ETDEWEB)

    Bhore, N. A.

    1989-05-01

    This report is aimed at identifying interesting modified rhodium systems and elucidating structure-activity relationships in these systems with the overall goal of understanding the scientific issues in the catalytic conversion of syngas to oxygenates. Specific additives (sodium and molybdenum) are selected based on the scoping experiments. The effect of the additives on supported rhodium catalysts is then investigated. Throughout the investigation, experiments and analysis were performed on real systems instead of ideal systems. 374 refs., 82 figs., 57 tabs.

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

    OpenAIRE

    Chen-Peng Chen; Chan-Cheng Chen; Hsu-Fang Chen

    2014-01-01

    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 molec...

  9. Drug Development of the Antimalarial Agent Artemisinin: Total Synthesis, Analog Synthesis, and Structure-Activity Relationship Studies

    Science.gov (United States)

    1990-08-15

    jHoluenesulfonyl hydrazide in tetrahydrofuran (THF), solvolysis of the ketal group and subsequent hydrazone formation was observed. Under base...ARTEMISININ: TOTAL SYNTHESIS , ANALOG SYNTHESIS , AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES mc Mitchell A. Avery, Ph.D. SRI International...Antimalarial Agent Artemisinin: Total Synthesis , Analog Synthesis and Structure-Activity Relationship Studies 12 PERSONAL AUTHOR(S) Mitchell A

  10. Interpretation of Quantitative Structure-Activity Relationship Models: Past, Present, and Future.

    Science.gov (United States)

    Polishchuk, Pavel

    2017-11-27

    This paper is an overview of the most significant and impactful interpretation approaches of quantitative structure-activity relationship (QSAR) models, their development, and application. The evolution of the interpretation paradigm from "model → descriptors → (structure)" to "model → structure" is indicated. The latter makes all models interpretable regardless of machine learning methods or descriptors used for modeling. This opens wide prospects for application of corresponding interpretation approaches to retrieve structure-property relationships captured by any models. Issues of separate approaches are discussed as well as general issues and prospects of QSAR model interpretation.

  11. 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

  12. 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.

  13. R-based Tool for a Pairwise Structure-Activity Relationship Analysis.

    Science.gov (United States)

    Klimenko, Kyrylo

    2017-10-25

    The Structure-Activity Relationship analysis is a complex process that can be enhanced by computational techniques. This article describes a simple tool for SAR analysis that has a graphic user interface and a flexible approach towards the input of molecular data. The application allows calculating molecular similarity represented by Tanimoto index & Euclid distance, as well as, determining activity cliffs by means of Structure-Activity Landscape Index. The calculation is performed in a pairwise manner either for the reference compound and other compounds or for all possible pairs in the data set. The results of SAR analysis are visualized using two types of plot. The application capability is demonstrated by the analysis of a set of COX2 inhibitors with respect to Isoxicam. This tool is available online: it includes manual and input file examples. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Synthesis and Structure-Activity Relationships of Novel Ecdysteroid Dioxolanes as MDR Modulators in Cancer

    Directory of Open Access Journals (Sweden)

    Ana Martins

    2013-12-01

    Full Text Available Ecdysteroids, molting hormones of insects, can exert several mild, non-hormonal bioactivities in mammals, including humans. In a previous study, we have found a significant effect of certain derivatives on the ABCB1 transporter mediated multi-drug resistance of a transfected murine leukemia cell line. In this paper, we present a structure-activity relationship study focused on the apolar dioxolane derivatives of 20-hydroxyecdysone. Semi-synthesis and bioactivity of a total of 32 ecdysteroids, including 20 new compounds, is presented, supplemented with their complete 1H- and 13C-NMR signal assignment.

  15. Curating and Preparing High-Throughput Screening Data for Quantitative Structure-Activity Relationship Modeling.

    Science.gov (United States)

    Kim, Marlene T; Wang, Wenyi; Sedykh, Alexander; Zhu, Hao

    2016-01-01

    Publicly available bioassay data often contains errors. Curating massive bioassay data, especially high-throughput screening (HTS) data, for Quantitative Structure-Activity Relationship (QSAR) modeling requires the assistance of automated data curation tools. Using automated data curation tools are beneficial to users, especially ones without prior computer skills, because many platforms have been developed and optimized based on standardized requirements. As a result, the users do not need to extensively configure the curation tool prior to the application procedure. In this chapter, a freely available automatic tool to curate and prepare HTS data for QSAR modeling purposes will be described.

  16. Antispasmodic effects and structure-activity relationships of labdane diterpenoids from Marrubium globosum ssp. libanoticum.

    Science.gov (United States)

    Rigano, Daniela; Aviello, Gabriella; Bruno, Maurizio; Formisano, Carmen; Rosselli, Sergio; Capasso, Raffaele; Senatore, Felice; Izzo, Angelo A; Borrelli, Francesca

    2009-08-01

    Marrubium globosum ssp. libanoticum is a medicinal plant used in Lebanon to reduce pain and smooth muscle spasms. A chloroform extract obtained from M. globosum aerial parts reduced acetylcholine-induced contractions in the isolated mouse ileum. The purification of this extract identified, among 12 isolated labdane diterpenoids, four new compounds, named 13-epicyllenin A (4), 13,15-diepicyllenin A (5), marrulibacetal (9), and marrulactone (11). Their structures were determined by spectroscopic methods. Compound 9, which exerted antispasmodic activity, is likely the active ingredient of the extract. Preliminary structure-activity relationships for this class of compounds are suggested.

  17. Structure-Activity Relationships on the Molecular Descriptors Family Project at the End

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2007-12-01

    Full Text Available Molecular Descriptors Family (MDF on the Structure-Activity Relationships (SAR, a promising approach in investigation and quantification of the link between 2D and 3D structural information and the activity, and its potential in the analysis of the biological active compounds is summarized. The approach, attempts to correlate molecular descriptors family generated and calculated on a set of biological active compounds with their observed activity. The estimation as well as prediction abilities of the approach are presented. The obtained MDF SAR models can be used to predict the biological activity of unknown substrates in a series of compounds.

  18. Investigating the Structure-Activity Relationship of the Insecticidal Natural Product Rocaglamide.

    Science.gov (United States)

    Hall, Roger G; Bruce, Ian; Cooke, Nigel G; Diorazio, Louis J; Cederbaum, Fredrik; Dobler, Markus R; Irving, Ed

    2017-12-01

    The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi-step syntheses with control of stereochemistry were required to probe the structure-activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper.

  19. 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)

  20. Is There a Relationship between Speech Identification in Noise and Categorical Perception in Children with Dyslexia?

    Science.gov (United States)

    Calcus, Axelle; Lorenzi, Christian; Collet, Gregory; Colin, Cécile; Kolinsky, Régine

    2016-01-01

    Purpose: Children with dyslexia have been suggested to experience deficits in both categorical perception (CP) and speech identification in noise (SIN) perception. However, results regarding both abilities are inconsistent, and the relationship between them is still unclear. Therefore, this study aimed to investigate the relationship between CP…

  1. Exploring the usefulness of key green physicochemical properties: Quantitative structure-activity relationship for solvents from biomass.

    Science.gov (United States)

    Zuriaga, Estefanía; Giner, Beatriz; Ribate, María Pilar; García, Cristina B; Lomba, Laura

    2018-04-01

    In recent decades there has been a growing interest in the development of new solvents from biomass. Some of these new solvents have been classified as green because of their renewable and sustainable source. However, characterization from the ecotoxicological and physicochemical points of view is needed to categorize them as green solvents. We have selected several key physicochemical properties that can reflect environmental features (density, boiling point, critical aggregation concentration, and log p) and explored their usefulness for preliminarily assessing the green character of the studied solvents. Specifically, we have studied several solvents from biomass: lactate family (methyl, ethyl, and butyl lactate), furfural family (furfural, 5-methylfurfural, furfuryl alcohol, and tetrahydrofurfuryl alcohol), and levulinate family (methyl, ethyl, and butyl levulinate). To fill the gaps and complete some toxicity data for the environment, we have measured the ecotoxicity using 2 of the most common and versatile biomodels, bacteria Vibrio fischeri and crustacean Daphnia magna, for furfural- and lactate-derived compounds. The results indicate that solvents from biomass can be categorized as green because their toxicity for the environment is low. Finally, a quantitative structure-activity relationship (QSAR) study was performed with the selected key properties and the ecotoxicological information. Despite the different structure of the chemicals under study, good correlations were found for the studied organisms. It seems that log p and critical aggregation concentration reflect the greatest part of the ecotoxic behavior, whereas density and boiling point cannot reflect toxicity signals. However, these properties are rather useful for assessing the final environmental fate of the studied chemicals. Environ Toxicol Chem 2018;37:1014-1023. © 2017 SETAC. © 2017 SETAC.

  2. Biosynthesis and structure-activity relationships of the lipid a family of glycolipids.

    Science.gov (United States)

    Xiao, Xirui; Sankaranarayanan, Karthik; Khosla, Chaitan

    2017-10-01

    Lipopolysaccharide (LPS), a glycolipid found in the outer membrane of Gram-negative bacteria, is a potent elicitor of innate immune responses in mammals. A typical LPS molecule is composed of three different structural domains: a polysaccharide called the O-antigen, a core oligosaccharide, and Lipid A. Lipid A is the amphipathic glycolipid moiety of LPS. It stimulates the immune system by tightly binding to Toll-like receptor 4. More recently, Lipid A has also been shown to activate intracellular caspase-4 and caspase-5. An impressive diversity is observed in Lipid A structures from different Gram-negative bacteria, and it is well established that subtle changes in chemical structure can result in dramatically different immune activities. For example, Lipid A from Escherichia coli is highly toxic to humans, whereas a biosynthetic precursor called Lipid IV A blocks this toxic activity, and monophosphoryl Lipid A from Salmonella minnesota is a vaccine adjuvant. Thus, an understanding of structure-activity relationships in this glycolipid family could be used to design useful immunomodulatory agents. Here we review the biosynthesis, modification, and structure-activity relationships of Lipid A. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Development and validation of a quantitative structure-activity relationship for chronic narcosis to fish.

    Science.gov (United States)

    Claeys, Lieve; Iaccino, Federica; Janssen, Colin R; Van Sprang, Patrick; Verdonck, Frederik

    2013-10-01

    Vertebrate testing under the European Union's regulation on Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) is discouraged, and the use of alternative nontesting approaches such as quantitative structure-activity relationships (QSARs) is encouraged. However, robust QSARs predicting chronic ecotoxicity of organic compounds to fish are not available. The Ecological Structure Activity Relationships (ECOSAR) Class Program is a computerized predictive system that estimates the acute and chronic toxicity of organic compounds for several chemical classes based on their log octanol-water partition coefficient (K(OW)). For those chemical classes for which chronic training data sets are lacking, acute to chronic ratios are used to predict chronic toxicity to aquatic organisms. Although ECOSAR reaches a high score against the Organisation for Economic Co-operation and Development (OECD) principles for QSAR validation, the chronic QSARs in ECOSAR are not fully compliant with OECD criteria in the framework of REACH or CLP (classification, labeling, and packaging) regulation. The objective of the present study was to develop a chronic ecotoxicity QSAR for fish for compounds acting via nonpolar and polar narcosis. These QSARs were built using a database of quality screened toxicity values, considering only chronic exposure durations and relevant end points. After statistical multivariate diagnostic analysis, literature-based, mechanistically relevant descriptors were selected to develop a multivariate regression model. Finally, these QSARs were tested for their acceptance for regulatory purposes and were found to be compliant with the OECD principles for the validation of a QSAR. © 2013 SETAC.

  4. Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids

    Directory of Open Access Journals (Sweden)

    Emmy Tuenter

    2017-02-01

    Full Text Available Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14-, or 15-membered ring. The ring system consists of a hydroxystyrylamine moiety, an amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, comprised of one or two more amino acid moieties. In vitro antiplasmodial activity was shown before for several compounds belonging to this class, and in this paper the antiplasmodial and cytotoxic activities of ten more cyclopeptide alkaloids are reported. Combining these results and the IC50 values that were reported by our group previously, a library consisting of 19 cyclopeptide alkaloids was created. A qualitative SAR (structure-activity relationship study indicated that a 13-membered macrocyclic ring is preferable over a 14-membered one. Furthermore, the presence of a β-hydroxy proline moiety could correlate with higher antiplasmodial activity, and methoxylation (or, to a lesser extent, hydroxylation of the styrylamine moiety could be important for displaying antiplasmodial activity. In addition, QSAR (quantitative structure-activity relationship models were developed, using PLS (partial least squares regression and MLR (multiple linear regression. On the one hand, these models allow for the indication of the most important descriptors (molecular properties responsible for the antiplasmodial activity. Additionally, predictions made for interesting structures did not contradict the expectations raised in the qualitative SAR study.

  5. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    Science.gov (United States)

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-05-13

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

  6. Stimulation of Orobanche ramosa seed germination by fusicoccin derivatives: a structure-activity relationship study.

    Science.gov (United States)

    Evidente, Antonio; Andolfi, Anna; Fiore, Michele; Boari, Angela; Vurro, Maurizio

    2006-01-01

    A structure-activity relationship study was conducted assaying 25 natural analogues and derivatives of fusicoccin (FC), and cotylenol, the aglycone of cotylenins, for their ability to stimulate the seed germination of the parasitic species Orobanche ramosa. Some of the compounds tested proved to be highly active, being 8,9-isopropylidene of the corresponding FC aglycone and the dideacetyl derivative the most active FC derivatives. In both groups of glucosides and aglycones (including cotylenol), the most important structural feature to impart activity appears to be the presence of the primary hydroxy group at C-19. Furthermore, the functionalities and the conformation of the carbotricyclic ring proved to play a significant role. The dideacetyl derivative of FC, being easily and rapidly obtainable in high yield starting by FC, could be of interest for its practical application as a stimulant of Orobanche ramosa seed germination, inducing the "suicidal germination", an interesting approach for parasitic plant management.

  7. Environmental properties of long-chain alcohols. Structure-activity Relationship for Chronic Aquatic Toxicity

    DEFF Research Database (Denmark)

    Schaefers, Christoph; Sanderson, Hans; Boshof, Udo

    2009-01-01

    Daphnia magna reproduction tests were performed with C10, C12, C14 and C15 alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test...... substances and the need to test as close as possible to their water solubility limits. Test concentrations were determined by GC-MS before and after test solution renewal. Whereas apparent toxicity based on survival and reproduction increased with increasing C-chain lengths up to C14, observations...... of toxicity to C15 alcohol were not in line with lower chain lengths due to the lack of toxicity below the level of water solubility. When omitting C15, the slope of most (Q)SARs approach -1, being consistent with the expectation of a non-polar narcotic mode of action. Further testing at higher chain lengths...

  8. Heterocyclic Schiff bases as non toxic antioxidants: Solvent effect, structure activity relationship and mechanism of action

    Science.gov (United States)

    Shanty, Angamaly Antony; Mohanan, Puzhavoorparambil Velayudhan

    2018-03-01

    Phenolic heterocyclic imine based Schiff bases from Thiophene-2-carboxaldehyde and Pyrrole-2-carboxaldehyde were synthesized and characterized as novel antioxidants. The solvent effects of these Schiff bases were determined and compared with standard antioxidants, BHA employing DPPH assay and ABTS assay. Fixed reaction time and Steady state measurement were used for study. IC50 and EC50 were calculated. Structure-activity relationship revealed that the electron donating group in the phenolic ring increases the activity where as the electron withdrawing moiety decreases the activity. The Schiff base derivatives showed antioxidant property by two different pathways namely SPLET and HAT mechanisms in DPPH assay. While in ABTS method, the reaction between ABTS radical and Schiff bases involves electron transfer followed by proton transfer (ET-PT) mechanism. The cytotoxicity of these compounds has been evaluated by MTT assay. The results showed that all these compounds are non toxic in nature.

  9. Structure-activity relationships of diverse xanthones against multidrug resistant human tumor cells.

    Science.gov (United States)

    Wang, Qiwen; Ma, Chenyao; Ma, Yun; Li, Xiang; Chen, Yong; Chen, Jianwei

    2017-02-01

    Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Biosynthesis-driven structure-activity relationship study of premonensin-derivatives.

    Science.gov (United States)

    Ismail-Ali, A; Fansa, E K; Pryk, N; Yahiaoui, S; Kushnir, S; Pflieger, M; Wittinghofer, A; Schulz, F

    2016-08-10

    The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.

  11. Modeling the nucleophilic reactivity of small organochlorine electrophiles: A mechanistically based quantitative structure-activity relationship

    Energy Technology Data Exchange (ETDEWEB)

    Verhaar, H.J.M.; Seinen, W.; Hermens, J.L.M. [Utrecht Univ. (Netherlands); Rorije, E. [Dutch Inst. of Public Health and Environmental Protection, Bilthoven (Netherlands); Borkent, H. [Univ. of Nijmegen (Netherlands)

    1996-06-01

    Environmental pollutants can be divided into four broad categories, narcosis-type chemicals, less inert (polar narcosis) chemicals, reactive chemicals, and specifically acting chemicals. For narcosis-type, or baseline, chemicals and for less inert chemicals, adequate quantitative structure-activity relationships (QSARs) are available for estimation of toxicity to aquatic species. This is not the case for reactive chemicals and specifically acting chemicals. A possible approach to develop aquatic toxicity QSARs for reactive chemicals based on simple considerations regarding their reactivity is given. It is shown that quantum chemical calculations on reaction transition states can be used to quantitatively predict the reactivity of sets of reactive chemicals. These predictions can then be used to develop aquatic toxicity QSARs.

  12. Quantitative Structure Activity Relationship of Cinnamaldehyde Compounds against Wood-Decaying Fungi

    Directory of Open Access Journals (Sweden)

    Dongmei Yang

    2016-11-01

    Full Text Available Cinnamaldehyde, of the genius Cinnamomum, is a major constituent of the bark of the cinnamon tree and possesses broad-spectrum antimicrobial activity. In this study, we used best multiple linear regression (BMLR to develop quantitative structure activity relationship (QSAR models for cinnamaldehyde derivatives against wood-decaying fungi Trametes versicolor and Gloeophyllun trabeum. Based on the two optimal QSAR models, we then designed and synthesized two novel cinnamaldehyde compounds. The QSAR models exhibited good correlation coefficients: R2Tv = 0.910 for Trametes versicolor and R2Gt = 0.926 for Gloeophyllun trabeum. Small errors between the experimental and calculated values of two designed compounds indicated that these two QSAR models have strong predictability and stability.

  13. Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor.

    Science.gov (United States)

    Vitale, Rosa Maria; Antenucci, Lina; Gavagnin, Margherita; Raimo, Gennaro; Amodeo, Pietro

    2017-12-01

    Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism.

  14. In vivo toxicity of nitroaromatics: A comprehensive quantitative structure-activity relationship study.

    Science.gov (United States)

    Gooch, Aminah; Sizochenko, Natalia; Rasulev, Bakhtiyor; Gorb, Leonid; Leszczynski, Jerzy

    2017-08-01

    The toxicity data of 90 nitroaromatic compounds related to their 50% lethal dose concentration for rats (LD50) were analyzed to develop quantitative structure-activity relationship (QSAR) models. Quantum-chemically calculated descriptors together with molecular descriptors generated by DRAGON, PaDEL, and HiT-QSAR software were utilized to build QSAR models. Quality and validity of the models were determined by internal and external validation techniques. The results show that the toxicity of nitroaromatic compounds depends on various factors, such as the number of nitro-groups, the topological state, and the presence of certain structural fragments. The developed models based on the largest (to date) dataset of nitroaromatics in vivo toxicity showed a good predictive ability. The results provide important input that could be applied in a preliminary assessment of nitroaromatic compounds' toxicity to mammals. Environ Toxicol Chem 2017;36:2227-2233. © 2017 SETAC. © 2017 SETAC.

  15. Quantitative structure-activity relationship and molecular docking studies on designing inhibitors of the perforin.

    Science.gov (United States)

    Song, Fucheng; Cui, Lianhua; Piao, Jinmei; Liang, Hui; Si, Hongzong; Duan, Yunbo; Zhai, Honglin

    2017-10-01

    Quantitative structure-activity relationship (QSAR) studies were performed on a series of 5-arylidene-2thioxoimidazolidin-4-ones derivatives as the inhibitors of perforin and to gain insights about the structural determinants for designing new drug molecules. The heuristic method could explore the descriptors responsible for bioactivity and gain a best linear model with R 2 .82. Gene expression programming method generated a novel nonlinear function model with R 2 .92 for training set and R 2 .85 for test set. The predicted IC 50 by QSAR, molecular docking analysis, and property explorer applet show that 42a acts as a well-pleasing potent inhibitor for perforin. This study may lay a reliable theoretical foundation for the development of designing perforin inhibitor structures. © 2017 John Wiley & Sons A/S.

  16. Synthesis, evaluation and quantitative structure-activity relationship (QSAR) analysis of Wogonin derivatives as cytotoxic agents.

    Science.gov (United States)

    Bian, Jinlei; Li, Tinghan; Weng, Tianwei; Wang, Jubo; Chen, Yu; Li, Zhiyu

    2017-02-15

    A novel series of 49 wogonin derivatives were synthesized by introducing group at 7-, 8- or B ring of wogonin. The cytotoxic activities against HepG2, A549 and BCG-823 cancer cell lines were also investigated in vitro. Several of them showed obvious cytotoxic activities and compound 3h possessed the highest potency against HepG2, A549, and BCG-823 with IC 50 values of 1.07μM, 1.74μM and 0.98μM, respectively. A quantitative structure-activity relationship (QSAR) study of these synthetic derivatives as well as wogonin indicated that high solubility and low octanol/water partition coefficient are favorable, and excessive electrostatic properties and refractivity are unfavorable for the cytotoxic activities of these wogonin derivatives. These findings and results provide a base for further investigations. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Paul Robert Martin Werfette

    2010-06-01

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

  18. Quantitative structure activity relationship (QSAR) studies on nitazoxanide-based analogues against Clostridium difficile In vitro.

    Science.gov (United States)

    Zhang, Han; Liu, Xiwang; Yang, Yajun; Li, Jianyong

    2016-09-01

    Quantitative structure activity relationship (QSAR) has been established between the various physiochemical parameters of a series of nitazoxanide-based analogues and its antibacterial activity against Clostridium difficile. Genetic function approximation (GFA) and comparative molecular field analysis (CoMFA) techniques were used to identify the descriptors that have influence on biological activity. The most influencing molecular descriptors identified in 2D-QSAR include spatial, topological, and electronic descriptors, while electrostatic and stereoscopic fields were the most influencing molecular descriptors identified in 3D-QSAR. Statistical qualities (r2, q2) indicated the significance and predictability of the developed models. The study indicated that antibacterial activity of Clostridium difficile can be improved by increasing molecular connectivity index, local charge surface index, sharp index and decreasing molecular flexibility index.

  19. Design, synthesis and exploring the quantitative structure-activity relationship of some antioxidant flavonoid analogues.

    Science.gov (United States)

    Das, Sreeparna; Mitra, Indrani; Batuta, Shaikh; Niharul Alam, Md; Roy, Kunal; Begum, Naznin Ara

    2014-11-01

    A series of flavonoid analogues were synthesized and screened for the in vitro antioxidant activity through their ability to quench 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. The activity of these compounds, measured in comparison to the well-known standard antioxidants (29-32), their precursors (38-42) and other bioactive moieties (38-42) resembling partially the flavone skeleton was analyzed further to develop Quantitative Structure-Activity Relationship (QSAR) models using the Genetic Function Approximation (GFA) technique. Based on the essential structural requirements predicted by the QSAR models, some analogues were designed, synthesized and tested for activity. The predicted and experimental activities of these compounds were well correlated. Flavone analogue 20 was found to be the most potent antioxidant. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Quantitative structure-activity relationship of antifungal activity of rosin derivatives.

    Science.gov (United States)

    Wang, Hui; Nguyen, Thi Thanh Hien; Li, Shujun; Liang, Tao; Zhang, Yuanyuan; Li, Jian

    2015-01-15

    To develop new rosin-based wood preservatives with good antifungal activity, 24 rosin derivatives were synthesized, bioassay tested with Trametes versicolor and Gloeophyllum trabeum, and subjected to analysis of their quantitative structure-activity relationships (QSAR). A QSAR analysis using Ampac 9.2.1 and Codessa 2.7.16 software built two QSAR models of antifungal ratio for T. versicolor and G. trabeum with values of R(2)=0.9740 and 0.9692, respectively. Based on the models, tri-N-(3-hydroabietoxy-2-hydroxy) propyl-triethyl ammonium chloride was designed and the bioassay test result proved its better inhibitory effect against the two selected fungi as expected. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

    Science.gov (United States)

    Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

    2017-06-15

    Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. First insight into structure-activity relationships of selective meprin β inhibitors.

    Science.gov (United States)

    Ramsbeck, Daniel; Hamann, Antje; Schlenzig, Dagmar; Schilling, Stephan; Buchholz, Mirko

    2017-06-01

    The astacin proteases meprin α and β are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin β inhibitors was performed, leading to compounds with activities in the lower nanomolar range. Considering the preference of meprin β for acidic residues in the P1' position, the compounds were optimized. Acidic modifications induced potent inhibition and >100-fold selectivity over other structurally related metalloproteases such as MMP-2 or ADAM10. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. 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.

  4. Nonlinear optical studies and structure-activity relationship of chalcone derivatives with in silico insights

    Science.gov (United States)

    Kar, Swayamsiddha; Adithya, K. S.; Shankar, Pruthvik; Jagadeesh Babu, N.; Srivastava, Sailesh; Nageswara Rao, G.

    2017-07-01

    Nine chalcones were prepared via Claisen-Schmidt condensation, and characterized by UV-vis, IR, 1H NMR, 13C NMR and mass spectrometry. One of the representative member 4-NDM-TC has been studied via single crystal XRD and the TGA/DTA technique. SHG efficiency and NLO susceptibilities of the chalcones have been evaluated by the Kurtz and Perry method and Degenerate Four Wave Mixing techniques respectively. 3-Cl-4‧-HC was noted to possess SHG efficiency 1.37 times that of urea while 4-NDM-TC returned the highest third order NLO susceptibilities with respect to CS2. In silico studies help evaluate various physical parameters, in correlating the observed activities. In conclusion, the structure-activity relationship was derived based on the in silico and experimental results for the third order NLO susceptibilities.

  5. Introducing the LASSO graph for compound data set representation and structure-activity relationship analysis.

    Science.gov (United States)

    Gupta-Ostermann, Disha; Hu, Ye; Bajorath, Jürgen

    2012-06-14

    A graphical method is introduced for compound data mining and structure-activity relationship (SAR) data analysis that is based upon a canonical structural organization scheme and captures a compound-scaffold-skeleton hierarchy. The graph representation has a constant layout, integrates compound activity data, and provides direct access to SAR information. Characteristic SAR patterns that emerge from the graph are easily identified. The molecular hierarchy enables "forward-backward" analysis of compound data and reveals both global and local SAR patterns. For example, in heterogeneous data sets, compound series are immediately identified that convey interpretable SAR information in isolation or in the structural context of related series, which often define SAR pathways through data sets.

  6. Semantic categorization and reading skill across Dutch primary grades: development yes, relationship no

    NARCIS (Netherlands)

    Gijsel, M.A.R.; Ormel, E.A.; Hermans, D.; Verhoeven, L.T.W.; Bosman, A.M.T.

    2011-01-01

    In the present study, the development of semantic categorization and its relationship with reading was investigated across Dutch primary grade students. Three Exemplar-level tasks (Experiment 1) and two Superordinate-level tasks (Experiment 2) with different types of distracters (phonological,

  7. Localized heuristic inverse quantitative structure activity relationship with bulk descriptors using numerical gradients.

    Science.gov (United States)

    Stålring, Jonna; Almeida, Pedro R; Carlsson, Lars; Helgee Ahlberg, Ernst; Hasselgren, Catrin; Boyer, Scott

    2013-08-26

    State-of-the-art quantitative structure-activity relationship (QSAR) models are often based on nonlinear machine learning algorithms, which are difficult to interpret. From a pharmaceutical perspective, QSARs are used to enhance the chemical design process. Ultimately, they should not only provide a prediction but also contribute to a mechanistic understanding and guide modifications to the chemical structure, promoting compounds with desirable biological activity profiles. Global ranking of descriptor importance and inverse QSAR have been used for these purposes. This paper introduces localized heuristic inverse QSAR, which provides an assessment of the relative ability of the descriptors to influence the biological response in an area localized around the predicted compound. The method is based on numerical gradients with parameters optimized using data sets sampled from analytical functions. The heuristic character of the method reduces the computational requirements and makes it applicable not only to fragment based methods but also to QSARs based on bulk descriptors. The application of the method is illustrated on congeneric QSAR data sets, and it is shown that the predicted influential descriptors can be used to guide structural modifications that affect the biological response in the desired direction. The method is implemented into the AZOrange Open Source QSAR package. The current implementation of localized heuristic inverse QSAR is a step toward a generally applicable method for elucidating the structure activity relationship specifically for a congeneric region of chemical space when using QSARs based on bulk properties. Consequently, this method could contribute to accelerating the chemical design process in pharmaceutical projects, as well as provide information that could enhance the mechanistic understanding for individual scaffolds.

  8. QSAR DataBank repository: open and linked qualitative and quantitative structure-activity relationship models.

    Science.gov (United States)

    Ruusmann, V; Sild, S; Maran, U

    2015-01-01

    Structure-activity relationship models have been used to gain insight into chemical and physical processes in biomedicine, toxicology, biotechnology, etc. for almost a century. They have been recognized as valuable tools in decision support workflows for qualitative and quantitative predictions. The main obstacle preventing broader adoption of quantitative structure-activity relationships [(Q)SARs] is that published models are still relatively difficult to discover, retrieve and redeploy in a modern computer-oriented environment. This publication describes a digital repository that makes in silico (Q)SAR-type descriptive and predictive models archivable, citable and usable in a novel way for most common research and applied science purposes. The QSAR DataBank (QsarDB) repository aims to make the processes and outcomes of in silico modelling work transparent, reproducible and accessible. Briefly, the models are represented in the QsarDB data format and stored in a content-aware repository (a.k.a. smart repository). Content awareness has two dimensions. First, models are organized into collections and then into collection hierarchies based on their metadata. Second, the repository is not only an environment for browsing and downloading models (the QDB archive) but also offers integrated services, such as model analysis and visualization and prediction making. The QsarDB repository unlocks the potential of descriptive and predictive in silico (Q)SAR-type models by allowing new and different types of collaboration between model developers and model users. The key enabling factor is the representation of (Q)SAR models in the QsarDB data format, which makes it easy to preserve and share all relevant data, information and knowledge. Model developers can become more productive by effectively reusing prior art. Model users can make more confident decisions by relying on supporting information that is larger and more diverse than before. Furthermore, the smart repository

  9. Exploiting Feature and Class Relationships in Video Categorization with Regularized Deep Neural Networks.

    Science.gov (United States)

    Jiang, Yu-Gang; Wu, Zuxuan; Wang, Jun; Xue, Xiangyang; Chang, Shih-Fu

    2018-02-01

    In this paper, we study the challenging problem of categorizing videos according to high-level semantics such as the existence of a particular human action or a complex event. Although extensive efforts have been devoted in recent years, most existing works combined multiple video features using simple fusion strategies and neglected the utilization of inter-class semantic relationships. This paper proposes a novel unified framework that jointly exploits the feature relationships and the class relationships for improved categorization performance. Specifically, these two types of relationships are estimated and utilized by imposing regularizations in the learning process of a deep neural network (DNN). Through arming the DNN with better capability of harnessing both the feature and the class relationships, the proposed regularized DNN (rDNN) is more suitable for modeling video semantics. We show that rDNN produces better performance over several state-of-the-art approaches. Competitive results are reported on the well-known Hollywood2 and Columbia Consumer Video benchmarks. In addition, to stimulate future research on large scale video categorization, we collect and release a new benchmark dataset, called FCVID, which contains 91,223 Internet videos and 239 manually annotated categories.

  10. Structure-activity relationships for chloro- and nitrophenol toxicity in the pollen tube growth test

    Energy Technology Data Exchange (ETDEWEB)

    Schueuermann, G. [UFZ Centre for Environmental Research, Leipzig (Germany). Dept. of Chemical Ecotoxicology; Somashekar, R.K. [Bangalore Univ. (India). Dept. of Botany; Kristen, U. [Univ. Hamburg (Germany). Inst. fuer Allgemeine Botanik

    1996-10-01

    Acute toxicity of 10 chlorophenols and 10 nitrophenols with identical substitution patterns is analyzed with the pollen tube growth (PTG) test. Concentration values of 50% growth inhibition (IC50) between 0.1 and 300 mg/L indicate that the absolute sensitivity of this alternative biotest is comparable to conventional aquatic test systems. Analysis of quantitative structure-activity relationships using lipophilicity (log K{sub ow}), acidity (pK{sub a}), and quantum chemical parameters to model intrinsic acidity, solvation interactions, and nucleophilicity reveals substantial differences between the intraseries trends of log IC50. With chlorophenols, a narcotic-type relationship is derived, which, however, shows marked differences in slope and intercept when compared to reference regression equations for polar narcosis. Regression analysis of nitrophenol toxicity suggests interpretation in terms of two modes of action: oxidative uncoupling activity is associated with a pK{sub a} window from 3.8 to 8.5, and more acidic congeners with diortho-substitution show a transition from uncoupling to a narcotic mode of action with decreasing pK{sub a} and log K{sub ow}. Model calculations for phenol nucleophilicity suggest that differences in the phenol readiness for glucuronic acid conjugation as a major phase-II detoxication pathway have no direct influence on acute PTG toxicity of the compounds.

  11. Using quantitative structure-activity relationships (QSAR) to predict toxic endpoints for polycyclic aromatic hydrocarbons (PAH).

    Science.gov (United States)

    Bruce, Erica D; Autenrieth, Robin L; Burghardt, Robert C; Donnelly, K C; McDonald, Thomas J

    2008-01-01

    Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.

  12. Quantitative structure-activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models.

    Science.gov (United States)

    Naik, P K; Singh, T; Singh, H

    2009-07-01

    Quantitative structure-activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero value, simple correlation and multi-collinearity tests as well as the use of a genetic algorithm allowed the optimal selection of the descriptors used to generate the models. The QSAR models developed for both organophosphate and carbamate groups revealed good predictability with r(2) values of 0.949 and 0.838 as well as [image omitted] values of 0.890 and 0.765, respectively. In addition, a linear correlation was observed between the predicted and experimental LD(50) values for the test set data with r(2) of 0.871 and 0.788 for both the organophosphate and carbamate groups, indicating that the prediction accuracy of the QSAR models was acceptable. The models were also tested successfully from external validation criteria. QSAR models developed in this study should help further design of novel potent insecticides.

  13. Quantitative structure-activity relationships for aqueous metal-siderophore complexes.

    Science.gov (United States)

    Duckworth, Owen W; Bargar, John R; Sposito, Garrison

    2009-01-15

    Siderophores, biogenic chelating agents that facilitate the solubilization and uptake of ferric iron, form stable complexes with a wide range of nutrient and contaminant metals and thus may profoundly affect their fate, transport, and biogeochemical cycling. To understand more comprehensively the factors that control the stability and reactivity, as well as the potential for microbial uptake, of metal-siderophore complexes, we probed the structures of complexes formed between the trihydroxamate siderophore desferrioxamine B (DFOB) and Cu(II), Ga(III), Mn(II), Ni(II), and Zn(II) in solution by using extended X-ray absorption fine structure (EXAFS) spectroscopy. We find that all metals studied are dominantly in octahedral coordination, with significant Jahn-Teller distortion of the Cu(II)HDFOB(0) complex. Additionally, log-transformed complex stability constants correlate not only with the charge-normalized interatomic distances within the complex, affirming and expanding existing predictive relationships, but also with the Debye-Waller parameter of the first coordination shell. The derived structure-activity relationships not only quantitatively relate the measured physical architecture of aqueous complexes to their observed stability but also allow for the prediction of siderophore-metal stability constants.

  14. Structure-Activity Relationship Analysis of the Thermal Stabilities of Nitroaromatic Compounds Following Different Decomposition Mechanisms.

    Science.gov (United States)

    Li, Jiazhong; Liu, Huanxiang; Huo, Xing; Gramatica, Paola

    2013-02-01

    The decomposition behavior of energetic materials is very important for the safety problems concerning their production, transportation, use and storage, because molecular decomposition is intimately connected to their explosive properties. Nitroaromatic compounds, particularly nitrobenzene derivatives, are often considered as prototypical energetic molecules, and some of them are commonly used as high explosives. Quantitative structure-activity relationship (QSAR) represents a potential tool for predicting the thermal stability properties of energetic materials. But it is reported that constructing general reliable models to predict their stability and their potential explosive properties is a very difficult task. In this work, we make our efforts to investigate the relationship between the molecular structures and corresponding thermal stabilities of 77 nitrobenzene derivatives with various substituent functional groups (in ortho, meta and/or para positions). The proposed best MLR model, developed by the new software QSARINS, based on Genetic Algorithm for variable selection and with various validation tools, is robust, stable and predictive with R(2) of 0.86, QLOO (2) of 0.79 and CCC of 0.90. The results indicated that, though difficult, it is possible to build predictive, externally validated QSAR models to estimate the thermal stability of nitroaromatic compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Development and Validation of Quantitative Structure-Activity Relationship Models for Compounds Acting on Serotoninergic Receptors

    Directory of Open Access Journals (Sweden)

    Grażyna Żydek

    2012-01-01

    Full Text Available A quantitative structure-activity relationship (QSAR study has been made on 20 compounds with serotonin (5-HT receptor affinity. Thin-layer chromatographic (TLC data and physicochemical parameters were applied in this study. RP2 TLC 60F254 plates (silanized impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids and their mixtures (denoted as S1–S7 biochromatographic models were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R2=0.78–0.84 obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. “Leave-one-out” (LOO and “leave-N-out” (LNO cross-validation methods were used to judge the predictive power of final regression equations.

  16. Leishmanicidal Activity and Structure-Activity Relationships of Essential Oil Constituents.

    Science.gov (United States)

    Silva, Audrey R S T; Scher, Ricardo; Santos, Flaviane V; Ferreira, Sebastião R; Cavalcanti, Sócrates C H; Correa, Cristiane B; Bueno, Lilian L; Alves, Ricardo J; Souza, Damião P; Fujiwara, Ricardo T; Dolabella, Silvio S

    2017-05-16

    Several constituents of essential oils have been shown to be active against pathogens such as bacteria, fungi, and protozoa. This study demonstrated the in vitro action of ten compounds present in essential oils against Leishmania amazonensis promastigotes. With the exception of p -cymene, all evaluated compounds presented leishmanicidal activity, exhibiting IC 50 between 25.4 and 568.1 μg mL -1 . Compounds with the best leishmanicidal activity presented a phenolic moiety (IC 50 between 25.4 and 82.9 μg mL -1 ). Alicyclic alcohols ((-)-menthol and isoborneol) and ketones ((-)-carvone) promoted similar activity against the parasite (IC 50 between 190.2 and 198.9 μg mL -1 ). Most of the compounds showed low cytotoxicity in L929 fibroblasts. Analysis of the structure-activity relationship of these compounds showed the importance of the phenolic structure for the biological action against the promastigote forms of the parasite.

  17. Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors.

    Science.gov (United States)

    Rauhamäki, Sanna; Postila, Pekka A; Niinivehmas, Sanna; Kortet, Sami; Schildt, Emmi; Pasanen, Mira; Manivannan, Elangovan; Ahinko, Mira; Koskimies, Pasi; Nyberg, Niina; Huuskonen, Pasi; Multamäki, Elina; Pasanen, Markku; Juvonen, Risto O; Raunio, Hannu; Huuskonen, Juhani; Pentikäinen, Olli T

    2018-01-01

    Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM-1 μM. The IC 50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1 , present unique pharmacological features worth considering in future drug development.

  18. QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIPS ANALYSIS ANTIMUTAGENIC BENZALACETONE DERIVATIVES BY PRINCIPAL COMPONENT REGRESSION APPROACH

    Directory of Open Access Journals (Sweden)

    Yuliana Yuliana

    2010-06-01

    Full Text Available Quantitative Electronic Structure Activity Relationship (QSAR analysis of a series of benzalacetones has been investigated based on semi empirical PM3 calculation data using Principal Components Regression (PCR. Investigation has been done based on antimutagen activity from benzalacetone compounds (presented by log 1/IC50 and was studied as linear correlation with latent variables (Tx resulted from transformation of atomic net charges using Principal Component Analysis (PCA. QSAR equation was determinated based on distribution of selected components and then was analysed with PCR. The result was described by the following QSAR equation : log 1/IC50 = 6.555 + (2.177.T1 + (2.284.T2 + (1.933.T3 The equation was significant on the 95% level with statistical parameters : n = 28 r = 0.766  SE  = 0.245  Fcalculation/Ftable = 3.780 and gave the PRESS result 0.002. It means that there were only a relatively few deviations between the experimental and theoretical data of antimutagenic activity.          New types of benzalacetone derivative compounds were designed  and their theoretical activity were predicted based on the best QSAR equation. It was found that compounds number 29, 30, 31, 32, 33, 35, 36, 37, 38, 40, 41, 42, 44, 47, 48, 49 and 50  have  a relatively high antimutagenic activity.   Keywords: QSAR; antimutagenic activity; benzalaceton; atomic net charge

  19. Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships.

    Science.gov (United States)

    Amico, Vincenzo; Barresi, Vincenza; Condorelli, Daniele; Spatafora, Carmela; Tringali, Corrado

    2006-02-08

    Bioassay-guided fractionation of the EtOAc crude extract from Sicilian almond hulls, a waste material from Prunus dulcis crop, allowed identification of 10 constituents, isolated as pure compounds (1-5, 7, and 10) or unseparable mixtures (5 + 6 and 8 + 9). All compounds were subjected to spectroscopic analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide bioassay on MCF-7 human breast cancer cells. In addition to the main components oleanolic (1), ursolic (2), and betulinic (3) acids, the 2-hydroxy analogues alphitolic (4), corosolic (5), and maslinic (6) acids, as well as the related aldehydes, namely, betulinic (7), oleanolic (8), and ursolic (9), were identified. From a more polar fraction, the beta-sitosterol 3-O-glucoside (10) was also identified. A sample of commercially available betulin (11) was also included in bioassays as further support to a structure-activity relationship study. Betulinic acid showed antiproliferative activity toward MCF-7 cells (GI50 = 0.27 microM), higher than the anticancer drug 5-fluorouracil.

  20. Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.

    Science.gov (United States)

    Nolte, Tom M; Peijnenburg, Willie J G M; Hendriks, A Jan; van de Meent, Dik

    2017-07-01

    After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural diverse polymers which are capable to estimate green algae growth inhibition (EC50). The model (N = 43, R 2  = 0.73, RMSE = 0.28) is a regression-based decision tree using one structural descriptor for each of three polymer classes separated based on charge. The QSAR is applicable to linear homo polymers as well as copolymers and does not require information on the size of the polymer particle or underlying core material. Highly branched polymers, non-nitrogen cationic polymers and polymeric surfactants are not included in the model and thus cannot be evaluated. The model works best for cationic and non-ionic polymers for which cellular adsorption, disruption of the cell wall and photosynthesis inhibition were the mechanisms of action. For anionic polymers, specific properties of the polymer and test characteristics need to be known for detailed assessment. The data and QSAR results for anionic polymers, when combined with molecular dynamics simulations indicated that nutrient depletion is likely the dominant mode of toxicity. Nutrient depletion in turn, is determined by the non-linear interplay between polymer charge density and backbone flexibility. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure-activity relationship studies.

    Science.gov (United States)

    Ning, Chengqing; Mo, Liumei; Chen, Xuwei; Tu, Wentong; Wu, Jun; Hou, Shengtao; Xu, Jing

    2018-02-15

    Owning to the promising neuroprotective profile and the ability to cross the blood-brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure-activity relationship studies for Alzheimer's disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aβ 1-42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. 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.

  3. Demystifying Multitask Deep Neural Networks for Quantitative Structure-Activity Relationships.

    Science.gov (United States)

    Xu, Yuting; Ma, Junshui; Liaw, Andy; Sheridan, Robert P; Svetnik, Vladimir

    2017-10-23

    Deep neural networks (DNNs) are complex computational models that have found great success in many artificial intelligence applications, such as computer vision1,2 and natural language processing.3,4 In the past four years, DNNs have also generated promising results for quantitative structure-activity relationship (QSAR) tasks.5,6 Previous work showed that DNNs can routinely make better predictions than traditional methods, such as random forests, on a diverse collection of QSAR data sets. It was also found that multitask DNN models-those trained on and predicting multiple QSAR properties simultaneously-outperform DNNs trained separately on the individual data sets in many, but not all, tasks. To date there has been no satisfactory explanation of why the QSAR of one task embedded in a multitask DNN can borrow information from other unrelated QSAR tasks. Thus, using multitask DNNs in a way that consistently provides a predictive advantage becomes a challenge. In this work, we explored why multitask DNNs make a difference in predictive performance. Our results show that during prediction a multitask DNN does borrow "signal" from molecules with similar structures in the training sets of the other tasks. However, whether this borrowing leads to better or worse predictive performance depends on whether the activities are correlated. On the basis of this, we have developed a strategy to use multitask DNNs that incorporate prior domain knowledge to select training sets with correlated activities, and we demonstrate its effectiveness on several examples.

  4. In-silico prediction of sweetness using structure-activity relationship models.

    Science.gov (United States)

    Goel, Anukrati; Gajula, Kishore; Gupta, Rakesh; Rai, Beena

    2018-07-01

    Quantitative structure activity relationship (QSAR) models appear to be an ideal tool for quick screening of promising candidates from a vast library of molecules, which can then be further designed, synthesized and tested using a combination of rigorous first principle simulations, such as molecular docking, molecular dynamics simulation and experiments. In this study, QSAR models have been built with an extensive dataset of 487 compounds to predict the sweetness potency relative to sucrose (ranging 0.2-220,000). The whole dataset was randomly split into training and test sets in a 70:30 ratio. The models were developed using Genetic Function Approximation (R test 2  = 0.832) and Artificial Neural Network (R test 2  = 0.831). Our models thus offer a convenient route for fast screening of molecules prior to synthesis and testing. Additionally, this study can supplement a molecular modelling approach to improve binding of molecules with sweet taste receptors, leading to design of novel sweeteners. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure-Activity Relationships.

    Science.gov (United States)

    Poli, Giulio; Di Fabio, Romano; Ferrante, Luca; Summa, Vincenzo; Botta, Maurizio

    2017-12-07

    Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as an inhibitor of histone deacetylases (HDACs) and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported, allowing the identification of important structure-activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profiles, anticancer activity, and pharmacokinetic properties. The aim of this review is to concisely summarize the information obtained by biological evaluations of the various largazole analogues reported to date, with particular attention given to the latest analogues, as well as to analyze the various SAR obtained from this data, with the purpose of providing useful guidelines for the development of novel potent and selective HDAC inhibitors to be used as anticancer agents. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. 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.

  7. Advances in the molecular modeling and quantitative structure-activity relationship-based design for antihistamines.

    Science.gov (United States)

    Galvez, Jorge; Galvez-Llompart, Maria; Zanni, Riccardo; Garcia-Domenech, Ramon

    2013-03-01

    Nowadays the use of antihistamines (AH) is increasing steadily. These drugs are able to act on a variety of pathological conditions of the organism. A number of computer-aided (in silico) approaches have been developed to discover and develop novel AH drugs. Among these methods stand the ones based on drug-receptor docking, thermodynamics, as well as the quantitative structure-activity relationships (QSAR). This review collates the most recent advances in the use of computer approaches for the search and characterization of novel AH drugs. Within the QSAR methods, particular attention will be paid to those based on molecular topology (MT) because of their demonstrated efficacy in discovering new drugs. Collateral topics will also be dealt with including: docking studies, thermodynamic aspects, molecular modeling and so on. These issues will be treated to the extent that they have interest as complementary to QSAR-MT. Given the importance of the use of AHs, the search for new drugs in this field has become imperative today. In this regard, the use of QSAR methods based on MT, namely QSAR-MT, has proven to be a powerful tool when the goal is discovering new hit or lead structures. It has been shown that antihistaminic activity is complex and different for the four known types of receptors (H1 to H4) and that electronic, steric and physicochemical issues determine drug activity. These factors, along with the purely structural ones, can be deduced from topological and topochemical information.

  8. Activity cliff clusters as a source of structure-activity relationship information.

    Science.gov (United States)

    Dimova, Dilyana; Stumpfe, Dagmar; Hu, Ye; Bajorath, Jürgen

    2015-05-01

    The activity cliff (AC) concept is widely applied in medicinal chemistry. ACs are formed by compounds with small structural changes having large differences in potency. Accordingly, ACs are a primary source of structure-activity relationship (SAR) information. Through large-scale compound data mining it has been shown that the vast majority of ACs are formed in a coordinated manner by groups of structurally analogous compounds with significant potency variations. In network representations coordinated ACs form clusters of varying size but frequently recurrent topology. Recently, computational methods have been introduced to systematically organize AC clusters and extract SAR information from them. AC clusters are widely distributed over compound activity classes and represent a rich source of SAR information. These clusters can be visualized in AC networks and isolated. However, it is challenging to extract SAR information from such clusters and make this information available to the practice of medicinal chemistry. Therefore, it is essential to go beyond subjective case-by-case analysis and design computational approaches to systematically access SAR information associated with AC clusters.

  9. Flavonoids as Vasorelaxant Agents: Synthesis, Biological Evaluation and Quantitative Structure Activities Relationship (QSAR Studies

    Directory of Open Access Journals (Sweden)

    Yongzhou Hu

    2011-09-01

    Full Text Available A series of 2-(2-diethylamino-ethoxychalcone and 6-prenyl(or its isomers-flavanones 10a,b and 11a–g were synthesized and evaluated for their vasorelaxant activities against rat aorta rings pretreated with 1 μM phenylephrine (PE. Several compounds showed potent vasorelaxant activities. Compound 10a (EC50 = 7.6 μM, Emax = 93.1%, the most potent one, would be a promising structural template for development of novel and more efficient vasodilators. Further, 2D-QSAR analysis of compounds 10a,b and 11c-e as well as thirty previously synthesized flavonoids 1-3 and 12-38 using Enhanced Replacement Method-Multiple Linear Regression (ERM-MLR was further performed based on an optimal set of molecular descriptors (H5m, SIC2, DISPe, Mor03u and L3m, leading to a reliable model with good predictive ability (Rtrain2 = 0.839, Qloo2 = 0.733 and Rtest2 = 0.804. The results provide good insights into the structure- activity relationships of the target compounds.

  10. Structure-activity relationships and molecular docking of thirteen synthesized flavonoids as horseradish peroxidase inhibitors.

    Science.gov (United States)

    Mahfoudi, Reguia; Djeridane, Amar; Benarous, Khedidja; Gaydou, Emile M; Yousfi, Mohamed

    2017-10-01

    For the first time, the structure-activity relationships of thirteen synthesized flavonoids have been investigated by evaluating their ability to modulate horseradish peroxidase (HRP) catalytic activity. Indeed, a modified spectrophotometrically method was carried out and optimized using 4-methylcatechol (4-MC) as peroxidase co-substrate. The results show that these flavonoids exhibit a great capacity to inhibit peroxidase with Ki values ranged from 0.14±0.01 to 65±0.04mM. Molecular docking has been achieved using Auto Dock Vina program to discuss the nature of interactions and the mechanism of inhibition. According to the docking results, all the flavonoids have shown great binding affinity to peroxidase. These molecular modeling studies suggested that pyran-4-one cycle acts as an inhibition key for peroxidase. Therefore, potent peroxidase inhibitors are flavonoids with these structural requirements: the presence of the hydroxyl (OH) group in 7, 5 and 4' positions and the absence of the methoxy (O-CH 3 ) group. Apigenin contributed better in HRP inhibitory activity. The present study has shown that the studied flavonoids could be promising HRP inhibitors, which can help in developing new molecules to control thyroid diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Structure-activity relationship studies on the macrolide exotoxin mycolactone of Mycobacterium ulcerans.

    Directory of Open Access Journals (Sweden)

    Nicole Scherr

    Full Text Available BACKGROUND: Mycolactones are a family of polyketide-derived macrolide exotoxins produced by Mycobacterium ulcerans, the causative agent of the chronic necrotizing skin disease Buruli ulcer. The toxin is synthesized by polyketide synthases encoded by the virulence plasmid pMUM. The apoptotic, necrotic and immunosuppressive properties of mycolactones play a central role in the pathogenesis of M. ulcerans. METHODOLOGY/PRINCIPAL FINDINGS: We have synthesized and tested a series of mycolactone derivatives to conduct structure-activity relationship studies. Flow cytometry, fluorescence microscopy and Alamar Blue-based metabolic assays were used to assess activities of mycolactones on the murine L929 fibroblast cell line. Modifications of the C-linked upper side chain (comprising C12-C20 caused less pronounced changes in cytotoxicity than modifications in the lower C5-O-linked polyunsaturated acyl side chain. A derivative with a truncated lower side chain was unique in having strong inhibitory effects on fibroblast metabolism and cell proliferation at non-cytotoxic concentrations. We also tested whether mycolactones have antimicrobial activity and found no activity against representatives of Gram-positive (Streptococcus pneumoniae or Gram-negative bacteria (Neisseria meningitis and Escherichia coli, the fungus Saccharomyces cerevisae or the amoeba Dictyostelium discoideum. CONCLUSION: Highly defined synthetic compounds allowed to unambiguously compare biological activities of mycolactones expressed by different M. ulcerans lineages and may help identifying target structures and triggering pathways.

  12. Prediction of environmental toxicity and fate using quantitative structure-activity relationships (QSARs

    Directory of Open Access Journals (Sweden)

    Dearden John C.

    2002-01-01

    Full Text Available Little or nothing is known about the toxicity of most of the >100,000 chemicals released into the environment. The cost of obtaining such information experimentally would be enormous in terms of money, time and animals. Companies and regulatory agencies are therefore turning to the prediction of environmental toxicity and fate through the use of quantitative structure-activity relationships (QSARs. This paper examines the use of QSARs in this context. Generally, QSARs are mechanism-specific, so that the first step is to classify a toxicant into one of four broad classes of toxicity: non-polar narcosis, polar narcosis, unselective reactivity and specific action (e.g. anticholinesterase activity. An appropriate QSAR can then be selected in order to predict the toxicity of a given chemical. There are also some expert systems available for toxicity prediction. QSAR predictions of bioconcentration, soil sorption and biodegradability can also be made; again, expert systems are available for such prediction. QSAR and expert system prediction of physico-chemical properties such as partition coefficient, aqueous solubility, melting and boiling point, vapour pressure and Henry's law constant can readily be made.

  13. Biocidal Compounds from Mentha sp. Essential Oils and Their Structure-Activity Relationships.

    Science.gov (United States)

    Kimbaris, Athanasios C; González-Coloma, Azucena; Andrés, Maria Fe; Vidali, Veroniki P; Polissiou, Moschos G; Santana-Méridas, Omar

    2017-03-01

    Essential oils from Greek Mentha species showed different chemical compositions for two populations of M. pulegium, characterized by piperitone and pulegone. Mentha spicata essential oil was characterized by endocyclic piperitenone epoxide, piperitone epoxide, and carvone. The bioactivities of these essential oils and their components have been tested against insect pests (Leptinotarsa decemlineata, Spodoptera littoralis and Myzus persicae), root-knot nematodes (Meloydogine javanica) and plants (Lactuca sativa, Lolium perenne, Solanum lycopersicum). The structure-activity relationships of these compounds have been studied including semi-synthetic endocyclic trans-carvone epoxide, exocyclic carvone epoxide, a new exocyclic piperitenone epoxide and trans-pulegone epoxide. Leptinotarsa decemlineata feeding was affected by piperitenone and piperitone epoxide. Spodoptera littoralis was affected by piperitone epoxide and pulegone. The strongest nematicidal agent was piperitenone epoxide, followed by piperitone epoxide, piperitenone and carvone. Germination of S. lycopersicum and L. perenne was significantly affected by piperitenone epoxide. This compound and carvone epoxide inhibited L. perenne root and leaf growth. Piperitenone epoxide also inhibited the root growth of S. lycopersicum. The presence of a C(1) epoxide resulted in strong antifeedant, nematicidal and phytotoxic compounds regardless of the C(4) substituent. New natural crop protectants could be developed through appropriate structural modifications in the p-menthane skeleton. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  14. Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction.

    Science.gov (United States)

    De Filippis, Vincenzo; Acquasaliente, Laura; Pontarollo, Giulia; Peterle, Daniele

    2018-01-01

    The advent of recombinant DNA technology allowed to site-specifically insert, delete, or mutate almost any amino acid in a given protein, significantly improving our knowledge of protein structure, stability, and function. Nevertheless, a quantitative description of the physical and chemical basis that makes a polypeptide chain to efficiently fold into a stable and functionally active conformation is still elusive. This mainly originates from the fact that nature combined, in a yet unknown manner, different properties (i.e., hydrophobicity, conformational propensity, polarizability, and hydrogen bonding capability) into the 20 standard natural amino acids, thus making difficult, if not impossible, to univocally relate the change in protein stability or function to the alteration of physicochemical properties caused by amino acid exchange(s). In this view, incorporation of noncoded amino acids with tailored side chains, allowing to finely tune the structure at a protein site, would facilitate to dissect the effects of a given mutation in terms of one or a few physicochemical properties, thus much expanding the scope of physical organic chemistry in the study of proteins. In this review, relevant applications from our laboratory will be presented on the use of noncoded amino acids in structure-activity relationships studies of hirudin binding to thrombin. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  15. Structure-activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase.

    Science.gov (United States)

    Kim, In-Hae; Lee, In-Hee; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

    2014-02-01

    We explored both structure-activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors. When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives. In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility. In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility. The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. 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.

  17. 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.

  18. Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

    Science.gov (United States)

    Jukić, Marijana; Rastija, Vesna; Opačak-Bernardi, Teuta; Stolić, Ivana; Krstulović, Luka; Bajić, Miroslav; Glavaš-Obrovac, Ljubica

    2017-04-01

    The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure-activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed.

  19. Quantitative structure-activity relationship: promising advances in drug discovery platforms.

    Science.gov (United States)

    Wang, Tao; Wu, Mian-Bin; Lin, Jian-Ping; Yang, Li-Rong

    2015-12-01

    Quantitative structure-activity relationship (QSAR) modeling is one of the most popular computer-aided tools employed in medicinal chemistry for drug discovery and lead optimization. It is especially powerful in the absence of 3D structures of specific drug targets. QSAR methods have been shown to draw public attention since they were first introduced. In this review, the authors provide a brief discussion of the basic principles of QSAR, model development and model validation. They also highlight the current applications of QSAR in different fields, particularly in virtual screening, rational drug design and multi-target QSAR. Finally, in view of recent controversies, the authors detail the challenges faced by QSAR modeling and the relevant solutions. The aim of this review is to show how QSAR modeling can be applied in novel drug discovery, design and lead optimization. QSAR should intentionally be used as a powerful tool for fragment-based drug design platforms in the field of drug discovery and design. Although there have been an increasing number of experimentally determined protein structures in recent years, a great number of protein structures cannot be easily obtained (i.e., membrane transport proteins and G-protein coupled receptors). Fragment-based drug discovery, such as QSAR, could be applied further and have a significant role in dealing with these problems. Moreover, along with the development of computer software and hardware, it is believed that QSAR will be increasingly important.

  20. Advances in quantitative structure-activity relationship models of anti-Alzheimer's agents.

    Science.gov (United States)

    Ambure, Pravin; Roy, Kunal

    2014-06-01

    Alzheimer's disease (AD) is one of the lethal diseases, mainly affecting older people. The unclear root cause and involvement of various enzymes in the pathological conditions confirm the complexity of the disease. Quantitative structure-activity relationship (QSAR) techniques are of great significance in the design of drugs against AD. In the present review, the authors provide a basic background about AD and QSAR techniques. Furthermore, they review the various QSAR studies reported against various targets of AD. The information provided for each QSAR study includes chemical scaffold and target enzyme under study, applied QSAR technique and outcomes of the respective study. In silico techniques like QSAR hold great potential in designing leads against a complex disease like AD. In combination with other in silico techniques, QSAR can provide more useful and rational insight to facilitate the discovery of novel compounds. Only few QSAR studies on imaging agents have been reported; hence, more QSAR studies are recommended to explore the biomarker or imaging agents for improving diagnosis. Again, for proper symptomatic treatment, multi-target drugs acting on more than one target are required. Hence, more multi-target QSAR studies are recommended in future to achieve this goal.

  1. Quantitative structure-activity relationship models of chemical transformations from matched pairs analyses.

    Science.gov (United States)

    Beck, Jeremy M; Springer, Clayton

    2014-04-28

    The concepts of activity cliffs and matched molecular pairs (MMP) are recent paradigms for analysis of data sets to identify structural changes that may be used to modify the potency of lead molecules in drug discovery projects. Analysis of MMPs was recently demonstrated as a feasible technique for quantitative structure-activity relationship (QSAR) modeling of prospective compounds. Although within a small data set, the lack of matched pairs, and the lack of knowledge about specific chemical transformations limit prospective applications. Here we present an alternative technique that determines pairwise descriptors for each matched pair and then uses a QSAR model to estimate the activity change associated with a chemical transformation. The descriptors effectively group similar transformations and incorporate information about the transformation and its local environment. Use of a transformation QSAR model allows one to estimate the activity change for novel transformations and therefore returns predictions for a larger fraction of test set compounds. Application of the proposed methodology to four public data sets results in increased model performance over a benchmark random forest and direct application of chemical transformations using QSAR-by-matched molecular pairs analysis (QSAR-by-MMPA).

  2. Quantitative Structure-activity Relationship (QSAR) Models for Docking Score Correction.

    Science.gov (United States)

    Fukunishi, Yoshifumi; Yamasaki, Satoshi; Yasumatsu, Isao; Takeuchi, Koh; Kurosawa, Takashi; Nakamura, Haruki

    2017-01-01

    In order to improve docking score correction, we developed several structure-based quantitative structure activity relationship (QSAR) models by protein-drug docking simulations and applied these models to public affinity data. The prediction models used descriptor-based regression, and the compound descriptor was a set of docking scores against multiple (∼600) proteins including nontargets. The binding free energy that corresponded to the docking score was approximated by a weighted average of docking scores for multiple proteins, and we tried linear, weighted linear and polynomial regression models considering the compound similarities. In addition, we tried a combination of these regression models for individual data sets such as IC 50 , K i , and %inhibition values. The cross-validation results showed that the weighted linear model was more accurate than the simple linear regression model. Thus, the QSAR approaches based on the affinity data of public databases should improve docking scores. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  3. Synthesis and anticancer structure activity relationship investigation of cationic anthraquinone analogs.

    Science.gov (United States)

    Shrestha, Jaya P; Fosso, Marina Y; Bearss, Jeremiah; Chang, Cheng-Wei Tom

    2014-04-22

    We have synthesized a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium salts, which can be viewed as analogs of cationic anthraquinones. Unlike the similar analogs that we have reported previously, these compounds show relatively weak antibacterial activities but exert strong anticancer activities (low μM to nM GI50), in particular, against melanoma, colon cancer, non-small cell lung cancer and central nervous system (CNS) cancer. These compounds are structurally different from their predecessors by having the aromatic group, instead of alkyl chains, directly attached to the cationic anthraquinone scaffold. Further investigation in the structure-activity relationship (SAR) reveals the significant role of electron donating substituents on the aromatic ring in enhancing the anticancer activities via resonance effect. Steric hindrance of these groups is disadvantageous but is less influential than the resonance effect. The difference in the attached groups at N-1 position of the cationic anthraquinone analog is the main structural factor for the switching of biological activity from antibacterial to anticancer. The discovery of these compounds may lead to the development of novel cancer chemotherapeutics. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication.

    Science.gov (United States)

    Kortagere, Sandhya; Xu, Jimmy P; Mankowski, Marie K; Ptak, Roger G; Cocklin, Simon

    2014-11-24

    Despite the considerable successes of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, cumulative drug toxicities and the development of multidrug-resistant virus necessitate the search for new classes of antiretroviral agents with novel modes of action. The HIV-1 capsid (CA) protein has been structurally and functionally characterized as a druggable target. We have recently designed a novel small molecule inhibitor I-XW-053 using the hybrid structure based method to block the interface between CA N-terminal domains (NTD-NTD interface) with micromolar affinity. In an effort to optimize and improve the efficacy of I-XW-053, we have developed the structure activity relationship of I-XW-053 compound series using ligand efficiency methods. Fifty-six analogues of I-XW-053 were designed that could be subclassified into four different core domains based on their ligand efficiency values computed as the ratio of binding efficiency (BEI) and surface efficiency (SEI) indices. Compound 34 belonging to subcore-3 showed an 11-fold improvement over I-XW-053 in blocking HIV-1 replication in primary human peripheral blood mononuclear cells (PBMCs). Surface plasmon resonance experiments confirmed the binding of compound 34 to purified HIV-1 CA protein. Molecular docking studies on compound 34 and I-XW-053 to HIV-1 CA protein suggested that they both bind to NTD-NTD interface region but with different binding modes, which was further validated using site-directed mutagenesis studies.

  5. Prediction of toxicity of phenols and anilines to algae by quantitative structure-activity relationship.

    Science.gov (United States)

    Lu, Guang-Hua; Wang, Chao; Guo, Xiao-Ling

    2008-06-01

    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. 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 (E(LUMO)) and the energy of the highest occupied molecular orbital (E(HOMO)) were obtained from the ChemOffice 2004 program using the quantum chemical method MOPAC, and the frontier orbital energy gap (deltaE) was obtained. The compounds exhibited a reasonably wide range of algal toxicity. The most toxic compound was alpha-naphthol, whereas the least toxic one was aniline. A two-descriptor model was derived from the algal toxicity and structural parameters: log1/EC50 = 0.268,logKow - 1.006deltaE + 11.769 (n = 20, r2 = 0.946). This model was stable and satisfactory for predicting toxicity. CONCLUSION Phenol, aniline, and their derivatives are polar narcotics. Their toxicity is greater than estimated by hydrophobicity only, and addition of the frontier orbital energy gap deltaE can significantly improve the prediction of logKow-dependent models.

  6. Quantitative structure-activity relationships of nitroaromatics toxicity to the algae (Scenedesmus obliguus).

    Science.gov (United States)

    Yan, Xiu-Fen; Xiao, He-Ming; Gong, Xue-Dong; Ju, Xue-Hai

    2005-04-01

    The DFT-B3LYP method, with the basis set 6-311G( * *), was employed to calculate the molecular geometries and electronic structures of 25 nitroaromatics. The acute toxicity (-lgEC(50)) of these compounds to the algae (Scenedesmus obliguus) along with hydrophobicity described by logK(OW), and two quantum chemical parameters-energy of the lowest unoccupied molecular orbital, E(LUMO), and the charge of the nitro group, [ForQ(NO2), were used to establish the quantitative structure-activity relationships (QSARs). For 18 mononitro derivatives, the hydrophobicity parameter logK(OW) could interpret the toxic mechanism successfully. Dinitro aromatic compounds were susceptible to be reduced to aniline for their electrophilic nature. Their toxicity was controlled mainly by electronic factors instead of hydrophobicity. The electronic parameters, E(LUMO) and Q(NO2), were used to yield the following model: -lg EC(50) = 3.746 - 25.053 E(LUMO) + 6.481 Q(NO2) (n=22, R=0.926, SE=0.206, F=56.854, Ptoxic values using the above equation are in good agreement with the experimental values.

  7. Synthesis, activity, and structure--activity relationship studies of novel cationic lipids for DNA transfer.

    Science.gov (United States)

    Byk, G; Dubertret, C; Escriou, V; Frederic, M; Jaslin, G; Rangara, R; Pitard, B; Crouzet, J; Wils, P; Schwartz, B; Scherman, D

    1998-01-15

    We have designed and synthesized original cationic lipids for gene delivery. A synthetic method on solid support allowed easy access to unsymmetrically monofunctionalized polyamine building blocks of variable geometries. These polyamine building blocks were introduced into cationic lipids. To optimize the transfection efficiency in the novel series, we have carried out structure-activity relationship studies by introduction of variable-length lipids, of variable-length linkers between lipid and cationic moiety, and of substituted linkers. We introduce the concept of using the linkers within cationic lipids molecules as carriers of side groups harboring various functionalities (side chain entity), as assessed by the introduction of a library composed of cationic entities, additional lipid chains, targeting groups, and finally the molecular probes rhodamine and biotin for cellular traffic studies. The transfection activity of the products was assayed in vitro on Hela carcinoma, on NIH3T3, and on CV1 fibroblasts and in vivo on the Lewis Lung carcinoma model. Products from the series displayed high transfection activities. Results indicated that the introduction of a targeting side chain moiety into the cationic lipid is permitted. A primary physicochemical characterization of the DNA/lipid complexes was demonstrated with this leading compound. Selected products from the series are currently being developed for preclinical studies, and the labeled lipopolyamines can be used to study the intracellular traffic of DNA/cationic lipid complexes.

  8. 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.

  9. Synthesis, photodynamic activity, and quantitative structure-activity relationship modelling of a series of BODIPYs.

    Science.gov (United States)

    Caruso, Enrico; Gariboldi, Marzia; Sangion, Alessandro; Gramatica, Paola; Banfi, Stefano

    2017-02-01

    Here we report the synthesis of eleven new BODIPYs (14-24) characterized by the presence of an aromatic ring on the 8 (meso) position and of iodine atoms on the pyrrolic 2,6 positions. These molecules, together with twelve BODIPYs already reported by us (1-12), represent a large panel of BODIPYs showing different atoms or groups as substituent of the aromatic moiety. Two physico-chemical features ( 1 O 2 generation rate and lipophilicity), which can play a fundamental role in the outcome as photosensitizers, have been studied. The in vitro photo-induced cell-killing efficacy of 23 PSs was studied on the SKOV3 cell line treating the cells for 24h in the dark then irradiating for 2h with a green LED device (fluence 25.2J/cm 2 ). The cell-killing efficacy was assessed with the MTT test and compared with that one of meso un-substituted compound (13). In order to understand the possible effect of the substituents, a predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, was developed. The results clearly indicate that the presence of an aromatic ring is fundamental for an excellent photodynamic response, whereas the electronic effects and the position of the substituents on the aromatic ring do not influence the photodynamic efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Luini, Mara; Monti, Elena; Gariboldi, Marzia B; Ravera, Mauro; Gabano, Elisabetta; Gaviglio, Luca; Osella, Domenico

    2010-09-01

    Several Pt(IV) complexes of the general formula [Pt(L)2(L')2(L'')2] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands L'' are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, Ep, and partition coefficient, log Po/w) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log Po/w or the number of secondary sp3 carbon atoms) plus an electronic descriptor (Ep, the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV)-->Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.

  11. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  12. Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter.

    Science.gov (United States)

    Kulkarni, Santosh S; Newman, Amy Hauck; Houlihan, William J

    2002-09-12

    A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of mazindol analogues using the comparative molecular field analysis (CoMFA) method with their corresponding binding affinities for the displacement of [(3)H]WIN 35 428 from rat caudate putamen tissue. The cross-validated CoMFA models were derived from a training set of 50 compounds, and the predictive ability of the resulting CoMFA models was evaluated against a test set of 21 compounds. A set of alignment rules was derived to superimpose these compounds onto a template structure, mazindol (1). These CoMFA models yielded significant cross-validated r(2)(cv) values. Inclusion of additional descriptors did not improve the significance of the CoMFA models; thus, steric and electrostatic fields are the relevant descriptors for these compounds. The best QSAR model was selected on the basis of the predictive ability of the activity on the external test set of compounds. The analysis of coefficient contour maps provided further insight into the binding interactions of mazindol analogues with the DAT. The aromatic rings C and D are involved in hydrophobic interactions in which ring D may bind in a large hydrophobic groove. The relative orientation of these two rings is also important for high binding affinity to the DAT.

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

    Science.gov (United States)

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

    2016-02-03

    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.

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

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    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.

  15. Biosynthetically Guided Structure-Activity Relationship Studies of Merochlorin A, an Antibiotic Marine Natural Product.

    Science.gov (United States)

    López-Pérez, Borja; Pepper, Henry P; Ma, Rong; Fawcett, Benjamin J; Pehere, Ashok D; Wei, Qi; Ji, Zengchun; Polyak, Steven W; Dai, Huanqin; Song, Fuhang; Abell, Andrew D; Zhang, Lixin; George, Jonathan H

    2017-12-07

    The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorin A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research.

    Science.gov (United States)

    Bradbury, S P

    1995-09-01

    In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. In this review, techniques to assess modes of toxic action from chemical structure are discussed, with consideration that toxicodynamic knowledge bases must be clearly defined with regard to exposure regimes, biological models/endpoints and compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases, classification systems, including rule-based expert systems, have been established for use in predictive aquatic toxicology applications. The establishment of QSAR techniques that are based on an understanding of toxic mechanisms is needed to provide a link to physiologically based toxicokinetic and toxicodynamic models, which can provide the means to extrapolate adverse effects across species and exposure regimes.

  17. (-)-Germacrene D receptor neurones in three species of heliothine moths: structure-activity relationships.

    Science.gov (United States)

    Stranden, M; Liblikas, I; König, W A; Almaas, T J; Borg-Karlson, A-K; Mustaparta, H

    2003-07-01

    Specificity of olfactory receptor neurones plays an important role in food and host preferences of a species, and may have become conserved or changed in the evolution of polyphagy and oligophagy. We have identified a major type of plant odour receptor neurones responding to the sesquiterpene germacrene D in three species of heliothine moths, the polyphagous Heliothis virescens and Helicoverpa armigera and the oligophagous Helicoverpa assulta. The neurones respond with high sensitivity and selectivity to (-)-germacrene D, as demonstrated by screening via gas chromatography with numerous mixtures of plant volatiles. Germacrene D was present in both host and non-host plants, but only in half of the tested species. The specificity of the neurones was similar in the three species, as shown by the "secondary" responses to a few other sesquiterpenes. The effect of (-)-germacrene D was about ten times stronger than that of the (+)-enantiomer, which again was about ten times stronger than that of (-)-alpha-ylangene. Weaker effects were obtained for (+)-beta-ylangene, (+)-alpha-copaene, beta-copaene and two unidentified sesquiterpenes. The structure-activity relationship shows that the important properties of (-)-germacrene D in activating the neurones are the ten-membered ring system and the three double bonds acting as electron-rich centres, in addition to the direction of the isopropyl-group responsible for the different effects of the germacrene D enantiomers.

  18. 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.

  19. Novel Methods for Prioritizing "Close-In" Analogs from Structure-Activity Relationship Matrices.

    Science.gov (United States)

    Zhang, Liying; Johnson, Kjell; Starr, Jeremy; Milbank, Jared; Kuhn, Andrew M; Poss, Christopher; Stanton, Robert V; Shanmugasundaram, Veerabahu

    2017-07-24

    Here we describe the development of novel methods for compound evaluation and prioritization based on the structure-activity relationship matrix (SARM) framework. The SARM data structure allows automatic and exhaustive extraction of SAR patterns from data sets and their organization into a chemically intuitive scaffold/functional-group format. While SARMs have been used in the retrospective analysis of SAR discontinuity and identifying underexplored regions of chemistry space, there have been only a few attempts to apply SARMs prospectively in the prioritization of "close-in" analogs. In this work, three new ways of prioritizing virtual compounds based on SARMs are described: (1) matrix pattern-based prioritization, (2) similarity weighted, matrix pattern-based prioritization, and (3) analysis of variance based prioritization (ANV). All of these methods yielded high predictive power for six benchmark data sets (prediction accuracy R 2 range from 0.63 to 0.82), yielding confidence in their application to new design ideas. In particular, the ANV method outperformed the previously reported SARM based method for five out of the six data sets tested. The impact of various SARM parameters were investigated and the reasons why SARM-based compound prioritization methods provide higher predictive power are discussed.

  20. Synthesis, structure-activity relationships studies of benzoxazinone derivatives as α-chymotrypsin inhibitors.

    Science.gov (United States)

    Marasini, Bishnu P; Rahim, Fazal; Perveen, Shahnaz; Karim, Aneela; Mohammed Khan, Khalid; Atta-Ur-Rahman; Choudhary, M Iqbal

    2017-02-01

    A series of benzoxazinones 1-28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1-18 showed a good inhibition of α-chymotrypsin with IC 50 ±SEM values between 6.5 and 341.1μM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho>meta>para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2μM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30μM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other α-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Gold(I) thiolates containing amino acid moieties. Cytotoxicity and structure-activity relationship studies.

    Science.gov (United States)

    Gutiérrez, Alejandro; Gracia-Fleta, Lucia; Marzo, Isabel; Cativiela, Carlos; Laguna, Antonio; Gimeno, M Concepción

    2014-12-07

    Several gold(I) complexes containing a thiolate ligand functionalised with several amino acid or peptide moieties of the type [Au(SPyCOR)(PPh2R')] (where R = OH, amino acid or dipeptide and R' = Ph or Py) were prepared. These thiolate gold complexes bearing biological molecules possess potential use as antitumor agents. Cytotoxicity assays in different tumour cell lines such as A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma) revealed that the complexes exhibit good antiproliferative activity, with IC50 values in the low micromolar range. Several structural modifications such as in the type of phosphine, number of metal atoms and amino acid (type, stereochemistry and functionalisation) were carried out in order to establish the structure-activity relationship in this family of complexes, which has led to the design of new and more potent cytotoxic complexes. Observations of different cellular events after addition of the complexes indicated the possible mechanism of action or the biological targets of this type of new gold(I) drug.

  2. 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.

  3. Fundamental Structure-Activity Relationships of Titanium Dioxide-Based Photocatalysts

    Science.gov (United States)

    Roberts, Charles A.

    Heterogeneous photocatalysis has been identified as a means of using renewable solar energy to produce the sustainable, non-carbon fuel H 2 and a variety of useful chemical intermediates. Currently, however, heterogeneous photocatalytic reactions are too inefficient to be industrially relevant and a deeper understanding of the effect of fundamental photocatalytic material properties on photoactivity is needed to further enhance the yields of desired products. In the general field of heterogeneous catalysis, structure-activity relationships aid in the rational design of improved catalysts and this ideology was applied to photocatalytic reactions over TiO2 based photocatalysts and model supported TiO2/SiO2 catalysts in this study. The model supported TiO2/SiO2 catalysts contain well-defined TiOx nanodomain structures that vary in domain size and electronic structure and greatly facilitate the determination of structure-photoactivity relationships. These catalysts were used in reactor studies during photocatalytic water splitting and cyclohexane photo-oxidation, and were monitored for production of H2 and cyclohexanone, respectively. It was found that for both reactions the trend in photoactivity for the TiOx nanodomains proceeded as: pure TiO2 (anatase) (24 nm) > TiO2 (anatase) nanoparticles (4--11 nm) > polymeric surface TiO5 (˜1 nm) > surface isolated TiO4 (˜0.4 nm). Photoluminescence (PL) spectroscopy was employed to yield insight into how exciton generation and recombination are related to TiOx domain size and, thus, to the photoactivity of the examined reactions. Transient PL decay studies determined that the larger bulk structure found in TiO 2 (anatase) nanoparticles (NPs) acts as a reservoir for excitons exhibiting slow recombination kinetics, which have an increased opportunity to participate in photochemistry at the surface active sites. The reactions were also studied using in situ attenuated total reflectance (ATR) Fourier transform infrared

  4. Novel peptide-specific quantitative structure-activity relationship (QSAR) analysis applied to collagen IV peptides with antiangiogenic activity.

    Science.gov (United States)

    Rivera, Corban G; Rosca, Elena V; Pandey, Niranjan B; Koskimaki, Jacob E; Bader, Joel S; Popel, Aleksander S

    2011-10-13

    Angiogenesis is the growth of new blood vessels from existing vasculature. Excessive vascularization is associated with a number of diseases including cancer. Antiangiogenic therapies have the potential to stunt cancer progression. Peptides derived from type IV collagen are potent inhibitors of angiogenesis. We wanted to gain a better understanding of collagen IV structure-activity relationships using a ligand-based approach. We developed novel peptide-specific QSAR models to study the activity of the peptides in endothelial cell proliferation, migration, and adhesion inhibition assays. We found that the models produced quantitatively accurate predictions of activity and provided insight into collagen IV derived peptide structure-activity relationships.

  5. Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity

    International Nuclear Information System (INIS)

    Morales, Aliuska Helguera; Perez, Miguel Angel Cabrera; Combes, Robert D.; Gonzalez, Maykel Perez

    2006-01-01

    Several nitrocompounds have been screened for carcinogenicity in rodents, but this is a lengthy and expensive process, taking two years and typically costing 2.5 million dollars, and uses large numbers of animals. There is, therefore, much impetus to develop suitable alternative methods. One possible way of predicting carcinogenicity is to use quantitative structure-activity relationships (QSARs). QSARs have been widely utilized for toxicity testing, thereby contributing to a reduction in the need for experimental animals. This paper describes the results of applying a TOPological substructural molecular design (TOPS-MODE) approach for predicting the rodent carcinogenicity of nitrocompounds. The model described 79.10% of the experimental variance, with a standard deviation of 0.424. The predictive power of the model was validated by leave-one-out validation, with a determination coefficient of 0.666. In addition, this approach enabled the contribution of different fragments to carcinogenic potency to be assessed, thereby making the relationships between structure and carcinogenicity to be transparent. It was found that the carcinogenic activity of the chemicals analysed was increased by the presence of a primary amine group bonded to the aromatic ring, a manner that was proportional to the ring aromaticity. The nitro group bonded to an aromatic carbon atom is a more important determinant of carcinogenicity than the nitro group bonded to an aliphatic carbon. Finally, the TOPS-MODE approach was compared with four other predictive models, but none of these could explain more than 66% of the variance in the carcinogenic potency with the same number of variables

  6. Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity.

    Science.gov (United States)

    Morales, Aliuska Helguera; Pérez, Miguel Angel Cabrera; Combes, Robert D; González, Maykel Pérez

    2006-03-01

    Several nitrocompounds have been screened for carcinogenicity in rodents, but this is a lengthy and expensive process, taking two years and typically costing 2.5 million dollars, and uses large numbers of animals. There is, therefore, much impetus to develop suitable alternative methods. One possible way of predicting carcinogenicity is to use quantitative structure-activity relationships (QSARs). QSARs have been widely utilized for toxicity testing, thereby contributing to a reduction in the need for experimental animals. This paper describes the results of applying a TOPological substructural molecular design (TOPS-MODE) approach for predicting the rodent carcinogenicity of nitrocompounds. The model described 79.10% of the experimental variance, with a standard deviation of 0.424. The predictive power of the model was validated by leave-one-out validation, with a determination coefficient of 0.666. In addition, this approach enabled the contribution of different fragments to carcinogenic potency to be assessed, thereby making the relationships between structure and carcinogenicity to be transparent. It was found that the carcinogenic activity of the chemicals analysed was increased by the presence of a primary amine group bonded to the aromatic ring, a manner that was proportional to the ring aromaticity. The nitro group bonded to an aromatic carbon atom is a more important determinant of carcinogenicity than the nitro group bonded to an aliphatic carbon. Finally, the TOPS-MODE approach was compared with four other predictive models, but none of these could explain more than 66% of the variance in the carcinogenic potency with the same number of variables.

  7. Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology.

    Science.gov (United States)

    Kaiser, K L E

    2007-01-01

    This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances

  8. Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity.

    Directory of Open Access Journals (Sweden)

    Luciana de C Tavares

    Full Text Available Zanthoxylum rhoifolium (Rutaceae is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1-3, and nine benzophenanthridine alkaloids (4-12 were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10, followed by avicine (12 and dihydrochelerythrine (4. The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14 was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive and Escherichia coli (Gram-negative were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective

  9. Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity.

    Science.gov (United States)

    Tavares, Luciana de C; Zanon, Graciane; Weber, Andréia D; Neto, Alexandre T; Mostardeiro, Clarice P; Da Cruz, Ivana B M; Oliveira, Raul M; Ilha, Vinicius; Dalcol, Ionara I; Morel, Ademir F

    2014-01-01

    Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1-3), and nine benzophenanthridine alkaloids (4-12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect

  10. Semisynthetic macrolide antibacterials derived from tylosin. Synthesis and structure-activity relationships of novel desmycosin analogues.

    Science.gov (United States)

    Mutak, Stjepan; Marsić, Natasa; Kramarić, Miroslava Dominis; Pavlović, Drazen

    2004-01-15

    A series of 20-O-substituted and 3,20-di-O-substituted derivatives of desmycosin were synthesized and their biological properties were evaluated. In particular, we have synthesized numerous side chain modified analogues of desmycosin as well as some analogues possessing a combination of modified side chain and alternative C-3 substituents. Thus, alpha,beta-unsaturated analogues of desmycosin (2), tylosin (1), 10,11,12,13-tetrahydrotylosin (11), and 2,3-didehydrodesmycosin (13) were prepared from the corresponding aldehydes by a Wittig reaction with the stabilized ylides (a-d), generating a trans-double bond, followed by modified Pfitzner-Moffat oxidation of the C-3 hydroxyl group. To evaluate the importance of the C-3 position of desmycosin for biological activity, the C-3 substituted derivatives were synthesized by a standard sequence of protective group chemistry followed by Wittig reaction and esterification as the key steps. For the attachment of the C-3 ester functionality, a mixed anhydride protocol was adopted. Reaction proceeded smoothly to give corresponding esters in yields ranging from 70 to 80%. Base- and acid-catalyzed rearrangement products including desmycosin 8,20-aldols (24a and 24b) and desmycosin 3,19-aldol (25) are also described. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in potency. In vitro evaluation of these derivatives demonstrated good antimicrobial activity against Gram-positive bacteria for most of the compounds. The present derivatives of 16-membered macrolides were active against MLS(B)-resistant strains that were inducibly resistant, but not those constitutively resistant to erythromycin.

  11. 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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Membrane-interaction quantitative structure--activity relationship (MI-QSAR) analyses of skin penetration enhancers.

    Science.gov (United States)

    Zheng, Tao; Hopfinger, A J; Esposito, Emilio X; Liu, Jianzhong; Tseng, Yufeng J

    2008-06-01

    Membrane-interaction quantitative structure-activity relationship (MI-QSAR) models for two skin penetration enhancer data sets of 61 and 42 compounds were constructed and compared to QSAR models constructed for the same two data sets using only classic intramolecular QSAR descriptors. These two data sets involve skin penetration enhancement of hydrocortisone and hydrocortisone acetate, and the enhancers are generally similar in structure to lipids and surfactants. A new MI-QSAR descriptor, the difference in the integrated cylindrical distribution functions over the phospholipid monolayer model, in and out of the presence of the skin penetration enhancer, DeltaSigma h(r), was developed. This descriptor is dominant in the optimized MI-QSAR models of both training sets studied and greatly reduces the size and complexity of the MI-QSAR models as compared to those QSAR models developed using the classic intramolecular descriptors. The MI-QSAR models indicate that good penetration enhancers make bigger "holes" in the monolayer and are less aqueous-soluble, so as to preferentially enter the monolayer, than are poor penetration enhancers. The skin penetration enhancer thus alters the structure and organization of the monolayer. This space and time alteration in the structure and dynamics of the membrane monolayer is captured by DeltaSigma h(r) and is simplistically referred to as "holes" in the monolayer. The MI-QSAR models explain 70-80% of the variance in skin penetration enhancement across each of the two training sets and are stable predictive models using accepted diagnostic measures of robustness and predictivity.

  13. Validation of quantitative structure-activity relationship (QSAR) model for photosensitizer activity prediction.

    Science.gov (United States)

    Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M; Rahman, Noorsaadah Abd

    2011-01-01

    Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR) method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT) activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, r(2) value, r(2) (CV) value and r(2) prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC(50) values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r(2) prediction for external test set) of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set.

  14. 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.

  15. Validation of Quantitative Structure-Activity Relationship (QSAR) Model for Photosensitizer Activity Prediction

    Science.gov (United States)

    Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.

    2011-01-01

    Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR) method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT) activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, r2 value, r2 (CV) value and r2 prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC50 values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r2 prediction for external test set) of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set. PMID:22272096

  16. 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.

  17. Structure-Activity Relationship of Benzophenanthridine Alkaloids from Zanthoxylum rhoifolium Having Antimicrobial Activity

    Science.gov (United States)

    Tavares, Luciana de C.; Zanon, Graciane; Weber, Andréia D.; Neto, Alexandre T.; Mostardeiro, Clarice P.; Da Cruz, Ivana B. M.; Oliveira, Raul M.; Ilha, Vinicius; Dalcol, Ionara I.; Morel, Ademir F.

    2014-01-01

    Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1–3), and nine benzophenanthridine alkaloids (4–12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect

  18. Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

    Science.gov (United States)

    Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

  19. Quantitative structure-activity relationship modeling of the toxicity of organothiophosphate pesticides to Daphnia magna and Cyprinus carpio

    NARCIS (Netherlands)

    Zvinavashe, E.; Du, T.; Griff, T.; Berg, van den J.H.J.; Soffers, A.E.M.F.; Vervoort, J.J.M.; Murk, A.J.; Rietjens, I.

    2009-01-01

    Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate

  20. A Review of Recent Advances towards the Development of (Quantitative) Structure-Activity Relationships for Metallic Nanomaterials.

    NARCIS (Netherlands)

    Chen, Guangchao; Vijver, Martina G; Xiao, Yinlong; Peijnenburg, Willie J G M

    2017-01-01

    Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The

  1. Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

    NARCIS (Netherlands)

    Murza, Alexandre; Sainsily, Xavier; Coquerel, David; Côté, Jérôme; Marx, Patricia; Besserer-Offroy, Élie; Longpré, Jean-Michel; Lainé, Jean; Reversade, Bruno; Salvail, Dany; Leduc, Richard; Dumaine, Robert; Lesur, Olivier; Auger-Messier, Mannix; Sarret, Philippe; Marsault, Éric

    2016-01-01

    ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure- activity relationships and

  2. 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.

  3. Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

    Science.gov (United States)

    Oprea, Tudor I.; García, Angel E.

    1996-06-01

    Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.

  4. A Review of Recent Advances towards the Development of (Quantitative) Structure-Activity Relationships for Metallic Nanomaterials

    OpenAIRE

    Chen G.; Vijver M.G.; Xiao Y.; Peijnenburg W.J.G.M.

    2017-01-01

    Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The preliminary attempts of correlating ENMs’ characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (Q)SARs in the nanotoxicity field. This review discusse...

  5. Structure?Activity Relationship Studies of Indole-Based Compounds as Small Molecule HIV-1 Fusion Inhibitors Targeting Glycoprotein 41

    OpenAIRE

    Zhou, Guangyan; Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A.; Mankowski, Marie K.; Hogan, Priscilla A.; Ptak, Roger G.; Gochin, Miriam

    2014-01-01

    We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure?activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell?cell fusion, and viral replication assays. Below a 1 ?M threshold, correlation between binding and biologi...

  6. Quantitative structure-activity relationship (QSAR) study of a series of benzimidazole derivatives as inhibitors of Saccharomyces cerevisiae.

    Science.gov (United States)

    Podunavac-Kuzmanović, Sonja O; Cvetković, Dragoljub D; Jevrić, Lidija R; Uzelac, Natasa J

    2013-01-01

    A quantitative structure activity relationship (QSAR) has been carried out on a series of benzimidazole derivatives to identify the structural requirements for their inhibitory activity against yeast Saccharomyces cerevisiae. A multiple linear regression (MLR) procedure was used to model the relationships between various physicochemical, steric, electronic, and structural molecular descriptors and antifungal activity of benzimidazole derivatives. The QSAR expressions were generated using a training set of 16 compounds and the predictive ability of the resulting models was evaluated against a test set of 8 compounds. The best QSAR models were further validated by leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. Therefore, satisfactory relationships between antifungal activity and molecular descriptors were found. QSAR analysis reveals that lipophilicity descriptor (logP), dipole moment (DM) and surface area grid (SAG) govern the inhibitory activity of compounds studied against Saccharomyces cerevisiae.

  7. Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567.

    Science.gov (United States)

    Kuduk, Scott D; Di Marco, Christina N; Bodmer-Narkevitch, Vera; Cook, Sean P; Cato, Matthew J; Jovanovska, Aneta; Urban, Mark O; Leitl, Michael; Sain, Nova; Liang, Annie; Spencer, Robert H; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

    2010-01-20

    The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.

  8. Structure-activity relationship study of phenylpyrazole derivatives as a novel class of anti-HIV agents.

    Science.gov (United States)

    Mizuhara, Tsukasa; Kato, Takayuki; Hirai, Atsushi; Kurihara, Hideki; Shimada, Yasuhiro; Taniguchi, Masahiko; Maeta, Hideki; Togami, Hiroaki; Shimura, Kazuya; Matsuoka, Masao; Okazaki, Shiho; Takeuchi, Tomoki; Ohno, Hiroaki; Oishi, Shinya; Fujii, Nobutaka

    2013-08-15

    The structure-activity relationship of phenylpyrazole derivative 1 was investigated for the development of novel anti-HIV agents. Initial efforts revealed that the diazenyl group can be replaced by an aminomethylene group. In addition, we synthesized various derivatives by the reductive amination of benzaldehydes with 5-aminopyrazoles and carried out parallel structural optimization on the benzyl group and the pyrazole ring. This optimization led to a six-fold more potent derivative 32j than the lead compound 1, and this derivative has a 3',4'-dichloro-(1,1'-biphenyl)-3-yl group. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Cytotoxic lanostane-type triterpenoids from the fruiting bodies of Ganoderma lucidum and their structure-activity relationships.

    Science.gov (United States)

    Chen, Shaodan; Li, Xiangmin; Yong, Tianqiao; Wang, Zhanggen; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen; Yang, Burton B

    2017-02-07

    We conducted a study of Ganoderma lucidum metabolites and isolated 35 lanostane-type triterpenoids, including 5 new ganoderols (1-5). By spectroscopy, we compared the structures of these compounds with known related compounds in this group. All of the isolated compounds were assayed for their effect against the human breast carcinoma cell line MDA-MB-231 and hepatocellular carcinoma cell line HepG2. Corresponding three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built and analyzed using Discovery Studio. These results provide further evidence for anti-cancer constituents within Ganoderma lucidum, and may provide a theoretical foundation for designing novel therapeutic compounds.

  10. Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Marrocchi, Assunta; Minuti, Lucio; Taticchi, Aldo

    2007-03-01

    Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure.

  11. Hot and Spicy versus Cool and Minty as an Example of Organic Structure-Activity Relationships

    Science.gov (United States)

    Kimbrough, Doris R.

    1997-07-01

    There are two classes of substances that activate neural receptors that are involved in temperature perception. Structures of substances found in spices and food that we normally associate with "hot" (or spicy) and "cool" (or minty) flavors are presented and discussed. Functional group similarities within the two groups provide an interesting example of the relationship between molecular structure and molecular function in organic chemistry.

  12. Promises and pitfalls of Quantitative Structure-Activity Relationship approaches for predicting metabolism and toxicity

    NARCIS (Netherlands)

    Zvinavashe, E.; Murk, A.J.; Rietjens, I.M.C.M.

    2008-01-01

    The description of quantitative structure¿activity relationship (QSAR) models has been a topic for scientific research for more than 40 years and a topic within the regulatory framework for more than 20 years. At present, efforts on QSAR development are increasing because of their promise for

  13. Anti-proliferation activity of terpenoids isolated from Euphorbia kansui in human cancer cells and their structure-activity relationship.

    Science.gov (United States)

    Hou, Jin-Jun; Shen, Yao; Yang, Zhou; Fang, Lin; Cai, Lu-Ying; Yao, Shuai; Long, Hua-Li; Wu, Wan-Ying; Guo, De-An

    2017-10-01

    Euphorbia kansui is a commonly used traditional Chinese medicine for the treatment of edema, pleural effusion, and asthma, etc. According to the previous researches, terpenoids in E. kansui possess various biological activities, e.g., anti-virus, anti-allergy, antitumor effects. In this work, twenty five terpenoids were isolated from E. kansui, including thirteen ingenane- and eight jatrophane-type diterpenoids (with two new compounds, kansuinin P and Q) and four triterpenoids. Eighteen of them were analyzed by MTS assay for in vitro anticancer activity in five human cancer cell lines. Structure-activity relationship for 12 ingenane-type diterpenoids in colorectal cancer Colo205 cells were preliminary studied. Significant anti-proliferation activities were observed in human melanoma cells breast cancer MDA-MB-435 cells and Colo205 cells. More than half of the isolated ingenane-type diterpenoids showed inhibitory activities in MDA-MB-435 cells. Eight ingenane- and one jatrophane-type diterpenoids possessed much lower IC 50 values in MDA-MB-435 cells than positive control staurosporine. Preliminary structure-activity relationship analysis showed that substituent on position 20 was important for the activity of ingenane-type diterpenoids in Colo205 cells and substituent on position 3 contributed more significant biological activity of the compounds than that on position 5 in both MDA-MB-435 and Colo205 cells. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  14. Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

    Science.gov (United States)

    Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

    2009-01-30

    In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

  15. Quantitative structure-activity relationship study on BTK inhibitors by modified multivariate adaptive regression spline and CoMSIA methods.

    Science.gov (United States)

    Xu, A; Zhang, Y; Ran, T; Liu, H; Lu, S; Xu, J; Xiong, X; Jiang, Y; Lu, T; Chen, Y

    2015-01-01

    Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell activation and development, and has emerged as a new molecular target for the treatment of autoimmune diseases and B-cell malignancies. In this study, two- and three-dimensional quantitative structure-activity relationship (2D and 3D-QSAR) analyses were performed on a series of pyridine and pyrimidine-based BTK inhibitors by means of genetic algorithm optimized multivariate adaptive regression spline (GA-MARS) and comparative molecular similarity index analysis (CoMSIA) methods. Here, we propose a modified MARS algorithm to develop 2D-QSAR models. The top ranked models showed satisfactory statistical results (2D-QSAR: Q(2) = 0.884, r(2) = 0.929, r(2)pred = 0.878; 3D-QSAR: q(2) = 0.616, r(2) = 0.987, r(2)pred = 0.905). Key descriptors selected by 2D-QSAR were in good agreement with the conclusions of 3D-QSAR, and the 3D-CoMSIA contour maps facilitated interpretation of the structure-activity relationship. A new molecular database was generated by molecular fragment replacement (MFR) and further evaluated with GA-MARS and CoMSIA prediction. Twenty-five pyridine and pyrimidine derivatives as novel potential BTK inhibitors were finally selected for further study. These results also demonstrated that our method can be a very efficient tool for the discovery of novel potent BTK inhibitors.

  16. Quantitative structure-activity relationship (QSAR) analysis to predict drug-drug interactions of ABC transporter ABCG2.

    Science.gov (United States)

    Ishikawa, T; Hirano, H; Saito, H; Sano, K; Ikegami, Y; Yamaotsu, N; Hirono, S

    2012-06-01

    Quantitative structure-activity relationship (QSAR) analysis is a practical approach by which chemical structure is quantitatively correlated with biological activity or chemical reactivity. Human ABC transporter ABCG2 exhibits broad substrate specificity toward structurally diverse compounds. To gain insight into the relationship between the molecular structures of compounds and the interaction with ABCG2, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. In addition, to support QSAR analysis, we developed a high-speed screening method for analyzing the drug-drug interactions of ABCG2. Based on both experimental results and computational QSAR analysis data, we propose a hypothetical mechanism underlying ABC-mediated drug transport and its interaction with drugs.

  17. [Quantitative structure-activity relationship prediction of carcinogenicity of N-nitroso compounds based on category approach and read-across].

    Science.gov (United States)

    Liang, Q Q; Zheng, W W; He, G S; Qu, W D

    2017-07-06

    Objective: New quantitative structure-activity relationship (QSAR) method was used to predict N-nitroso compounds (NOCs) carcinogenicity. This could provide evidences for health risk assessment of the chemicals. Methods: Total 74 chemical substances of NOCs were included as target chemicals for this validation study by using QSAR Toolbox based on category approach and read-across. The included 74 NOCs were categorized and subcategorized respectively using "Organic functional groups, Norbert Haider " profiler and "DNA binding by OASIS V.1.1" profiler. Carcinogenicity of rat were used as target of prediction, the carcinogenicity results: of analogues in chemical categories were cross-read to obtain the carcinogenic predictive results of the target chemicals. Results 74 NOCs included 26 nonclic N-nitrosamines, 24 cyclic N-nitrosamines and 24 N-nitrosamides The sensitivity, specificity and concordance of the category approach and read-across for predicting carcinogenicity of 74 NOCs were 75% (48/64), 70%(7/10) and 74% (55/74) respectively. The concordance for noncyclic N-nitrosamines, cyclic N-nitrosamines and N-nitrosamides were 88% (23/26), 71% (17/24) and 63% (15/24) respectively. Conclusion: QSAR based on category approach and read-across is good for prediction of NOCs carcinogenicity, and can be used for high-throughput qualitative prediction of NOCs carcinogenicity.

  18. Structure-activity relationship of condensed tannins and synergism with trans-cinnamaldehyde against Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Ropiak, Honorata M; Desrues, Olivier; Williams, Andrew Richard

    2016-01-01

    ). A nonsignificant correlation was evident between the ability of CT fractions to inhibit C. elegans motility and the molar proportion of prodelphinidin subunits in purified CT samples. Synergistic inhibition of motility was achieved by combinations of CT and CIN. Galloylation of procyanidins was also a key factor...... compounds possessing anthelmintic activity against GIN. We investigated the relationship between the chemical structure of contrasting, purified CT and nematocidal effects using Caenorhabditis elegans. We also explored whether the nematocidal activity of CT could synergize with trans-cinnamaldehyde (CIN...

  19. Design, Synthesis, and Structure-Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety.

    Science.gov (United States)

    Guan, Aiying; Liu, Changling; Chen, Wei; Yang, Fan; Xie, Yong; Zhang, Jinbo; Li, Zhinian; Wang, Mingan

    2017-02-15

    The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by 1 H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC 50 = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.

  20. Synthesis and structure-activity relationship exploration of some potent anti-cancer phenyl amidrazone derivatives.

    Science.gov (United States)

    Habashneh, Almeqdad Y; El-Abadelah, Mustafa M; Bardaweel, Sanaa K; Taha, Mutasem O

    2017-12-04

    Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies. All compounds were virtually nontoxic against normal fibroblast cells. Docking into the oncogenic kinase bcr/abl illustrated the critical importance of (i) p-halogen substituent on the ligand's phenyl ring and (ii) the presence of positive ionizable moiety at the ligand's piperazine fragment for anticancer activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium.

    Science.gov (United States)

    El Ashry, El Sayed H; El Nemr, Ahmed; Ragab, Safaa

    2012-03-01

    Quantum chemical calculations using the density functional theory (B3LYP/6-31G DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E (HOMO)), energy of lowest unoccupied molecular orbital (E (LUMO)) and dipole moment (μ) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (π) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives.

  2. Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as α-glucosidase inhibitors.

    Science.gov (United States)

    Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2013-11-01

    A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for α-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase α-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of α-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve α-glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of α-glucosidase inhibitor. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Structure-activity relationships and prediction of the phototoxicity and phototoxic potential of new drugs.

    Science.gov (United States)

    Barratt, Martin D

    2004-11-01

    Relationships between the structure and properties of chemicals can be programmed into knowledge-based systems such as DEREK for Windows (DEREK is an acronym for "Deductive Estimation of Risk from Existing Knowledge"). The DEREK for Windows computer system contains a subset of over 60 rules describing chemical substructures (toxophores) responsible for skin sensitisation. As part of the European Phototox Project, the rule base was supplemented by a number of rules for the prospective identification of photoallergens, either by extension of the scope of existing rules or by the generation of new rules where a sound mechanistic rationale for the biological activity could be established. The scope of the rules for photoallergenicity was then further refined by assessment against a list of chemicals identified as photosensitisers by the Centro de Farmacovigilancia de la Comunidad Valenciana, Valencia, Spain. This paper contains an analysis of the mechanistic bases of activity for eight important groups of photoallergens and phototoxins, together with rules for the prospective identification of the photobiological activity of new or untested chemicals belonging to those classes. The mechanism of action of one additional chemical, nitrofurantoin, is well established; however, it was deemed inappropriate to write a rule on the basis of a single chemical structure.

  4. 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.

  5. Pinus massoniana Bark Extract: Structure-Activity Relationship and Biomedical Potentials.

    Science.gov (United States)

    Feng, Jiao; Zhang, Xiao-Lu; Li, Ying-Ya; Cui, Ying-Yu; Chen, Yi-Han

    2016-01-01

    Proanthocyanidins (PAs) belong to the condensed tannin subfamily of natural flavonoids. Recent studies have shown that the main bioactive compounds of Pinus massoniana bark extract (PMBE) are PAs, especially the proanthocyanidins B series, which play important roles in cell cycle arrest, apoptosis induction and migration inhibition of cancer cells in vivo and in vitro. PA-Bs are mixtures of oligomers and polymers composed of flavan-3-ol, and the relationship between their structure and corresponding biomedical potentials is summarized in this paper. The hydroxyl at certain positions or the linkage between different carbon atoms of different rings determines or affects their anti-oxidant and free radical scavenging bioactivities. The degree of polymerization and the water solubility of the reaction system also influence their biomedical potential. Taken together, PMBE has a promising future in clinical drug development as a candidate anticancer drug and as a food additive to prevent tumorigenesis. We hope this review will encourage interested researchers to conduct further preclinical and clinical studies to evaluate the anticancer activities of PMBE, its active constituents and their derivatives.

  6. Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure-activity relationships.

    Science.gov (United States)

    Bohnert, Markus; Nützmann, Hans-Wilhelm; Schroeckh, Volker; Horn, Fabian; Dahse, Hans-Martin; Brakhage, Axel A; Hoffmeister, Dirk

    2014-09-01

    The fungal genus Armillaria is unique in that it is the only natural source of melleolide antibiotics, i.e., protoilludene alcohols esterified with orsellinic acid or its derivatives. This class of natural products is known to exert antimicrobial and cytotoxic effects. Here, we present a refined relationship between the structure and the antimicrobial activity of the melleolides. Using both agar diffusion and broth dilution assays, we identified the Δ(2,4)-double bond of the protoilludene moiety as a key structural feature for antifungal activity against Aspergillus nidulans, Aspergillus flavus, and Penicillium notatum. These findings contrast former reports on cytotoxic activities and may indicate a different mode of action towards susceptible fungi. We also report the isolation and structure elucidation of five melleolides (6'-dechloroarnamial, 6'-chloromelleolide F, 10-hydroxy-5'-methoxy-6'-chloroarmillane, and 13-deoxyarmellides A and B), along with the finding that treatment with an antifungal melleolide impacts transcription of A. nidulans natural product genes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Structure-Activity and Lipophilicity Relationships of Selected Antibacterial Natural Flavones and Flavanones of Chilean Flora

    Directory of Open Access Journals (Sweden)

    Javier Echeverría

    2017-04-01

    Full Text Available In this study, we tested eight naturally-occurring flavonoids—three flavanones and five flavones—for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10−10 and 12.3 × 10−10 m2/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3-O-methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7-O-dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis.

  8. Multistep continuous-flow synthesis in medicinal chemistry: discovery and preliminary structure-activity relationships of CCR8 ligands.

    Science.gov (United States)

    Petersen, Trine P; Mirsharghi, Sahar; Rummel, Pia C; Thiele, Stefanie; Rosenkilde, Mette M; Ritzén, Andreas; Ulven, Trond

    2013-07-08

    A three-step continuous-flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49-94%. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure-activity-relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single-digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.

    Science.gov (United States)

    Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

    2012-01-01

    We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

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

    International Nuclear Information System (INIS)

    Sadat Hayatshahi, Sayyed Hamed; Abdolmaleki, Parviz; Safarian, Shahrokh; Khajeh, Khosro

    2005-01-01

    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%

  11. Quantitative structure-activity relationships for predicting potential ecological hazard of organic chemicals for use in regulatory risk assessments.

    Science.gov (United States)

    Comber, Mike H I; Walker, John D; Watts, Chris; Hermens, Joop

    2003-08-01

    The use of quantitative structure-activity relationships (QSARs) for deriving the predicted no-effect concentration of discrete organic chemicals for the purposes of conducting a regulatory risk assessment in Europe and the United States is described. In the United States, under the Toxic Substances Control Act (TSCA), the TSCA Interagency Testing Committee and the U.S. Environmental Protection Agency (U.S. EPA) use SARs to estimate the hazards of existing and new chemicals. Within the Existing Substances Regulation in Europe, QSARs may be used for data evaluation, test strategy indications, and the identification and filling of data gaps. To illustrate where and when QSARs may be useful and when their use is more problematic, an example, methyl tertiary-butyl ether (MTBE), is given and the predicted and experimental data are compared. Improvements needed for new QSARs and tools for developing and using QSARs are discussed.

  12. α-Glucosidase inhibition by flavonoids: an in vitro and in silico structure-activity relationship study.

    Science.gov (United States)

    Proença, Carina; Freitas, Marisa; Ribeiro, Daniela; Oliveira, Eduardo F T; Sousa, Joana L C; Tomé, Sara M; Ramos, Maria J; Silva, Artur M S; Fernandes, Pedro A; Fernandes, Eduarda

    2017-12-01

    α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme's activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure-activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC 50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

  13. Pattern recognition on the structure-activity relationship of nano Pt-Ru catalysts: methodology and preliminary demonstration.

    Science.gov (United States)

    Lu, Qingye; Yang, Bo; Zhuang, Lin; Lu, Juntao

    2005-05-12

    The activity of nano Pt-Ru catalysts is a multivariate function of particle size, alloyed degree, oxide composition, and so forth. The monodependencies of catalytic activity on individual structure parameters (structure-activity relationship, SAR) are of great importance but, unfortunately, unobtainable in practical measurements. A pattern-recognition methodology is proposed for the first time to extract SAR information from all of the relative experimental data, which we hope will cast new light on the in-depth understanding of this important catalyst. As a preliminary demonstration, a multivariate linear regression and a generalized regression neural network were applied to analyze a small data set for methanol oxidation. It was found that both increasing the content of hydrous ruthenium oxides and decreasing the particle size would benefit the catalytic activity, whereas the effect of the Pt-Ru alloy degree turned out to be unremarkable.

  14. Structure-activity relationship study of tachykinin peptides for the development of novel neurokinin-3 receptor selective agonists.

    Science.gov (United States)

    Misu, Ryosuke; Noguchi, Taro; Ohno, Hiroaki; Oishi, Shinya; Fujii, Nobutaka

    2013-04-15

    Neurokinin B (NKB) is a potential regulator of pulsatile gonadotropin-releasing hormone (GnRH) secretion via activation of the neurokinin-3 receptor (NK3R). NKB with the consensus sequence of the tachykinin peptide family also binds to other tachykinin receptors [neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R)] with low selectivity. In order to identify the structural requirements for the development of novel potent and selective NK3R agonists, a structure-activity relationship (SAR) study of [MePhe(7)]-NKB and other naturally occurring tachykinin peptides was performed. The substitutions to naturally occurring tachykinins with Asp and MePhe improved the receptor binding and agonistic activity for NK3R. The corresponding substitutions to NKB provided an NK3R selective analog. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity.

    Science.gov (United States)

    Menezes, Carla M S; Rivera, Gildardo; Alves, Marina A; do Amaral, Daniel N; Thibaut, Jean Pierre B; Noël, François; Barreiro, Eliezer J; Lima, Lídia M

    2012-06-01

    The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure-activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N(1) H-C(2) (=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N(1) position) is not tolerated. © 2012 John Wiley & Sons A/S.

  16. The Pharmacophore Network: A Computational Method for Exploring Structure-Activity Relationships from a Large Chemical Data Set.

    Science.gov (United States)

    Métivier, Jean-Philippe; Cuissart, Bertrand; Bureau, Ronan; Lepailleur, Alban

    2018-04-18

    Historically, structure-activity relationship (SAR) analysis has focused on small sets of molecules, but in recent years, there has been increasing efforts to analyze the growing amount of data stored in public databases like ChEMBL. The pharmacophore network introduced herein is dedicated to the organization of a set of pharmacophores automatically discovered from a large data set of molecules. The network navigation allows to derive essential tasks of a drug discovery process, including the study of the relations between different chemical series, the analysis of the influence of additional chemical features on the compounds' activity, and the identification of diverse binding modes. This paper describes the method used to construct the pharmacophore network, and a case study dealing with BCR-ABL exemplifies its usage for large-scale SAR analysis. Thanks to a benchmarking study, we also demonstrate that the selection of a subset of representative pharmacophores can be used to conduct classification tasks.

  17. Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships.

    Science.gov (United States)

    Bhatia, Chitra; Oerum, Stephanie; Bray, James; Kavanagh, Kathryn L; Shafqat, Naeem; Yue, Wyatt; Oppermann, Udo

    2015-06-05

    Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways. Here we present an update on the human SDR superfamily and a ligand identification strategy using differential scanning fluorimetry (DSF) with a focused library of oxidoreductase and metabolic ligands to identify substrate classes and inhibitor chemotypes. This method is applicable to investigate structure-activity relationships of oxidoreductases and ultimately to better understand their physiological roles. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Quantitative structure-activity relationship (QSAR) study of toxicity of quaternary ammonium compounds on Chlorella pyrenoidosa and Scenedesmus quadricauda.

    Science.gov (United States)

    Jing, Guohua; Zhou, Zuoming; Zhuo, Jing

    2012-01-01

    The acute toxicity of 13 quaternary ammonium compounds (QACs) to Chlorella pyrenoidosa and Scenedesmus quadricauda was investigated in the present study. Significant inhibition on algae biomass was observed and 96 h EC(50)-value of 13 QACs was tested. Sixteen physicochemical and quantum chemical parameters of the QACs were calculated using the semi-empirical MOPAC AMI method. The multiple linear regression (MLR) was employed to derive the quantitative structure-activity relationship (QSAR) models, by which the calculated parameters were correlated to the toxicity of QACs on the two green algaes. Results showed that the alkyl chain lengths (CL) and total connectivity (T(Con)) were the main descriptors in governing the log (1/EC(50)) values of the QACs in the two QSAR models. The two models had high predictive ability and stability, and two parameters were proved to have the general applicability in QSAR study of QACs congeners. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors.

    Science.gov (United States)

    Sadeghian-Rizi, Sedighe; Sakhteman, Amirhossein; Hassanzadeh, Farshid

    2016-12-01

    In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600E B-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site.

  20. 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. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Computational modeling in nanomedicine: prediction of multiple antibacterial profiles of nanoparticles using a quantitative structure-activity relationship perturbation model.

    Science.gov (United States)

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, Maria Natália D S

    2015-01-01

    We introduce the first quantitative structure-activity relationship (QSAR) perturbation model for probing multiple antibacterial profiles of nanoparticles (NPs) under diverse experimental conditions. The dataset is based on 300 nanoparticles containing dissimilar chemical compositions, sizes, shapes and surface coatings. In general terms, the NPs were tested against different bacteria, by considering several measures of antibacterial activity and diverse assay times. The QSAR perturbation model was created from 69,231 nanoparticle-nanoparticle (NP-NP) pairs, which were randomly generated using a recently reported perturbation theory approach. The model displayed an accuracy rate of approximately 98% for classifying NPs as active or inactive, and a new copper-silver nanoalloy was correctly predicted by this model with consensus accuracy of 77.73%. Our QSAR perturbation model can be used as an efficacious tool for the virtual screening of antibacterial nanomaterials.

  2. The Development and Characterisation of a Structure-activity Relationship Model of the Draize Eye Irritation Test.

    Science.gov (United States)

    Rosenkranz, H S; Zhang, Y P; Klopman, G

    1998-01-01

    A structure-activity relationship (SAR) model based on the results of 297 chemicals tested in the Draize eye irritation assay was developed. The SAR model displayed a predictivity of 74% for chemicals not included in the model. The SAR analysis indicated that chemical reactivity was not a requirement for eye irritation. The major structural determinants included hydrophilicity, alkalinity (i.e. primary, secondary and tertiary amines), acidity (for example, the carboxylic acid moiety), and putative lipophobic 4.5-5.4Å receptor-binding ligands. The analysis revealed that, while there were significant structural overlaps between the SAR models of ocular irritation, allergic contact dermatitis and respiratory hypersensitivity, there was much less overlap between ocular irritation and cell toxicity. This decreased overlap must be considered in developing strategies to replace the Draize test with in vitro cellular toxicity assays. 1998 FRAME.

  3. A CASE-SAR (computer automated structure evaluation - structure-activity relationship) study of mammalian hepatic azoreduction

    Energy Technology Data Exchange (ETDEWEB)

    Newsnow, S.; Bergman, H.; Bryant, B.; Helton, S.; Richard, A.

    1988-01-01

    A group of 36 aryl azo dyes were examined for their ability to be reduced by rat liver microsomal azoreductase. This group of azo dyes features a variety of substituents, including sulfonic acid, phenol, nitro, amide, and methyl functionalities on phenyl, {alpha}-naphthyl, and {beta}-naphthyl rings. Reduction rates for each dye were obtained using a spectrophotometric method and anaerobic incubation conditions. These rates ranged from 0 to 7.35 nmol dye reduced/min {times} mg protein. The reduction rates and dye structures provided the data for a CASE-SAR (computer automated structure evaluation - structure-activity relationship) fragment analysis, and three major structure fragments associated with the ability of this group of azo dyes to be reduced were identified. The three CASE fragments correctly label 92% of the azo dye structures as active or inactive and may be useful in future predictions of the ability of azo dyes to undergo reduction by rat liver azoreductase.

  4. Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein.

    Science.gov (United States)

    Zhang, Hang; Xiong, Xiao-Feng; Boesgaard, Michael W; Underwood, Christina R; Bräuner-Osborne, Hans; Strømgaard, Kristian

    2017-06-07

    Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the G q subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective G q inhibitory activity. This provides pertinent information for the understanding of the G q inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Synthesis and Structure-Activity Relationships of Novel Amino/Nitro Substituted 3-Arylcoumarins as Antibacterial Agents

    Directory of Open Access Journals (Sweden)

    Ysabel Santos

    2013-01-01

    Full Text Available A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive and Escherichia coli (Gram-negative was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin. The preliminary structure-activity relationship (SAR study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported.

  6. 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.

  7. Structure-activity relationships for novel drug precursor N-substituted-6-acylbenzothiazolon derivatives: A theoretical approach

    Science.gov (United States)

    Sıdır, Yadigar Gülseven; Sıdır, İsa

    2013-08-01

    In this study, the twelve new modeled N-substituted-6-acylbenzothiazolon derivatives having analgesic analog structure have been investigated by quantum chemical methods using a lot of electronic parameters and structure-activity properties; such as molecular polarizability (α), dipole moment (μ), EHOMO, ELUMO, q-, qH+, molecular volume (Vm), ionization potential (IP), electron affinity (EA), electronegativity (χ), molecular hardness (η), molecular softness (S), electrophilic index (ω), heat of formation (HOF), molar refractivity (MR), octanol-water partition coefficient (log P), thermochemical properties (entropy (S), capacity of heat (Cv)); as to investigate activity relationships with molecular structure. The correlations of log P with Vm, MR, ω, EA, EHOMO - ELUMO (ΔE), HOF in aqueous phase, χ, μ, S, η parameters, respectively are obtained, while the linear relation of log P with IP, Cv, HOF in gas phase are not observed. The log P parameter is obtained to be depending on different properties of compounds due to their complexity.

  8. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Thermodynamics of engineered gold binding peptides: establishing the structure-activity relationships.

    Science.gov (United States)

    Seker, Urartu Ozgur Safak; Wilson, Brandon; Kulp, John L; Evans, John S; Tamerler, Candan; Sarikaya, Mehmet

    2014-07-14

    Adsorption behavior of a gold binding peptide was experimentally studied to achieve kinetics and thermodynamics parameters toward understanding of the binding of an engineered peptide onto a solid metal surface. The gold-binding peptide, GBP1, was originally selected using a cell surface display library and contains 14 amino acid residues. In this work, single- and three-repeats of GBP1 were used to assess the effects of two parameters: molecular architecture versus secondary structure on adsorption on to gold substrate. The adsorption measurements were carried out using surface plasmon resonance (SPR) spectroscopy at temperatures ranging from 10 to 55 °C. At all temperatures, two different regimes of peptide adsorption were observed, which, based on the model, correspond to two sets of thermodynamics values. The values of enthalpy, ΔH(ads), and entropy, ΔS(ads), in these two regimes were determined using the van't Hoff approach and Gibbs-Helmholtz relationship. In general, the values of enthalpy for both peptides are negative indicating GBP1 binding to gold is an exothermic phenomenon and that the binding of three repeat gold binding peptide (3l-GBP1) is almost 5 times tighter than that for the single repeat (l-GBP1). More intriguing result is that the entropy of adsorption for the 3l-GBP1 is negative (-43.4 ± 8.5 cal/(mol K)), while that for the l-GBP1 is positive (10.90 ± 1.3 cal/(mol K)). Among a number of factors that synergistically contribute to the decrease of entropy, long-range ordered self-assembly of the 3l-GBP1 on gold surface is the most effective, probably through both peptide-solid and peptide-peptide intermolecular interactions. Additional adsorption experiments were conducted in the presence of 2,2,2-trifluoroethanol (TFE) to determine how the conformational structures of the biomolecules responded to the environmental perturbation. We found that the peptides differ in their conformational responses to the change in solution conditions; while

  10. Quantitative structure-activity relationships and mixture toxicity of organic chemicals in Photobacterium phosphoreum: the Microtox test

    Energy Technology Data Exchange (ETDEWEB)

    Hermens, J.; Busser, F.; Leeuwangh, P.; Musch, A.

    1985-02-01

    Quantitative structure-activity relationships were calculated for the inhibition of bioluminescence of Photobacterium phosphoreum by 22 nonreactive organic chemicals. The inhibition was measured using the Microtox test and correlated with the partition coefficient between n-octanol and water (Poct), molar refractivity (MR), and molar volume (MW/d). At log Poct less than 1 and greater than 3, deviations from linearity were observed. Introduction of MR and MW/d improved the quality of the relationships. The influences of MR or MW/d may be related with an interaction of the tested chemicals to the enzyme system which produces the light emission. The sensitivity of the Microtox test to the 22 tested compounds is comparable to a 14-day acute mortality test with guppies for chemicals with log Poct less than 4. The inhibition of bioluminescence by a mixture of the tested compounds was slightly less than was expected in case of concentration addition. The Microtox test can give a good estimate of the total aspecific minimum toxicity of polluted waters. When rather lipophilic compounds or pollutants with more specific modes of action are present, this test will underestimate the toxicity to other aquatic life.

  11. Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor.

    Science.gov (United States)

    Jin, Chunyang; Decker, Ann M; Huang, Xi-Ping; Gilmour, Brian P; Blough, Bruce E; Roth, Bryan L; Hu, Yang; Gill, Joseph B; Zhang, X Peter

    2014-07-16

    GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.

  12. Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G

    Directory of Open Access Journals (Sweden)

    Eduarda C. Costa

    2016-06-01

    Full Text Available Sixteen 1,4-diaryl-1,2,3-triazole compounds 4–19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania amazonensis intracellular amastigotes. Triazole compounds 4–19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR, compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively, with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6. These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.

  13. Designing quantitative structure activity relationships to predict specific toxic endpoints for polybrominated diphenyl ethers in mammalian cells.

    Science.gov (United States)

    Rawat, S; Bruce, E D

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

  14. 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.

  15. Structural alerts for predicting clastogenic activity of pro-oxidant flavonoid compounds: quantitative structure-activity relationship study.

    Science.gov (United States)

    Yordi, Estela Guardado; Pérez, Enrique Molina; Matos, Maria Joao; Villares, Eugenio Uriarte

    2012-02-01

    Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food.

  16. 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.

  17. Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells.

    Science.gov (United States)

    Jiang, Wen-Jun; Daikonya, Akihiro; Ohkawara, Mitsuyoshi; Nemoto, Takashi; Noritake, Ryusuke; Takamiya, Tomoko; Kitanaka, Susumu; Iijima, Hiroshi

    2017-01-15

    We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R 3' =R 5' ). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q 2 value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Structure-Activity Relationship of Curcumin: Role of the Methoxy Group in Anti-inflammatory and Anticolitis Effects of Curcumin.

    Science.gov (United States)

    Yang, Haixia; Du, Zheyuan; Wang, Weicang; Song, Mingyue; Sanidad, Katherine; Sukamtoh, Elvira; Zheng, Jennifer; Tian, Li; Xiao, Hang; Liu, Zhenhua; Zhang, Guodong

    2017-06-07

    Curcumin, a dietary compound from turmeric, has beneficial effects on inflammatory diseases such as inflammatory bowel disease. Most previous studies have focused on the structure-activity relationship of the thiol-reactive α,β-unsaturated carbonyl groups of curcumin, so little is known about the roles of methoxy groups in biological activities of curcumin. Here we synthesized a series of curcumin analogues with different substitution groups (R = H-, Br-, Cl-, F-, NO 2 -, CH 3 -, and OH-) to replace the methoxy group and evaluated their biological effects in vitro and in vivo. Curcumin, Cur-OH, and Cur-Br (25 μM) suppressed 74.91 ± 0.88, 77.75 ± 0.89, and 71.75 ± 0.90% of LPS-induced NO production, respectively (P 0.05). In the dextran sulfate sodium (DSS)-induced colitis mouse model, the Cur-Br analogue also showed a beneficial effect the same as curcumin (P 0.05). Together, the analogues have dramatically different effects on inflammation, supporting that the substitution group on the methoxy position plays an important role in the anti-inflammatory effects of curcumin. The methoxy group is a potential structural candidate for modification to design curcumin-based drugs for inflammatory diseases.

  19. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    Science.gov (United States)

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils.

  20. Isolation of Insecticidal Constituent from Ruta graveolens and Structure-Activity Relationship Studies against Stored-Food Pests (Coleoptera).

    Science.gov (United States)

    Jeon, Ju-Hyun; Lee, Sang-Guei; Lee, Hoi-Seon

    2015-08-01

    Isolates from essential oil extracted from the flowers and leaves of Ruta graveolens and commercial phenolic analogs were evaluated using fumigant and contact toxicity bioassays against adults of the stored-food pests Sitophilus zeamais, Sitophilus oryzae, and Lasioderma serricorne. The insecticidal activity of these compounds was then compared with that of the synthetic insecticide dichlorvos. To investigate the structure-activity relationships, the activity of 2-isopropyl-5-methylphenol and its analogs was examined against these stored-food pests. Based on the 50% lethal dose, the most toxic compound against S. zeamais was 3-isopropylephenol, followed by 2-isopropylphenol, 4-isopropylphenol, 5-isopropyl-2-methylphenol, 2-isopropyl-5-methylphenol, 3-methylphenol, and 2-methylphenol. Similar results were observed with phenolic compounds against S. oryzae. However, when 2-isopropyl-5-methylphenol isolated from R. graveolens oil and its structurally related analogs were used against L. serricorne, little or no insecticidal activity was found regardless of bioassay. These results indicate that introducing and changing the positions of functional groups in the phenol skeleton have an important effect on insecticidal activity of these compounds against stored-food pests.

  1. Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships.

    Science.gov (United States)

    Morais, Thiago R; da Costa-Silva, Thais A; Tempone, Andre G; Borborema, Samanta Etel T; Scotti, Marcus T; de Sousa, Raquel Maria F; Araujo, Ana Carolina C; de Oliveira, Alberto; de Morais, Sérgio Antônio L; Sartorelli, Patricia; Lago, João Henrique G

    2014-05-05

    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.

  2. Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents

    Science.gov (United States)

    2014-01-01

    Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5. PMID:25408832

  3. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

    Energy Technology Data Exchange (ETDEWEB)

    Kumar G.; Swaminathan S.; Kumaran, D.; Ahmed, S. A.

    2012-05-01

    Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

  4. NOVEL DESIGN OF CALANONE DERIVATIVES AS ANTI-LEUKEMIA COMPOUNDS BASED ON QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

    Directory of Open Access Journals (Sweden)

    Ponco Iswanto

    2011-07-01

    Full Text Available Leukemia drug discovery based on calanone compound was conducted in previous research and produced 6 calanone derivatives. Most of them have lower activities against leukemia cell L1210 than pure calanone. A Quantitative Structure-Activity Relationship (QSAR analysis is conducted in this work to find more active calanone derivatives. Six compounds were used as the material of the research because they already have anti-leukemia activity data expressed in Inhibitory Concentration of Fifty Percent Cell Lethal (IC50, in mg/mL. Calculation of predictors was performed by AM1 semiempirical method. QSAR equation is determined using Principle Component Regression (PCR analysis, with Log IC50 as dependent variable. Independent variables (predictors are atomic net charges, dipole moment (m, and coefficient partition of n-octanol/water (Log P. This work recommends 3 novel designs of calanone derivatives that may have higher activities (in mg/mL than those already available, i.e. gemdiol calanone (57.78, 2,4-dinitrophenylhydrazone calanone (30.94 and 2,4,6-trinitrophenylhydrazone calanone (18.96.

  5. Quantitative structure-activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells.

    Science.gov (United States)

    Yokoi, Taiyo; Nakagawa, Yoshiaki; Miyagawa, Hisashi

    2017-12-01

    Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch-Fujita type of quantitative structure-activity relationship (QSAR) analysis for ITD analogs (Yokoi et al., Pestic. Biochem. Physiol.2015, 120, 40-50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n = 8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Orientation of monoclonal antibodies in ion-exchange chromatography: A predictive quantitative structure-activity relationship modeling approach.

    Science.gov (United States)

    Kittelmann, Jörg; Lang, Katharina M H; Ottens, Marcel; Hubbuch, Jürgen

    2017-08-11

    Chromatographic separation of biopharmaceuticals in general and monoclonal antibodies (mAbs) specifically is the bottleneck in terms of cost and throughput in preparative purification. Still, generalized platform processes are used, neglecting molecule specific characteristics, defining protein-resin interaction terms. Currently used in silico modeling approaches do not consider the orientation of the molecule towards the chromatographic resins as a result of the structural features on an atomic level. This paper describes a quantitative structure-activity relationship (QSAR) approach to model the orientation of mAbs on ion exchange chromatographic matrices as a function of property distribution and mobile phase characteristics. 6 mAbs were used to build a predictive QSAR model and to investigate the preferred binding orientations and resulting surface shielding on resins. Thereby different dominating orientations, caused by composition of F ab fragments of the mAbs, could be identified. The presented methodology is suitable to gain extended insight in molecule orientation on chromatographic resins and to tailor purification strategies based on molecule structure. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Modeling the Dispersibility of Single Walled Carbon Nanotubes in Organic Solvents by Quantitative Structure-Activity Relationship Approach

    Science.gov (United States)

    Yilmaz, Hayriye; Rasulev, Bakhtiyor; Leszczynski, Jerzy

    2015-01-01

    The knowledge of physico-chemical properties of carbon nanotubes, including behavior in organic solvents is very important for design, manufacturing and utilizing of their counterparts with improved properties. In the present study a quantitative structure-activity/property relationship (QSAR/QSPR) approach was applied to predict the dispersibility of single walled carbon nanotubes (SWNTs) in various organic solvents. A number of additive descriptors and quantum-chemical descriptors were calculated and utilized to build QSAR models. The best predictability is shown by a 4-variable model. The model showed statistically good results (R2training = 0.797, Q2 = 0.665, R2test = 0.807), with high internal and external correlation coefficients. Presence of the X0Av descriptor and its negative term suggest that small size solvents have better SWCNTs solubility. Mass weighted descriptor ATS6m also indicates that heavier solvents (and small in size) most probably are better solvents for SWCNTs. The presence of the Dipole Z descriptor indicates that higher polarizability of the solvent molecule increases the solubility. The developed model and contributed descriptors can help to understand the mechanism of the dispersion process and predictorganic solvents that improve the dispersibility of SWNTs. PMID:28347035

  10. A Review of Recent Advances towards the Development of (Quantitative Structure-Activity Relationships for Metallic Nanomaterials

    Directory of Open Access Journals (Sweden)

    Guangchao Chen

    2017-08-01

    Full Text Available Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs. The extension of conventional (quantitative structure-activity relationships ((QSARs approach to nanotoxicology, i.e., nano-(QSARs, is a possible solution. The preliminary attempts of correlating ENMs’ characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (QSARs in the nanotoxicity field. This review discusses the current knowledge on the development of nano-(QSARs for metallic ENMs, on the aspects of data sources, reported nano-(QSARs, and mechanistic interpretation. An outlook is given on the further development of this frontier. As concluded, the used experimental data mainly concern the uptake of ENMs by different cell lines and the toxicity of ENMs to cells lines and Escherichia coli. The widely applied techniques of deriving models are linear and non-linear regressions, support vector machine, artificial neural network, k-nearest neighbors, etc. Concluded from the descriptors, surface properties of ENMs are seen as vital for the cellular uptake of ENMs; the capability of releasing ions and surface redox properties of ENMs are of importance for evaluating nanotoxicity. This review aims to present key advances in relevant nano-modeling studies and stimulate future research efforts in this quickly developing field of research.

  11. Modeling the Dispersibility of Single Walled Carbon Nanotubes in Organic Solvents by Quantitative Structure-Activity Relationship Approach

    Directory of Open Access Journals (Sweden)

    Hayriye Yilmaz

    2015-05-01

    Full Text Available The knowledge of physico-chemical properties of carbon nanotubes, including behavior in organic solvents is very important for design, manufacturing and utilizing of their counterparts with improved properties. In the present study a quantitative structure-activity/property relationship (QSAR/QSPR approach was applied to predict the dispersibility of single walled carbon nanotubes (SWNTs in various organic solvents. A number of additive descriptors and quantum-chemical descriptors were calculated and utilized to build QSAR models. The best predictability is shown by a 4-variable model. The model showed statistically good results (R2training = 0.797, Q2 = 0.665, R2test = 0.807, with high internal and external correlation coefficients. Presence of the X0Av descriptor and its negative term suggest that small size solvents have better SWCNTs solubility. Mass weighted descriptor ATS6m also indicates that heavier solvents (and small in size most probably are better solvents for SWCNTs. The presence of the Dipole Z descriptor indicates that higher polarizability of the solvent molecule increases the solubility. The developed model and contributed descriptors can help to understand the mechanism of the dispersion process and predictorganic solvents that improve the dispersibility of SWNTs.

  12. 4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.

    Science.gov (United States)

    Matulenko, Mark A; Paight, Ernest S; Frey, Robin R; Gomtsyan, Arthur; DiDomenico, Stanley; Jiang, Meiqun; Lee, Chih-Hung; Stewart, Andrew O; Yu, Haixia; Kohlhaas, Kathy L; Alexander, Karen M; McGaraughty, Steve; Mikusa, Joseph; Marsh, Kennan C; Muchmore, Steven W; Jakob, Clarissa L; Kowaluk, Elizabeth A; Jarvis, Michael F; Bhagwat, Shripad S

    2007-02-15

    A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.

  13. Structure-activity relationship study and discovery of indazole 3-carboxamides as calcium-release activated calcium channel blockers.

    Science.gov (United States)

    Bai, Sha; Nagai, Masazumi; Koerner, Steffi K; Veves, Aristidis; Sun, Lijun

    2017-02-01

    Aberrant activation of mast cells contributes to the development of numerous diseases including cancer, autoimmune disorders, as well as diabetes and its complications. The influx of extracellular calcium via the highly calcium selective calcium-release activated calcium (CRAC) channel controls mast cell functions. Intracellular calcium homeostasis in mast cells can be maintained via the modulation of the CRAC channel, representing a critical point for therapeutic interventions. We describe the structure-activity relationship study (SAR) of indazole-3-carboxamides as potent CRAC channel blockers and their ability to stabilize mast cells. Our SAR results show that the unique regiochemistry of the amide linker is critical for the inhibition of calcium influx, the release of the pro-inflammatory mediators β-hexosaminidase and tumor necrosis factor α by activated mast cells. Thus, the indazole-3-carboxamide 12d actively inhibits calcium influx and stabilizes mast cells with sub-μM IC 50 . In contrast, its reverse amide isomer 9c is inactive in the calcium influx assay even at 100μM concentration. This requirement of the specific 3-carboxamide regiochemistry in indazoles is unprecedented in known CRAC channel blockers. The new structural scaffolds described in this report expand the structural diversity of the CRAC channel blockers and may lead to the discovery of novel immune modulators for the treatment of human diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Advantages of Relative versus Absolute Data for the Development of Quantitative Structure-Activity Relationship Classification Models.

    Science.gov (United States)

    Ruiz, Irene Luque; Gómez-Nieto, Miguel Ángel

    2017-11-27

    The appropriate selection of a chemical space represented by the data set, the selection of its chemical data representation, the development of a correct modeling process using a robust and reproducible algorithm, and the performance of an exhaustive training and external validation determine the usability and reproducibility of a quantitative structure-activity relationship (QSAR) classification model. In this paper, we show that the use of relative versus absolute data in the representation of the data sets produces better classification models when the other processes are not modified. Relative data considers a reference frame to measure the chemical characteristics involved in the classification model, refining the data set representation and smoothing the lack of chemical information. Three data sets with different characteristics have been used in this study, and classifications models have been built applying the support vector machine algorithm. For randomly selected training and test sets, values of accuracy and area under the receiver operating characteristic curve close to 100% have been obtained for the generation of the models and external validations in all cases.

  15. Applying quantitative structure-activity relationship (QSAR) methodology for modeling postmortem redistribution of benzodiazepines and tricyclic antidepressants.

    Science.gov (United States)

    Giaginis, Constantinos; Tsantili-Kakoulidou, Anna; Theocharis, Stamatios

    2014-06-01

    Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists. The present study aimed to apply quantitative structure-activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. For benzodiazepines, an adequate QSAR model was obtained (R(2) = 0.98, Q(2) = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics (R(2) = 0.95, Q(2) = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data.

  16. In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis▿ †

    Science.gov (United States)

    Kaur, Jaspreet; Kumar, Pranav; Tyagi, Sargam; Pathak, Richa; Batra, Sanjay; Singh, Prashant; Singh, Neeloo

    2011-01-01

    In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active on L. donovani amastigotes (50% inhibitory concentration [IC50] = 3 μM) than on promastigotes (IC50 = 29 μM). Compound 7 exhibited a Ki value of 0.72 μM in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis. PMID:21115787

  17. Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide.

    Science.gov (United States)

    Xu, Hongtao; Tang, Huanyu; Feng, Huijin; Li, Yuanchao

    2014-02-01

    Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure-activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41.

    Science.gov (United States)

    Zhou, Guangyan; Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A; Mankowski, Marie K; Hogan, Priscilla A; Ptak, Roger G; Gochin, Miriam

    2014-06-26

    We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure-activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell-cell fusion, and viral replication assays. Below a 1 μM threshold, correlation between binding and biological activity was diminished, indicating an amphipathic requirement for activity in cells. The most active inhibitor 6j exhibited 0.6 μM binding affinity and 0.2 μM EC50 against cell-cell fusion and live virus replication and was active against T20 resistant strains. Twenty-two compounds with the same connectivity displayed a consensus pose in docking calculations, with rank order matching the biological activity. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion and demonstrates a potent low molecular weight fusion inhibitor.

  19. 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. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Acaricidal and quantitative structure activity relationship of monoterpenes against the two-spotted spider mite, Tetranychus urticae.

    Science.gov (United States)

    Badawy, Mohamed E I; El-Arami, Sailan A A; Abdelgaleil, Samir A M

    2010-11-01

    The acaricidal activity of 12 monoterpenes against the two-spotted spider mite, Tetranychus urticae Koch, was examined using fumigation and direct contact application methods. Cuminaldehyde and (-)-linalool showed the highest fumigant toxicity with LC(50) = 0.31 and 0.56 mg/l, respectively. The other monoterpenes exhibited a strong fumigant toxicity, the LC(50) values ranging from 1.28 to 8.09 mg/l, except camphene, which was the least effective (LC(50) = 61.45 mg/l). Based on contact activity, the results were rather different: menthol displayed the highest acaricidal activity (LC(50) = 128.53 mg/l) followed by thymol (172.0 mg/l), geraniol (219.69 mg/l) and (-)-limonene (255.44 mg/l); 1-8-cineole, cuminaldehyde and (-)-linalool showed moderate toxicity. At 125 mg/l, (-)-Limonene and (-)-carvone caused the highest egg mortality among the tested compounds (70.6 and 66.9% mortality, respectively). In addition, the effect of molecular descriptors was also analyzed using the quantitative structure activity relationship (QSAR) procedure. The QSAR model showed excellent agreement between the estimated and experimentally measured toxicity parameter (LC(50)) for the tested monoterpenes and the fumigant activity increased significantly with the vapor pressure. Comparing the results of the fumigant and contact toxicity assays of monoterpenes against T. urticae with the results of acetylcholinesterase (AChE) inhibitory effect revealed that some of the tested compounds showed a strong acaricidal activity and a potent AChE inhibitory activity, such as cuminaldehyde, (-)-linalool, (-)-limonene and menthol. However, other compounds such as (-)-carvone revealed a strong fumigant activity but a weak AChE inhibitory activity.

  1. The antimicrobial efficacy and structure activity relationship of novel carbohydrate fatty acid derivatives against Listeria spp. and food spoilage microorganisms.

    Science.gov (United States)

    Nobmann, Patricia; Smith, Aoife; Dunne, Julie; Henehan, Gary; Bourke, Paula

    2009-01-15

    Novel mono-substituted carbohydrate fatty acid (CFA) esters and ethers were investigated for their antibacterial activity against a range of pathogenic and spoilage bacteria focussing on Listeria monocytogenes. Carbohydrate derivatives with structural differences enable comparative studies on the structure/activity relationship for antimicrobial efficacy and mechanism of action. The antimicrobial efficacy of the synthesized compounds was compared with commercially available compounds such as monolaurin and monocaprylin, as well as the pure free fatty acids, lauric acid and caprylic acid, which have proven antimicrobial activity. Compound efficacy was compared using an absorbance based broth microdilution assay to determine the minimum inhibitory concentration (MIC), increase in lag phase and decrease in maximum growth rate. Among the carbohydrate derivatives synthesized, lauric ether of methyl alpha-d-glucopyranoside and lauric ester of methyl alpha-d-mannopyranoside showed the highest growth-inhibitory effect with MIC values of 0.04 mM, comparable to monolaurin. CFA derivatives were generally more active against Gram positive bacteria than Gram negative bacteria. The analysis of both ester and ether fatty acid derivatives of the same carbohydrate, in tandem with alpha and beta configuration of the carbohydrate moiety suggest that the carbohydrate moiety is involved in the antimicrobial activity of the fatty acid derivatives and that the nature of the bond also has a significant effect on efficacy, which requires further investigation. This class of CFA derivatives has great potential for developing antibacterial agents relevant to the food industry, particularly for control of Listeria or other Gram-positive pathogens.

  2. Investigation of Antileishmanial Activities of Acridines Derivatives against Promastigotes and Amastigotes Form of Parasites Using Quantitative Structure Activity Relationship Analysis

    Directory of Open Access Journals (Sweden)

    Samir Chtita

    2016-01-01

    Full Text Available In a search of newer and potent antileishmanial (against promastigotes and amastigotes form of parasites drug, a series of 60 variously substituted acridines derivatives were subjected to a quantitative structure activity relationship (QSAR analysis for studying, interpreting, and predicting activities and designing new compounds by using multiple linear regression and artificial neural network (ANN methods. The used descriptors were computed with Gaussian 03, ACD/ChemSketch, Marvin Sketch, and ChemOffice programs. The QSAR models developed were validated according to the principles set up by the Organisation for Economic Co-operation and Development (OECD. The principal component analysis (PCA has been used to select descriptors that show a high correlation with activities. The univariate partitioning (UP method was used to divide the dataset into training and test sets. The multiple linear regression (MLR method showed a correlation coefficient of 0.850 and 0.814 for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. Internal and external validations were used to determine the statistical quality of QSAR of the two MLR models. The artificial neural network (ANN method, considering the relevant descriptors obtained from the MLR, showed a correlation coefficient of 0.933 and 0.918 with 7-3-1 and 6-3-1 ANN models architecture for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. The applicability domain of MLR models was investigated using simple and leverage approaches to detect outliers and outsides compounds. The effects of different descriptors in the activities were described and used to study and design new compounds with higher activities compared to the existing ones.

  3. Synthesis and quantitative structure-activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents.

    Science.gov (United States)

    Wang, Yi; Shao, Yonghua; Wang, Yangyang; Fan, Lingling; Yu, Xiang; Zhi, Xiaoyan; Yang, Chun; Qu, Huan; Yao, Xiaojun; Xu, Hui

    2012-08-29

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, 33 isoxazoline and oxime derivatives of podophyllotoxin modified in the C and D rings were synthesized and their structures were characterized by Proton nuclear magnetic resonance ((1)H NMR), high-resolution mass spectrometry (HRMS), electrospray ionization-mass spectrometry (ESI-MS), optical rotation, melting point (mp), and infrared (IR) spectroscopy. The stereochemical configurations of compounds 5e, 5f, and 9f were unambiguously determined by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of northern armyworm, Mythimna separata (Walker), in vivo. Compounds 5e, 9c, 11g, and 11h especially exhibited more promising insecticidal activity than toosendanin, a commercial botanical insecticide extracted from Melia azedarach . A genetic algorithm combined with multiple linear regression (GA-MLR) calculation is performed by the MOBY DIGS package. Five selected descriptors are as follows: one two-dimensional (2D) autocorrelation descriptor (GATS4e), one edge adjacency indice (EEig06x), one RDF descriptor (RDF080v), one three-dimensional (3D) MoRSE descriptor (Mor09v), and one atom-centered fragment (H-052) descriptor. Quantitative structure-activity relationship studies demonstrated that the insecticidal activity of these compounds was mainly influenced by many factors, such as electronic distribution, steric factors, etc. For this model, the standard deviation error in prediction (SDEP) is 0.0592, the correlation coefficient (R(2)) is 0.861, and the leave-one-out cross-validation correlation coefficient (Q(2)loo) is 0.797.

  4. New Quantitative Structure-Activity Relationship Model for Angiotensin-Converting Enzyme Inhibitory Dipeptides Based on Integrated Descriptors.

    Science.gov (United States)

    Deng, Baichuan; Ni, Xiaojun; Zhai, Zhenya; Tang, Tianyue; Tan, Chengquan; Yan, Yijing; Deng, Jinping; Yin, Yulong

    2017-11-08

    Angiotensin-converting enzyme (ACE) inhibitory peptides derived from food proteins have been widely reported for hypertension treatment. In this paper, a benchmark data set containing 141 unique ACE inhibitory dipeptides was constructed through database mining, and a quantitative structure-activity relationships (QSAR) study was carried out to predict half-inhibitory concentration (IC 50 ) of ACE activity. Sixteen descriptors were tested and the model generated by G-scale descriptor showed the best predictive performance with the coefficient of determination (R 2 ) and cross-validated R 2 (Q 2 ) of 0.6692 and 0.6220, respectively. For most other descriptors, R 2 were ranging from 0.52 to 0.68 and Q 2 were ranging from 0.48 to 0.61. A complex model combining all 16 descriptors was carried out and variable selection was performed in order to further improve the prediction performance. The quality of model using integrated descriptors (R 2 0.7340 ± 0.0038, Q 2 0.7151 ± 0.0019) was better than that of G-scale. An in-depth study of variable importance showed that the most correlated properties to ACE inhibitory activity were hydrophobicity, steric, and electronic properties and C-terminal amino acids contribute more than N-terminal amino acids. Five novel predicted ACE-inhibitory peptides were synthesized, and their IC 50 values were validated through in vitro experiments. The results indicated that the constructed model could give a reliable prediction of ACE-inhibitory activity of peptides, and it may be useful in the design of novel ACE-inhibitory peptides.

  5. Synthesis and quantitative structure activity relationship (QSAR) of arylidene (benzimidazol-1-yl)acetohydrazones as potential antibacterial agents.

    Science.gov (United States)

    El-Kilany, Yeldez; Nahas, Nariman M; Al-Ghamdi, Mariam A; Badawy, Mohamed E I; El Ashry, El Sayed H

    2015-01-01

    Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1-yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1-yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r (2)), the ratio between regression and residual variances (f, Fisher's statistic), the standard error of estimates and

  6. A structure-activity relationship study on antiosteoclastogenesis effect of triterpenoids from the leaves of loquat (Eriobotrya japonica).

    Science.gov (United States)

    Tan, Hui; Ashour, Ahmed; Katakura, Yoshinori; Shimizu, Kuniyoshi

    2015-04-15

    Our previous results elucidated that the leaves of Eriobotrya japonica possessed the potential to suppress ovariectomy-induced bone mineral density deterioration, and ursolic acid, the major bioactive component in these leaves, suppressed the osteoclast differentiation. The aim of this study was to discover more candidates for development of novel antiosteoclastogenesis agents from the leaves of E. japonica. Phytochemical analysis following a cell-based osteoclastic tartrate-resistant acid phosphatase (TRAP) activity assay revealed 11 more compounds with a potent antiosteoclastogenesis effect. The potency of ursane-type triterpenoids from the leaves of E. japonica prompted us to investigate the structure-activity relationships underlying their antiosteoclastogenesis. The results revealed that both the hydroxyl group at C-3 and the carboxylic group at C-17 played indispensable roles in the antiosteoclastogenesis activity of ursane-type triterpenoids. The configuration at C-3 (a beta-form of the hydroxyl group) was found to be important for this activity. While introducing a hydroxyl group at C-19 increased the inhibitory activity of ursane-type triterpenoids carrying an alpha-form hydroxyl group at C-3. The bioactivity analyses of ursolic acid and oleanolic acid demonstrated that the antiosteoclastogenesis effect of ursolic acid may be related to different positions of the C-29 and C-30 methyl groups on the E-ring, since oleanolic acid showed limited activity. The addition of a hydroxyl group at C-2 would dramatically improve the inhibition of oleanane-type triterpenoids. Collectively, these findings could provide important clues for the improvement of multi-targeted antiosteoclastogenesis agents from the leaves of E. japonica. Copyright © 2015 Elsevier GmbH. All rights reserved.

  7. The discovery and structure-activity relationships of pyrano[3,4-b]indole based inhibitors of hepatitis C virus NS5B polymerase.

    Science.gov (United States)

    LaPorte, Matthew G; Draper, Tandy L; Miller, Lori E; Blackledge, Charles W; Leister, Lara K; Amparo, Eugene; Hussey, Alison R; Young, Dorothy C; Chunduru, Srinivas K; Benetatos, Christopher A; Rhodes, Gerry; Gopalsamy, Ariamala; Herbertz, Torsten; Burns, Christopher J; Condon, Stephen M

    2010-05-01

    We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12. 2010 Elsevier Ltd. All rights reserved.

  8. Binary classification of a large collection of environmental chemicals from estrogen receptor assays by quantitative structure-activity relationship and machine learning methods.

    Science.gov (United States)

    Zang, Qingda; Rotroff, Daniel M; Judson, Richard S

    2013-12-23

    There are thousands of environmental chemicals subject to regulatory decisions for endocrine disrupting potential. The ToxCast and Tox21 programs have tested ∼8200 chemicals in a broad screening panel of in vitro high-throughput screening (HTS) assays for estrogen receptor (ER) agonist and antagonist activity. The present work uses this large data set to develop in silico quantitative structure-activity relationship (QSAR) models using machine learning (ML) methods and a novel approach to manage the imbalanced data distribution. Training compounds from the ToxCast project were categorized as active or inactive (binding or nonbinding) classes based on a composite ER Interaction Score derived from a collection of 13 ER in vitro assays. A total of 1537 chemicals from ToxCast were used to derive and optimize the binary classification models while 5073 additional chemicals from the Tox21 project, evaluated in 2 of the 13 in vitro assays, were used to externally validate the model performance. In order to handle the imbalanced distribution of active and inactive chemicals, we developed a cluster-selection strategy to minimize information loss and increase predictive performance and compared this strategy to three currently popular techniques: cost-sensitive learning, oversampling of the minority class, and undersampling of the majority class. QSAR classification models were built to relate the molecular structures of chemicals to their ER activities using linear discriminant analysis (LDA), classification and regression trees (CART), and support vector machines (SVM) with 51 molecular descriptors from QikProp and 4328 bits of structural fingerprints as explanatory variables. A random forest (RF) feature selection method was employed to extract the structural features most relevant to the ER activity. The best model was obtained using SVM in combination with a subset of descriptors identified from a large set via the RF algorithm, which recognized the active and

  9. Fuzzy tricentric pharmacophore fingerprints. 2. Application of topological fuzzy pharmacophore triplets in quantitative structure-activity relationships.

    Science.gov (United States)

    Bonachéra, Fanny; Horvath, Dragos

    2008-02-01

    Topological fuzzy pharmacophore triplets (2D-FPT), using the number of interposed bonds to measure separation between the atoms representing pharmacophore types, were employed to establish and validate quantitative structure-activity relationships (QSAR). Thirteen data sets for which state-of-the-art QSAR models were reported in literature were revisited in order to benchmark 2D-FPT biological activity-explaining propensities. Linear and nonlinear QSAR models were constructed for each compound series (following the original author's splitting into training/validation subsets) with three different 2D-FPT versions, using the genetic algorithm-driven Stochastic QSAR sampler (SQS) to pick relevant triplets and fit their coefficients. 2D-FPT QSARs are computationally cheap, interpretable, and perform well in benchmarking. In a majority of cases (10/13), default 2D-FPT models validated better than or as well as the best among those reported, including 3D overlay-dependent approaches. Most of the analogues series, either unaffected by protonation equilibria or unambiguously adopting expected protonation states, were equally well described by rule- or pKa-based pharmacophore flagging. Thermolysin inhibitors represent a notable exception: pKa-based flagging boosts model quality, although--surprisingly--not due to proteolytic equilibrium effects. The optimal degree of 2D-FPT fuzziness is compound set dependent. This work further confirmed the higher robustness of nonlinear over linear SQS models. In spite of the wealth of studied sets, benchmarking is nevertheless flawed by low intraset diversity: a whole series of thereby caused artifacts were evidenced, implicitly raising questions about the way QSAR studies are conducted nowadays. An in-depth investigation of thrombin inhibition models revealed that some of the selected triplets make sense (one of these stands for a topological pharmacophore covering the P1 and P2 binding pockets). Nevertheless, equations were either

  10. Discovery and preliminary structure-activity relationship of the marine natural product manzamines as herpes simplex virus type-1 inhibitors.

    Science.gov (United States)

    Palem, Jayavardhana R; Mudit, Mudit; Hsia, Shao-Chung V; Sayed, Khalid A El

    2017-01-01

    Herpes simplex virus type-1 (HSV-1) is a member of alpha-herpesviridae family and is known to cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites. A small library of marine natural product classes 1-10 has been screened to discover a new hit entity active against HSV-1. Manzamine A showed potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a β-carboline alkaloid isolated from the Indo-Pacific sponge Acanthostrongylophora species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared with 50 µM acyclovir, manzamine A at 1 µM concentration produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells in recent studies. The potent anti-HSV-1 activity of manzamine A prompted a preliminary structure-activity relationship study by testing targeted manzamines. These included 8-hydroxymanzamine A (11), to test the effect of the C-8 hydroxy substitution at the β-carboline moiety; manzamine E (12), to assess the importance of substitution at the azacyclooctane ring; and ircinal A (13), to determine whether the β-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride (14) and manzamine A monotartrate (15), to test whether improving water solubility and hydrophilicity will positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed the reduced anti-HSV-1 activity of 11, suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 12 and 13 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and β-carboline rings to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 14 and 15, suggesting that improving the overall water solubility

  11. 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

  12. Prediction of the relationship between the structural features of andrographolide derivatives and α-glucosidase inhibitory activity: a quantitative structure-activity relationship (QSAR) study.

    Science.gov (United States)

    Moorthy, N S Hari Narayana; Ramos, Maria J; Fernandes, Pedro A

    2011-02-01

    In order to predict the structural features responsible for α-glucosidase inhibitory activity, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of andrographolide derivatives. To determine the quantitative relationship for the statistically significant models in terms of r (>0.8), F (99%) and Q(2) (>0.71) values were selected. The promising results we obtained could be used to predict the structural requirements for the inhibition of α-glucosidase activity. The models developed included: subdivided surface area, adjacency, surface volume and shape, molecular orbital package (MOPAC) and partial charge descriptors and showed a high correlation with the inhibitory activity. The descriptors used revealed that a van der Waals (vdW) surface with significant polar volume is favourable to the activity. The positive effect of the shape descriptors; PM3-LUMO and vsurf_wp7 and the negative effect of GCUT_PEOE_2 indicated that the active site may contain some nucleophilic positions that could interact with the ligand and the hydrogen acceptor and/or donor groups for hydrogen bonding with inhibitors.

  13. 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.…

  14. Augmented multivariate image analysis applied to quantitative structure-activity relationship modeling of the phytotoxicities of benzoxazinone herbicides and related compounds on problematic weeds.

    Science.gov (United States)

    Freitas, Mirlaine R; Matias, Stella V B G; Macedo, Renato L G; Freitas, Matheus P; Venturin, Nelson

    2013-09-11

    Two of major weeds affecting cereal crops worldwide are Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass). Thus, development of new herbicides against these weeds is required; in line with this, benzoxazinones, their degradation products, and analogues have been shown to be important allelochemicals and natural herbicides. Despite earlier structure-activity studies demonstrating that hydrophobicity (log P) of aminophenoxazines correlates to phytotoxicity, our findings for a series of benzoxazinone derivatives do not show any relationship between phytotoxicity and log P nor with other two usual molecular descriptors. On the other hand, a quantitative structure-activity relationship (QSAR) analysis based on molecular graphs representing structural shape, atomic sizes, and colors to encode other atomic properties performed very accurately for the prediction of phytotoxicities of these compounds against wild oat and rigid ryegrass. Therefore, these QSAR models can be used to estimate the phytotoxicity of new congeners of benzoxazinone herbicides toward A. fatua L. and L. rigidum Gaud.

  15. Effect of O-methylated and glucuronosylated flavonoids from Tamarix gallica on α-glucosidase inhibitory activity: structure-activity relationship and synergistic potential.

    Science.gov (United States)

    Ben Hmidene, Asma; Smaoui, Abderrazak; Abdelly, Chedly; Isoda, Hiroko; Shigemori, Hideyuki

    2017-03-01

    O-Methylated and glucuronosylated flavonoids were isolated from Tamarix gallica as α-glucosidase inhibitors. Structure-activity relationship of these flavonoids suggests that catechol moiety and glucuronic acid at C-3 are factors in the increase in α-glucosidase inhibitory activity. Furthermore, rhamnetin, tamarixetin, rhamnazin, KGlcA, KGlcA-Me, QGlcA, and QGlcA-Me exhibit synergistic potential when applied with a very low concentration of acarbose to α-glucosidase from rat intestine.

  16. Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7.

    Science.gov (United States)

    Hu, Yi; Ma, Lifu; Wu, Min; Wong, Melissa S; Li, Bei; Corral, Sergio; Yu, Zhizhou; Nomanbhoy, Tyzoon; Alemayehu, Senaiet; Fuller, Stacy R; Rosenblum, Jonathan S; Rozenkrants, Natasha; Minimo, Lauro C; Ripka, William C; Szardenings, Anna K; Kozarich, John W; Shreder, Kevin R

    2005-10-01

    The structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against three dipeptidyl peptidases (DPPs) was studied. In a series of N-cycloalkyl analogs, DPP4 and fibroblast activation protein-alpha (FAP) optimally preferred N-cycloheptyl whereas DPP7 tolerated even larger cycloalkyl rings. Gly alpha-carbon derivatization of N-cyclohexyl or N-(2-adamantyl) Gly-boro-Pro resulted in a significant decrease in potency against all the three DPPs.

  17. p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.

    Science.gov (United States)

    Fukushi, Saori; Yoshino, Hironori; Yoshizawa, Atsushi; Kashiwakura, Ikuo

    2016-07-25

    We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as "mesogenic compounds") in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure-activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells. The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed. The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1-C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound. We showed the p53-indepdent structure-activity relationships of mesogenic compounds related to the cytotoxic effects. These structure-activity relationships will be helpful in the development of more effective and cancer-specific agents.

  18. Application of cultured human mast cells (CHMC) for the design and structure-activity relationship of IgE-mediated mast cell activation inhibitors.

    Science.gov (United States)

    Argade, Ankush; Bhamidipati, Somasekhar; Li, Hui; Carroll, David; Clough, Jeffrey; Keim, Holger; Sylvain, Catherine; Rossi, Alexander B; Coquilla, Christina; Issakani, Sarkiz D; Masuda, Esteban S; Payan, Donald G; Singh, Rajinder

    2015-01-01

    Here we report the optimization of small molecule inhibitors of human mast cell degranulation via anti-IgE-mediated tryptase release following cross-linking and activation of IgE-loaded FcεR1 receptors. The compounds are selective upstream inhibitors of FcεR1-dependent human mast cell degranulation and proved to be devoid of activity in downstream ionomycin mediated degranulation. Structure-activity relationship (SAR) leading to compound 26 is outlined. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

    Science.gov (United States)

    Norinder, U; Högberg, T

    1992-04-01

    The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

  20. Jatrophane diterpenes as P-glycoprotein inhibitors. First insights of structure-activity relationships and discovery of a new, powerful lead.

    Science.gov (United States)

    Corea, Gabriella; Fattorusso, Ernesto; Lanzotti, Virginia; Taglialatela-Scafati, Orazio; Appendino, Giovanni; Ballero, Mauro; Simon, Pierre-Noël; Dumontet, Charles; Di Pietro, Attilio

    2003-07-17

    The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure-activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the general role of lipophilicity for activity, also highlighted the relevance of the substitution pattern at the positions 2, 3, and 5, suggesting the involvement of this fragment in binding. The most powerful compound of the series, euphodendroidin D (4), outperformed cyclosporin by a factor of 2 to inhibit Pgp-mediated daunomycin transport.

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

    DEFF Research Database (Denmark)

    Gimenéz-Arnau, Elena; Andersen, K E; 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...

  2. Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum.

    Science.gov (United States)

    Kannan Sivaraman, Komagal; Paiardini, Alessandro; Sieńczyk, Marcin; Ruggeri, Chiara; Oellig, Christine A; Dalton, John P; Scammells, Peter J; Drag, Marcin; McGowan, Sheena

    2013-06-27

    The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.

  3. Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A role played by the lactone moiety.

    Science.gov (United States)

    Qiu, Haibo; Qian, Shan; Head, Sarah A; Liu, Jun O; Jin, Zhendong

    2016-10-01

    Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, a new analog ZJ-109 was designed and synthesized to probe the importance of the lactone moiety of the molecule by replacing the lactone in ZJ-101 with a lactam. The biological evaluation showed that ZJ-109 is about 8-12 times less active against cancer cells in vitro than ZJ-101, suggesting that the lactone moiety of the molecule is important for its anticancer activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Structure-activity relationship of the ionic cocrystal: 5-amino-2-naphthalene sulfonate·ammonium ions for pharmaceutical applications

    Science.gov (United States)

    Sangeetha, M.; Mathammal, R.

    2018-02-01

    The ionic cocrystals of 5-amino-2-naphthalene sulfonate · ammonium ions (ANSA-ṡNH4+) were grown under slow evaporation method and examined in detail for pharmaceutical applications. The crystal structure and intermolecular interactions were studied from the single X-ray diffraction analysis and the Hirshfeld surfaces. The 2D fingerprint plots displayed the inter-contacts possible in the ionic crystal. Computational DFT method was established to determine the structural, physical and chemical properties. The molecular geometries obtained from the X-ray studies were compared with the optimized geometrical parameters calculated using DFT/6-31 + G(d,p) method. The band gap energy calculated from the UV-Visible spectral analysis and the HOMO-LUMO energy gap are compared. The theoretical UV-Visible calculations helped in determining the type of electronic transition taking place in the title molecule. The maximum absorption bands and transitions involved in the molecule represented the drug reaction possible. Non-linear optical properties were characterized from SHG efficiency measurements experimentally and the NLO parameters are also calculated from the optimized structure. The reactive sites within the molecule are detailed from the MEP surface maps. The molecular docking studies evident the structure-activity of the ionic cocrystal for anti-cancer drug property.

  5. Structure-based and multiple potential three-dimensional quantitative structure-activity relationship (SB-MP-3D-QSAR) for inhibitor design.

    Science.gov (United States)

    Du, Qi-Shi; Gao, Jing; Wei, Yu-Tuo; Du, Li-Qin; Wang, Shu-Qing; Huang, Ri-Bo

    2012-04-23

    The inhibitions of enzymes (proteins) are determined by the binding interactions between ligands and targeting proteins. However, traditional QSAR (quantitative structure-activity relationship) is a one-side technique, only considering the structures and physicochemical properties of inhibitors. In this study, the structure-based and multiple potential three-dimensional quantitative structure-activity relationship (SB-MP-3D-QSAR) is presented, in which the structural information of host protein is involved in the QSAR calculations. The SB-MP-3D-QSAR actually is a combinational method of docking approach and QSAR technique. Multiple docking calculations are performed first between the host protein and ligand molecules in a training set. In the targeting protein, the functional residues are selected, which make the major contribution to the binding free energy. The binding free energy between ligand and targeting protein is the summation of multiple potential energies, including van der Waals energy, electrostatic energy, hydrophobic energy, and hydrogen-bond energy, and may include nonthermodynamic factors. In the foundational QSAR equation, two sets of weighting coefficients {aj} and {bp} are assigned to the potential energy terms and to the functional residues, respectively. The two coefficient sets are solved by using iterative double least-squares (IDLS) technique in the training set. Then, the two sets of weighting coefficients are used to predict the bioactivities of inquired ligands. In an application example, the new developed method obtained much better results than that of docking calculations.

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

    Science.gov (United States)

    Arnau, E G; Andersen, K E; Bruze, M; Frosch, P J; Johansen, J D; Menné, T; Rastogi, S C; White, I R; Lepoittevin, J P

    2000-12-01

    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 test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their 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 mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

  7. Comparison between 5,10,15,20-tetraaryl- and 5,15-diarylporphyrins as photosensitizers: synthesis, photodynamic activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Banfi, Stefano; Caruso, Enrico; Buccafurni, Loredana; Murano, Roberto; Monti, Elena; Gariboldi, Marzia; Papa, Ester; Gramatica, Paola

    2006-06-01

    The synthesis of a panel of seven nonsymmetric 5,10,15,20-tetraarylporphyrins, 13 symmetric and nonsymmetric 5,15-diarylporphyrins, and one 5,15-diarylchlorin is described. In vitro photodynamic activities on HCT116 human colon adenocarcinoma cells were evaluated by standard cytotoxicity assays. A predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, of a series of 34 tetrapyrrolic photosensitizers (PSs), including the 24 compounds synthesized in this work, was developed to describe the relationship between structural features and photodynamic activity. The present study demonstrates that structural features significantly influence the photodynamic activity of tetrapyrrolic derivatives: diaryl compounds were more active with respect to the tetraarylporphyrins, and among the diaryl derivatives, hydroxy-substituted compounds were more effective than the corresponding methoxy-substituted ones. Furthermore, three monoarylporphyrins, isolated as byproducts during diarylporphyrin synthesis, were considered for both photodynamic and QSAR studies; surprisingly they were found to be particularly active photosensitizers.

  8. Categorizing operational radioactive wastes

    International Nuclear Information System (INIS)

    2007-04-01

    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

  9. Positive Relationship Between Individuality and Social Identity in Virtual Communities: Self-Categorization and Social Identification as Distinct Forms of Social Identity.

    Science.gov (United States)

    Guo, Tian-Chao; Li, Xuemei

    2016-11-01

    Previous studies have reported conflicting results regarding the relationship between individuality and social identity, indicating this area requires further examination. This study constructed a research model to help understand the positive role of individualized behavior and social identity in virtual communities. The results of an online survey conducted to assess our theoretical research model indicated that social identity can be expressed in two ways: self-categorization and social identification. Furthermore, we found individualized behavior was positively related to social identification, while self-categorization was directly derived from social identification.

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

    International Nuclear Information System (INIS)

    Salahinejad, M.; Mirshojaei, S.F.

    2016-01-01

    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)

  11. 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

    as the principal toxic components of oil sands process-affected water (OSPW), and microbial degradation of lower molecular weight (MW) NAs decreases the toxicity of NA mixtures in OSPW.  Analysis by proton nuclear magnetic resonance spectroscopy indicated that larger, more cyclic NAs contain greater carboxylic...... acid content, thereby decreasing their hydrophobicity and acute toxicity in comparison to lower MW NAs.  The relationship between the acute toxicity of NAs and hydrophobicity suggests that narcosis is the probable mode of acute toxic action.  The applicability of a (Quantitative) Structure...

  12. Sticky Categorizations

    DEFF Research Database (Denmark)

    Lagermann, Laila Colding

    2015-01-01

    What are the possibilities and/or limitations in becoming subjects who are differenciated from earlier processes of categorizations that certain students are subjected to? This is the question explored in the analysis of this paper, based on observations of, and narratives and perspectives of two...

  13. Synthesis and quantitative structure-activity relationship of hydrazones of N-amino-N'-hydroxyguanidine as electron acceptors for xanthine oxidase.

    Science.gov (United States)

    Prusis, Peteris; Dambrova, Maija; Andrianov, Victor; Rozhkov, Eugene; Semenikhina, Valentina; Piskunova, Irena; Ongwae, Enock; Lundstedt, Torbjörn; Kalvinsh, Ivars; Wikberg, Jarl E S

    2004-06-03

    A series of new N-hydroxyguanidines were synthesized and tested for electron acceptor activity on bovine milk xanthine oxidase using xanthine as reducing substrate. Manual inspection of the structure-activity data revealed that molecules containing nitro groups ("set A") show a different structure-activity relationship pattern compared to non-nitro compounds ("set B"). Accordingly separate QSAR models were built and validated for the two sets. Substantial differences were found in properties governing acceptor activity for the models, the only common property being sterical access to the imino nitrogen atom of the hydroxyguanidinimines. For set A molecules the presence of a nitro substituent at a certain distance range from the hydroxuguanidino group was most important. In addition, the presence of a nitro group in the ortho position interacting with NH(2) of the hydroxyguanidino group, and the mutual geometry of the phenyl ring, hydroxyguanidine, and imine groups was important for this set. By contrast, for set B molecules the acceptor activity was most influenced by the geometry of methoxy groups and the size and geometry of meta and para substituents of the phenyl ring.

  14. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Quantitative structure activity relationships (QSAR) for binary mixtures at non-equitoxic ratios based on toxic ratios-effects curves.

    Science.gov (United States)

    Tian, Dayong; Lin, Zhifen; Yin, Daqiang

    2013-01-01

    The present study proposed a QSAR model to predict joint effects at non-equitoxic ratios for binary mixtures containing reactive toxicants, cyanogenic compounds and aldehydes. Toxicity of single and binary mixtures was measured by quantifying the decrease in light emission from the Photobacterium phosphoreum for 15 min. The joint effects of binary mixtures (TU sum) can thus be obtained. The results showed that the relationships between toxic ratios of the individual chemicals and their joint effects can be described by normal distribution function. Based on normal distribution equations, the joint effects of binary mixtures at non-equitoxic ratios ( [Formula: see text]) can be predicted quantitatively using the joint effects at equitoxic ratios ( [Formula: see text]). Combined with a QSAR model of [Formula: see text]in our previous work, a novel QSAR model can be proposed to predict the joint effects of mixtures at non-equitoxic ratios ( [Formula: see text]). The proposed model has been validated using additional mixtures other than the one used for the development of the model. Predicted and observed results were similar (p>0.05). This study provides an approach to the prediction of joint effects for binary mixtures at non-equitoxic ratios.

  16. Kinetics and structure-activity relationship of dendritic bridged hindered phenol antioxidants to protect styrene against free radical induced peroxidation

    Science.gov (United States)

    Li, Cui-Qin; Guo, Su-Yue; Wang, Jun; Shi, Wei-Guang; Zhang, Zhi-Qiu; Wang, Peng-Xiang

    2017-12-01

    A series of dendritic poly(amido-amine) (PAMAM) bridged hindered phenols antioxidants were synthesized. The active antioxidant group (3-(3,5-di- tert-butyl-4-hydroxyphenyl)propionic acid) was attached to two generations of PAMAM dendrimers, and their structure was verified by nuclear magnetic resonance (NMR) and fourier transform infrared spectra (FT-IR). The antioxidant abilities of the dendritic phenols to inhibit the oxidation of styrene were evaluated and the relationships between the length of core, the generation of dendrimers and the antioxidant activities were established. The reaction kinetics of scavenging peroxyl radicals was followed by oxygen consumption. The inhibition time ( t inh) values showed the dendritic phenols had the ability of scavenging peroxyl radicals, and that the antioxidant ability increased with the increasing length of the core and the generation. The kinetic analysis demonstrated that dendritic phenols could slow the rate of styrene peroxidation induced by AIBN, as shown by the number of trapping ROO· ( n), and this role was in accordance with that of the t inh values.

  17. Structure-activity relationships of flavonoids as natural inhibitors against E. coli β-glucuronidase.

    Science.gov (United States)

    Weng, Zi-Miao; Wang, Ping; Ge, Guang-Bo; Dai, Zi-Ru; Wu, Da-Chang; Zou, Li-Wei; Dou, Tong-Yi; Zhang, Tong-Yan; Yang, Ling; Hou, Jie

    2017-11-01

    Bacterial β-glucuronidases play key roles in the deconjugation of a variety of endogenous and drug glucuronides, thus have been recognized as important targets to modulate the enterohepatic circulation of various glucuronides. In this study, more than 30 natural flavonoids were collected and their inhibitory effects against E. coli β-glucuronidase (EcGUS) were assayed. The results demonstrated that some flavonoids including scutellarein, luteolin, baicalein, quercetin and scutellarin displayed strong to moderate inhibitory effects against EcGUS, with the IC 50 values ranging from 5.76 μM to 29.64 μM, while isoflavones and dihydroflavones displayed weak inhibitory effects against EcGUS. Further investigation on inhibition kinetics revealed that scutellarein and luteolin functioned as potent competitive inhibitors against EcGUS-mediated PNPG hydrolysis, with the K i values less than 3.0 μM. Molecular docking simulations demonstrated that scutellarein and luteolin could be well-docked into the catalytic site of EcGUS, while the binding areas of these two natural inhibitors on EcGUS were highly overlapped with that of PNPG on EcGUS. Additionally, the structure-inhibition relationships of natural flavonoids against EcGUS are also summarized, which will be very helpful for the medicinal chemists to design and develop more potent flavonoid-type inhibitors against EcGUS. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Mammalian olfactory receptors: molecular mechanisms of odorant detection, 3D-modeling, and structure-activity relationships.

    Science.gov (United States)

    Persuy, Marie-Annick; Sanz, Guenhaël; Tromelin, Anne; Thomas-Danguin, Thierry; Gibrat, Jean-François; Pajot-Augy, Edith

    2015-01-01

    This chapter describes the main characteristics of olfactory receptor (OR) genes of vertebrates, including generation of this large multigenic family and pseudogenization. OR genes are compared in relation to evolution and among species. OR gene structure and selection of a given gene for expression in an olfactory sensory neuron (OSN) are tackled. The specificities of OR proteins, their expression, and their function are presented. The expression of OR proteins in locations other than the nasal cavity is regulated by different mechanisms, and ORs display various additional functions. A conventional olfactory signal transduction cascade is observed in OSNs, but individual ORs can also mediate different signaling pathways, through the involvement of other molecular partners and depending on the odorant ligand encountered. ORs are engaged in constitutive dimers. Ligand binding induces conformational changes in the ORs that regulate their level of activity depending on odorant dose. When present, odorant binding proteins induce an allosteric modulation of OR activity. Since no 3D structure of an OR has been yet resolved, modeling has to be performed using the closest G-protein-coupled receptor 3D structures available, to facilitate virtual ligand screening using the models. The study of odorant binding modes and affinities may infer best-bet OR ligands, to be subsequently checked experimentally. The relationship between spatial and steric features of odorants and their activity in terms of perceived odor quality are also fields of research that development of computing tools may enhance. © 2015 Elsevier Inc. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Baiyang, E-mail: poplar_chen@hotmail.com [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China); Zhang, Tian [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China); Bond, Tom [Department of Civil and Environmental Engineering, Imperial College, London SW7 2AZ (United Kingdom); Gan, Yiqun [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China)

    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.

  20. 2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships.

    Science.gov (United States)

    Deaton, David N; Haffner, Curt D; Henke, Brad R; Jeune, Michael R; Shearer, Barry G; Stewart, Eugene L; Stuart, J Darren; Ulrich, John C

    2018-03-15

    Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Structure-activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans.

    Science.gov (United States)

    Liu, Runhui; Chen, Xinyu; Falk, Shaun P; Mowery, Brendan P; Karlsson, Amy J; Weisblum, Bernard; Palecek, Sean P; Masters, Kristyn S; Gellman, Samuel H

    2014-03-19

    Fungal infections are a major challenge to human health that is heightened by pathogen resistance to current therapeutic agents. Previously, we were inspired by host-defense peptides to develop nylon-3 polymers (poly-β-peptides) that are toxic toward the fungal pathogen Candida albicans but exert little effect on mammalian cells. Based on subsequent analysis of structure-activity relationships among antifungal nylon-3 polymers, we have now identified readily prepared cationic homopolymers active against strains of C. albicans that are resistant to the antifungal drugs fluconazole and amphotericin B. These nylon-3 polymers are nonhemolytic. In addition, we have identified cationic-hydrophobic copolymers that are highly active against a second fungal pathogen, Cryptococcus neoformans, and moderately active against a third pathogen, Aspergillus fumigatus.

  2. Synthesis and structure-activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS).

    Science.gov (United States)

    Williams, John D; Torhan, Matthew C; Neelagiri, Venugopal R; Brown, Carson; Bowlin, Nicholas O; Di, Ming; McCarthy, Courtney T; Aiello, Daniel; Peet, Norton P; Bowlin, Terry L; Moir, Donald T

    2015-03-01

    The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Structure-activity relationship studies of 5,7-dihydroxyflavones as naturally occurring inhibitors of cell proliferation in human leukemia HL-60 cells.

    Science.gov (United States)

    Ninomiya, Masayuki; Nishida, Kyohei; Tanaka, Kaori; Watanabe, Kunitomo; Koketsu, Mamoru

    2013-07-01

    Flavonoids are widely occurring polyphenols that are found in plants. The aim of this study was to investigate the structure-activity relationships of 5,7-dihydroxyflavones, with a focus on the effect of B ring structure substitution on the antiproliferative effects of the compounds in human leukemia HL-60 cells. We prepared a series of 5,7-dihydroxyflavones and evaluated their ability to inhibit the proliferation of HL-60 cells by using the MTT assay. The apoptosis- and cell differentiation-inducing ability of the most potent flavones were investigated using staining and morphological analyses. This study explored the antileukemic and chemopreventive potency of 5,7-dihydroxyflavones, particularly diosmetin and chrysoeriol, which have both hydroxy and methoxy groups on the B ring.

  4. The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

    Science.gov (United States)

    Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

    2014-02-15

    We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    DEFF Research Database (Denmark)

    Gimenéz-Arnau, Elena; Andersen, K E; 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......" in their 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...

  6. 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.

  7. Synthesis and structure-activity relationship study of FD-891: importance of the side chain and C8-C9 epoxide for cytotoxic activity against cancer cells.

    Science.gov (United States)

    Itagaki, Tomohiro; Kawamata, Ayano; Takeuchi, Miho; Hamada, Keisuke; Iwabuchi, Yoshiharu; Eguchi, Tadashi; Kudo, Fumitaka; Usui, Takeo; Kanoh, Naoki

    2016-04-01

    Unified synthesis of FD-891 analogs and their structure-activity relationship are described. By using stereoselective allylation/crotylation and Evans aldol chemistry, six side-chain fragments having different length and terminus were synthesized. These fragments were coupled with a macrolactone fragment, improved synthesis of which was also developed here, to generate FD-891 and five truncated analogs. These synthetic compounds as well as three analogs obtained from fermentation of gene-disrupted Streptomyces graminofaciens mutants were tested for in vitro cytotoxic activity against HeLa cells. As a result, coexistence of the C8-C9 epoxide and side-chain terminus was found to be critical for the cytotoxic activity.

  8. Antimitotic antitumor agents: synthesis, structure-activity relationships, and biological characterization of N-aryl-N'-(2-chloroethyl)ureas as new selective alkylating agents.

    Science.gov (United States)

    Mounetou, E; Legault, J; Lacroix, J; C-Gaudreault, R

    2001-03-01

    A series of N-aryl-N'-(2-chloroethyl)ureas (CEUs) and derivatives were synthesized and evaluated for antiproliferative activity against a wide panel of tumor cell lines. Systematic structure--activity relationship (SAR) studies indicated that: (i) a branched alkyl chain or a halogen at the 4-position of the phenyl ring or a fluorenyl/indanyl group, (ii) an exocyclic urea function, and (iii) a N'-2-chloroethyl moiety were required to ensure significant cytotoxicity. Biological experiments, such as immunofluorescence microscopy, confirmed that these promising compounds alter the cytoskeleton by inducing microtubule depolymerization via selective alkylation of beta-tubulin. Subsequent evaluations demonstrated that potent CEUs were weak alkylators, were non-DNA-damaging agents, and did not interact with the thiol function of either glutathione or glutathione reductase. Therefore, CEUs are part of a new class of antimitotic agents. Finally, among the series of CEUs evaluated, compounds 12, 15, 16, and 27 were selected for further in vivo trials.

  9. Synthesis and quantitative structure-activity relationship (QSAR) analysis of some novel oxadiazolo[3,4-d]pyrimidine nucleosides derivatives as antiviral agents.

    Science.gov (United States)

    Xu, Xiaojuan; Wang, Jun; Yao, Qizheng

    2015-01-15

    We have synthesized a series of 4H,6H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide nucleoside and their anti-vesicular stomatitis virus (VSV) activities in Wish cell were also investigated in vitro. It was found that most compounds showed obvious anti-VSV activities and compound 9 with ribofuranoside improved the anti-VSV activity by approximately 10 times and 18 times compared to didanosine (DDI) and acyclovir, respectively. A quantitative structure-activity relationship (QSAR) study of these compounds as well as previous reported oxadiazolo[3,4-d]pyrimidine nucleoside derivatives indicated that compounds with high activity should have small values of logP(o/w), vsurf_G and a large logS value. These findings and results provide a base for further investigations. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Ma, Bin; Chen, Huaihai; Xu, Minmin; Hayat, Tahir; He, Yan; Xu, Jianming

    2010-08-01

    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. Copyright 2010 Elsevier Ltd. All rights reserved.

  11. Use of Quantitative Structure-Activity Relationship (QSAR) and ADMET prediction studies as screening methods for design of benzyl urea derivatives for anti-cancer activity.

    Science.gov (United States)

    Lokwani, Deepak; Bhandari, Shashikant; Pujari, Radha; Shastri, Padma; Shelke, Ganesh; Pawar, Vidya

    2011-06-01

    2D and 3D quantitative structure-activity relationship studies have been carried out for establishing a correlation between the structural properties of benzyl urea derivatives and their anti-tumour activities. From this correlation, the new chemical entities were designed, and their activity and absorption, distribution, metabolism, excretion, and toxicity properties were also predicted. Finally, the most promising compounds from these screening were synthesized and biologically evaluated for their anti-cancer properties. Compound 1-(2, 4-dimethylphenyl)-3, 3-dimethyl-1-(2-nitrobenzyl) urea (7d) showed significant anti-proliferative activity (at 100 µg/mL) in human cancer cell lines-T-cell leukemia (Jurkat J6), myelogenous leukemia (K562), and breast cancer (MCF-7) compared to reference standard 5-flurouracil.

  12. 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.

  13. Identification of novel benzimidazole derivatives as anti-Trypanosoma cruzi agents: solid-phase synthesis, structure-activity relationships and molecular docking studies.

    Science.gov (United States)

    Ríos, Natalia; Varela, Javier; Birriel, Estefania; González, Mercedes; Cerecetto, Hugo; Merlino, Alicia; Porcal, Williams

    2013-10-01

    In this paper, we report the solid-phase synthesis of 33 novel 1,2,5-tri-substituted benzimidazole derivatives and their in vitro activity on cruzipain and Trypanosoma cruzi epimastigotes. Seven compounds were potent inhibitors of T. cruzi growth with IC50 values in the range 6-16 µM. Applying structure-activity relationships and principal component analysis strategies we were able to determine ring substituent effects and physicochemical properties that are important for the antichagasic activity of these novel derivatives, as well as get an insight into their possible mechanisms of action. Molecular docking studies revealed the binding orientation of the ligands in the active site of cruzipain providing new guidelines for the further design of better inhibitors. Compound 2a constitute a promising hit compound for novel anti-T. cruzi agents showing that the benzimidazole scaffold may represent an interesting therapeutic alternative for the treatment of Chagas disease.

  14. Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents.

    Science.gov (United States)

    Ferreira, Rafaela S; Dessoy, Marco A; Pauli, Ivani; Souza, Mariana L; Krogh, Renata; Sales, Ana I L; Oliva, Glaucius; Dias, Luiz C; Andricopulo, Adriano D

    2014-03-27

    The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 μM). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K(i) = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease.

  15. Facile synthesis and quantitative structure-activity relationship study of antitumor active 2-(4-oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles.

    Science.gov (United States)

    Hanna, Mona Maurice; George, Riham François

    2012-01-01

    2-(5-Arylidene-4-oxo-3-phenyl-thiazolidin-2-ylidene)-3-oxo-propionitriles 4a-j were prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a,b. The latter was obtained via electrophilic attack of phenylisothiocyanate on 3-oxo-propionitriles 1a,b followed by reaction with chloroacetyl chloride under basic condition. Additionally, 2-(5-heteroalicyclic methylene) analogues 5a-h were prepared via Mannich reaction of the appropriate secondary amines and formaldehyde with 4-thiazolidinones 3a,b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116 and breast T47D cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explain the observed antitumor properties.

  16. Seamless integration of dose-response screening and flow chemistry: efficient generation of structure-activity relationship data of β-secretase (BACE1) inhibitors.

    Science.gov (United States)

    Werner, Michael; Kuratli, Christoph; Martin, Rainer E; Hochstrasser, Remo; Wechsler, David; Enderle, Thilo; Alanine, Alexander I; Vogel, Horst

    2014-02-03

    Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure-activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow-based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in-line quantification of compound concentration. This novel synthesis-screening platform enables to obtain SAR data on b-secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. 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...

  18. 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].

  19. From bird's eye views to molecular communities: two-layered visualization of structure-activity relationships in large compound data sets

    Science.gov (United States)

    Kayastha, Shilva; Kunimoto, Ryo; Horvath, Dragos; Varnek, Alexandre; Bajorath, Jürgen

    2017-11-01

    The analysis of structure-activity relationships (SARs) becomes rather challenging when large and heterogeneous compound data sets are studied. In such cases, many different compounds and their activities need to be compared, which quickly goes beyond the capacity of subjective assessments. For a comprehensive large-scale exploration of SARs, computational analysis and visualization methods are required. Herein, we introduce a two-layered SAR visualization scheme specifically designed for increasingly large compound data sets. The approach combines a new compound pair-based variant of generative topographic mapping (GTM), a machine learning approach for nonlinear mapping, with chemical space networks (CSNs). The GTM component provides a global view of the activity landscapes of large compound data sets, in which informative local SAR environments are identified, augmented by a numerical SAR scoring scheme. Prioritized local SAR regions are then projected into CSNs that resolve these regions at the level of individual compounds and their relationships. Analysis of CSNs makes it possible to distinguish between regions having different SAR characteristics and select compound subsets that are rich in SAR information.

  20. From bird's eye views to molecular communities: two-layered visualization of structure-activity relationships in large compound data sets.

    Science.gov (United States)

    Kayastha, Shilva; Kunimoto, Ryo; Horvath, Dragos; Varnek, Alexandre; Bajorath, Jürgen

    2017-11-01

    The analysis of structure-activity relationships (SARs) becomes rather challenging when large and heterogeneous compound data sets are studied. In such cases, many different compounds and their activities need to be compared, which quickly goes beyond the capacity of subjective assessments. For a comprehensive large-scale exploration of SARs, computational analysis and visualization methods are required. Herein, we introduce a two-layered SAR visualization scheme specifically designed for increasingly large compound data sets. The approach combines a new compound pair-based variant of generative topographic mapping (GTM), a machine learning approach for nonlinear mapping, with chemical space networks (CSNs). The GTM component provides a global view of the activity landscapes of large compound data sets, in which informative local SAR environments are identified, augmented by a numerical SAR scoring scheme. Prioritized local SAR regions are then projected into CSNs that resolve these regions at the level of individual compounds and their relationships. Analysis of CSNs makes it possible to distinguish between regions having different SAR characteristics and select compound subsets that are rich in SAR information.

  1. Improvement of multivariate image analysis applied to quantitative structure-activity relationship (QSAR) analysis by using wavelet-principal component analysis ranking variable selection and least-squares support vector machine regression: QSAR study of checkpoint kinase WEE1 inhibitors.

    Science.gov (United States)

    Cormanich, Rodrigo A; Goodarzi, Mohammad; Freitas, Matheus P

    2009-02-01

    Inhibition of tyrosine kinase enzyme WEE1 is an important step for the treatment of cancer. The bioactivities of a series of WEE1 inhibitors have been previously modeled through comparative molecular field analyses (CoMFA and CoMSIA), but a two-dimensional image-based quantitative structure-activity relationship approach has shown to be highly predictive for other compound classes. This method, called multivariate image analysis applied to quantitative structure-activity relationship, was applied here to derive quantitative structure-activity relationship models. Whilst the well-known bilinear and multilinear partial least squares regressions (PLS and N-PLS, respectively) correlated multivariate image analysis descriptors with the corresponding dependent variables only reasonably well, the use of wavelet and principal component ranking as variable selection methods, together with least-squares support vector machine, improved significantly the prediction statistics. These recently implemented mathematical tools, particularly novel in quantitative structure-activity relationship studies, represent an important advance for the development of more predictive quantitative structure-activity relationship models and, consequently, new drugs.

  2. 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

  3. Synthesis, Cytotoxic Activity on Leukemia Cell Lines and Quantitative Structure-Activity Relationships (QSAR) Studies of Morita-Baylis-Hillman Adducts.

    Science.gov (United States)

    Lima-, Claudio G; Faheina-Martins, Gláucia V; Bomfim, Caio C B; Dantas, Bruna B; Silva, Everton P; Araújo, Demetrius A M de; Filho, Edilson B A; Vasconcellos, Mário L A A

    2016-01-01

    The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita-Baylis-Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-Leishmania chagasi and Leishmania amazonensis, anti- Trypanosoma cruzi, anti-Plasmodium falciparum and Plasmodium berghei, lethal against Biomphalaria glabrata, antibacterial, antifungal, herbicide and others. The goal of this work is to describe the primary cytotoxic activities against strains of human leukemia HL-60 cell line for thirty-four Morita-Baylis- Hillman adducts (MBHA), followed by a Quantitative Structure-Activity Relationships study (QSAR). The conventional or microwave-assisted syntheses of MBHA, derived from substituted aromatics or Isatin, were performed in good to excellent yields (70-100%) in short reaction times, using protocols recently developed by us. Isatin derivatives, MBHA 31 and 32, were the most active in this congener series of compounds, with IC50 values of 10.8 μM and 7.8 μM, respectively. The primary cytotoxic activities against chronic leukemia cells (K562) were also evaluated to these two most active compounds (MBHA 31 and 32), presenting IC50 values of 53 μM and 43 μM respectively. QSAR study was performed considering 3D, 2D and constitutional molecular descriptors. These were selected from Ordered Predictor Selection algorithm and submitted to Partial Least Squares Modeling. We present an interesting investigation about cytotoxic activities on human leukemia cell line (HL-60) for 34 synthetic MBHA. In a good way we discovered that the most cytotoxic compounds (31-32, 10.8 μM and 7.8 μM respectively) were also prepared quantitatively (100% yields) in a short reaction time using microwave irradiation. We demonstrate that 31 and 32 induced

  4. Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.

    Science.gov (United States)

    Mori, Yoshikazu; Hirokawa, Takatsugu; Aoki, Katsuyuki; Satomi, Hisanori; Takeda, Shuichi; Aburada, Masaki; Miyamoto, Ken-ichi

    2008-05-01

    We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.

  5. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Quantitative structure-activity relationship and classification analysis of diaryl ureas against vascular endothelial growth factor receptor-2 kinase using linear and non-linear models.

    Science.gov (United States)

    Sun, Min; Chen, Junqing; Wei, Hongtao; Yin, Shuangqing; Yang, Yan; Ji, Min

    2009-06-01

    Quantitative structure-activity relationship analysis has been carried out for 74 diaryl ureas including aminobenzoisoxazole ureas, aminoindazole ureas, aminopyrazolopyridine ureas against vascular endothelial growth factor receptor-2 kinase using both linear and non-linear models. Considering simplicity and predictivity, multivariate linear regression was first employed in combination with various variable selection methods, including forward selection, genetic algorithm and enhanced replacement method based on descriptors generated by e-dragon software. Another model using support vector regression has also been constructed and compared. Performances of these models are rigorously validated by leave-one-out cross-validation, fivefold cross-validation and external validation. The enhanced replacement method model significantly outperforms the others with R(2) = 0.813 and R(2)(pred) = 0.809. Robustness and predictive ability of this model is prudently evaluated. Moreover, to find out the most significant features associated with the difference between highly active compounds and moderate ones, two classification models using linear discriminant analysis and support vector machine were further developed. The performance of support vector machine significantly outperforms linear discriminant analysis, with leave-one-out cross-validation and external validation prediction accuracy reaching 0.838 and 0.857, respectively. The resulting models could act as an efficient strategy for estimating the vascular endothelial growth factor receptor-2 inhibiting activity of novel diaryl ureas and provide some insights into the structural features related to the biological activity of these compounds.

  7. 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)

    Le Calve, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaelle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Francoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Veronique; Dufrasne, Francois; Van Antwerpen, Pierre; Poumay, Yves

    2011-01-01

    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.

  8. Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System.

    Science.gov (United States)

    Elaziz, Mohamed Abd; Moemen, Yasmine S; Hassanien, Aboul Ella; Xiong, Shengwu

    2018-01-24

    The global prevalence of hepatitis C Virus (HCV) is approximately 3% and one-fifth of all HCV carriers live in the Middle East, where Egypt has the highest global incidence of HCV infection. Quantitative structure-activity relationship (QSAR) models were used in many applications for predicting the potential effects of chemicals on human health and environment. The adaptive neuro-fuzzy inference system (ANFIS) is one of the most popular regression methods for building a nonlinear QSAR model. However, the quality of ANFIS is influenced by the size of the descriptors, so descriptor selection methods have been proposed, although these methods are affected by slow convergence and high time complexity. To avoid these limitations, the antlion optimizer was used to select relevant descriptors, before constructing a nonlinear QSAR model based on the PIC 50 and these descriptors using ANFIS. In our experiments, 1029 compounds were used, which comprised 579 HCVNS5B inhibitors (PIC 50   ~14). The experimental results showed that the proposed QSAR model obtained acceptable accuracy according to different measures, where [Formula: see text] was 0.952 and 0.923 for the training and testing sets, respectively, using cross-validation, while [Formula: see text] was 0.8822 using leave-one-out (LOO).

  9. Structure-activity relationship studies of 1,7-diheteroarylhepta-1,4,6-trien-3-ones with two different terminal rings in prostate epithelial cell models.

    Science.gov (United States)

    Wang, Rubing; Zhang, Xiaojie; Chen, Chengsheng; Chen, Guanglin; Sarabia, Cristian; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2017-06-16

    To systematically investigate the structure-activity relationships of 1,7-diheteroarylhepta-1,4,6-trien-3-ones in three human prostate cancer cell models and one human prostate non-neoplastic epithelial cell model, thirty five 1,7-diarylhepta-1,4,6-trien-3-ones with different terminal heteroaromatic rings have been designed for evaluation of their anti-proliferative potency in vitro. These target compounds have been successfully synthesized through two sequential Horner-Wadsworth-Emmons reactions starting from the appropriate aldehydes and tetraethyl (2-oxopropane-1,3-diyl)bis(phosphonate). Their anti-proliferative potency against PC-3, DU-145 and LNCaP human prostate cancer cell lines can be significantly enhanced by the manipulation of the terminal heteroaromatic rings, further demonstrating the utility of 1,7-diarylhepta-1,4,6-trien-3-one as a potential scaffold for the development of anti-prostate cancer agents. The optimal analog 40 is 82-, 67-, and 39-fold more potent than curcumin toward the three prostate cancer cell lines, respectively. The experimental data also reveal that the trienones with two different terminal aromatic rings possess greater potency toward three prostate cancer cell lines, but also have greater capability of suppressing the proliferation of PWR-1E benign human prostate epithelial cells, as compared to the corresponding counterparts with two identical terminal rings and curcumin. The terminal aromatic rings also affect the cell apoptosis perturbation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship study of a quinoline thiourea.

    Science.gov (United States)

    Dolan, Niamh; Gavin, Declan P; Eshwika, Ahmed; Kavanagh, Kevin; McGinley, John; Stephens, John C

    2016-01-15

    We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. 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.

  12. Evaluating Molecular Properties Involved in Transport of Small Molecules in Stratum Corneum: A Quantitative Structure-Activity Relationship for Skin Permeability

    Directory of Open Access Journals (Sweden)

    Chen-Peng Chen

    2018-04-01

    Full Text Available The skin permeability (Kp defines the rate of a chemical penetrating across the stratum corneum. This value is widely used to quantitatively describe the transport of molecules in the outermost layer of epidermal skin and indicate the significance of skin absorption. This study defined a Kp quantitative structure-activity relationship (QSAR based on 106 chemical substances of Kp measured using human skin and interpreted the molecular interactions underlying transport behavior of small molecules in the stratum corneum. The Kp QSAR developed in this study identified four molecular descriptors that described the molecular cyclicity in the molecule reflecting local geometrical environments, topological distances between pairs of oxygen and chlorine atoms, lipophilicity, and similarity to antineoplastics in molecular properties. This Kp QSAR considered the octanol-water partition coefficient to be a direct influence on transdermal movement of molecules. Moreover, the Kp QSAR identified a sub-domain of molecular properties initially defined to describe the antineoplastic resemblance of a compound as a significant factor in affecting transdermal permeation of solutes. This finding suggests that the influence of molecular size on the chemical’s skin-permeating capability should be interpreted with other relevant physicochemical properties rather than being represented by molecular weight alone.

  13. In-silico Comparative Study and Quantitative Structure-activity Relationship Analysis of Some Structural and Physiochemical Descriptors of Elvitegravir Analogs.

    Science.gov (United States)

    Satpathy, R; Ghosh, S

    2011-07-01

    Elvitegravir is a new-generation drug which acts as an integrase inhibitor of the HIV virus. The potential inhibition has been tested from the clinical trial data. Here the work basically deals with the quantitative structure-activity relationship (QSAR) analysis by considering some of the physiochemical descriptors like molecular weight, logP, molar volume, and structural descriptors like Winers index, and molecular topological index of the drug analogs. The descriptors were calculated from the E-Dragon server and the multiple linear regression equation models were built by using Minitab tools. The different combinations of structural and physiochemical descriptors were considered for model derivation. The best three models were chosen by observing high R-Sq value, high F-value and low residual errors. The P values (regression) for the three models indicates the significance of the considered descriptors.The overall results obtained with these model suggest that for this perticular drug the activity is dependent on physiochemical descriptors.

  14. Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship.

    Science.gov (United States)

    Scott, Alison J; Oyler, Benjamin L; Goodlett, David R; Ernst, Robert K

    2017-11-01

    Strategies utilizing Toll-like receptor 4 (TLR4) agonists for treatment of cancer, infectious diseases, and other targets report promising results. Potent TLR4 antagonists are also gaining attention as therapeutic leads. Though some principles for TLR4 modulation by lipid A have been described, a thorough understanding of the structure-activity relationship (SAR) is lacking. Only through a complete definition of lipid A-TLR4 SAR is it possible to predict TLR4 signaling effects of discrete lipid A structures, rendering them more pharmacologically relevant. A limited 'toolbox' of lipid A-modifying enzymes has been defined and is largely composed of enzymes from mesophile human and zoonotic pathogens. Expansion of this 'toolbox' will result from extending the search into lipid A biosynthesis and modification by bacteria living at the extremes. Here, we review the fundamentals of lipid A structure, advances in lipid A uses in TLR4 modulation, and the search for novel lipid A-modifying systems in extremophile bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Studies on synthesis and structure-activity relationship (SAR) of derivatives of a new natural product from marine fungi as inhibitors of influenza virus neuraminidase.

    Science.gov (United States)

    Li, Jing; Zhang, Dingmei; Zhu, Xun; He, Zhenjian; Liu, Shu; Li, Mengfeng; Pang, Jiyan; Lin, Yongcheng

    2011-01-01

    Based on the natural isoprenyl phenyl ether from a mangrove-derived fungus, 32 analogues were synthesized and evaluated for inhibitory activity against influenza H1N1 neuraminidase. Compound 15 (3-(allyloxy)-4-hydroxybenzaldehyde) exhibited the most potent inhibitory activity, with IC(50) values of 26.96 μM for A/GuangdongSB/01/2009 (H1N1), 27.73 μM for A/Guangdong/03/2009 (H1N1), and 25.13 μM for A/Guangdong/ 05/2009 (H1N1), respectively, which is stronger than the benzoic acid derivatives (~mM level). These are a new kind of non-nitrogenous aromatic ether Neuraminidase (NA) inhibitors. Their structures are simple and the synthesis routes are not complex. The structure-activity relationship (SAR) analysis revealed that the aryl aldehyde and unsubstituted hydroxyl were important to NA inhibitory activities. Molecular docking studies were carried out to explain the SAR of the compounds, and provided valuable information for further structure modification.

  16. Studies on Synthesis and Structure-Activity Relationship (SAR of Derivatives of a New Natural Product from Marine Fungi as Inhibitors of Influenza Virus Neuraminidase

    Directory of Open Access Journals (Sweden)

    Yongcheng Lin

    2011-10-01

    Full Text Available Based on the natural isoprenyl phenyl ether from a mangrove-derived fungus, 32 analogues were synthesized and evaluated for inhibitory activity against influenza H1N1 neuraminidase. Compound 15 (3-(allyloxy-4-hydroxybenzaldehyde exhibited the most potent inhibitory activity, with IC50 values of 26.96 μM for A/GuangdongSB/01/2009 (H1N1, 27.73 μM for A/Guangdong/03/2009 (H1N1, and 25.13 μM for A/Guangdong/05/2009 (H1N1, respectively, which is stronger than the benzoic acid derivatives (~mM level. These are a new kind of non-nitrogenous aromatic ether Neuraminidase (NA inhibitors. Their structures are simple and the synthesis routes are not complex. The structure-activity relationship (SAR analysis revealed that the aryl aldehyde and unsubstituted hydroxyl were important to NA inhibitory activities. Molecular docking studies were carried out to explain the SAR of the compounds, and provided valuable information for further structure modification.

  17. Structure-activity relationships and molecular docking studies of chromene and chromene based azo chromophores: A novel series of potent antimicrobial and anticancer agents.

    Science.gov (United States)

    Afifi, Tarek H; Okasha, Rawda M; Ahmed, Hany E A; Ilaš, Janez; Saleh, Tarek; Abd-El-Aziz, Alaa S

    2017-01-01

    The design of novel materials with significant biological properties is a main target in drug design research. Chromene compounds represent an interesting medicinal scaffold in drug replacement systems. This report illustrates a successful synthesis and characterization of two novel series of chromene compounds using multi-component reactions. The synthesis of the first example of azo chromophores containing chromene moieties has also been established using the same methodology. The antimicrobial activity of the new molecules has been tested against seven human pathogens including two Gm+ve, two Gm-ve bacteria, and four fungi, and the results of the inhibition zones with minimum inhibitory concentrations were reported as compared to reference drugs. All the designed compounds showed significant potent antimicrobial activities, among of them, four potent compounds 4b , 4c , 13e , and 13i showed promising MIC from 0.007 to 3.9 µg/mL. In addition, antiproliferative analysis against three target cell lines was examined for the novel compounds. Compounds 4a , 4b , 4c , and 7c possessed significant antiproliferative activity against three cell lines with an IC 50 of 0.3 to 2 µg/mL. Apoptotic analysis was performed for the most potent compounds via caspase enzyme activity assays as a potential mechanism for their antiproliferative effects. Finally, the computational 2D QSAR and docking simulations were accomplished for structure-activity relationship analyses.

  18. Structure-activity relationships of dimethylsphingosine (DMS) derivatives and their effects on intracellular pH and Ca2+ in the U937 monocyte cell line.

    Science.gov (United States)

    Chang, Young-Ja; Lee, Yun-Kyung; Lee, Eun-Hee; Park, Jeong-Ju; Chung, Sung-Kee; Im, Dong-Soon

    2006-08-01

    We recently reported that dimethylsphingosine (DMS), a metabolite of sphingolipids, increased intracellular pH and Ca2+ concentration in U937 human monocytes. In the present study, we found that dimethylphytosphingosine (DMPH) induced the above responses more robustly than DMS. However, phytosphingosine, monomethylphytosphingosine or trimethylsphingosine showed little or no activity. Synthetic C3 deoxy analogues of sphingosine did show similar activities, with the C16 analogue more so than C18. The following structure-activity relationships were observed between DMS derivatives and the intracellular pH and Ca2+ concentrations in U937 monocytes; 1) dimethyl modification is important for the DMS-induced increase of intracellular pH and Ca2+, 2) the addition of an OH group on C4 enhances both activities, 3) the deletion of the OH group on C3 has a negligible effect on the activities, and 4) C16 appears to be more effective than C18. We also found that W-7, a calmodulin inhibitor, blocked the DMS-induced pH increase, whereas, KN-62, ML9, and MMPX, specific inhibitors for calmodulin-dependent kinase II, myosin light chain kinase, and Ca(2+)-calmodulin-dependent phosphodiesterase, respectively, did not affect DMS-induced increases of pH in the U937 monocytes.

  19. Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners.

    Science.gov (United States)

    Rayne, Sierra; Forest, Kaya

    2010-01-01

    A quantitative structure-activity relationship (QSAR) was developed to predict the congener specific ryanodine receptor type RyR1 activity of all 209 polychlorinated biphenyl (PCB) congeners. A three-variable QSAR equation was obtained via stepwise forward linear regression on an unsupervised forward selection reduced data set from an initial database. Application of the QSAR towards predicting EC(2x) values for all 209 PCB congeners indicated good agreement in substitution pattern trends between the experimental and estimated data sets. The QSAR model predicts a less than two-fold increase in maximal potency among all congeners outside the experimental database, and it appears that no high-potency PCB congeners with EC(2x) values much less than 0.2 microM exist. Increasing RyR1-neuro toxicity equivalents with increasing homologue number and Aroclor chlorination likely reflect indirect molecular controls on toxicity, since congeners with multiple ortho substituents-the primary structural feature controlling a lack of coplanarity and resulting neurotoxicity-are more likely to be found in higher homologues.

  20. Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1' pocket and their quantitative structure-activity relationship (QSAR) study.

    Science.gov (United States)

    Yang, Jee Sun; Chun, Kwangwoo; Park, Jung Eun; Cho, Misun; Seo, Jeongjea; Song, Doona; Yoon, Hongchul; Park, Chun-Ho; Joe, Bo-Young; Choi, Jong-Hee; Kim, Myung-Hwa; Han, Gyoonhee

    2010-12-15

    A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals. II. Using oral slope factor as a measure of carcinogenic potency.

    Science.gov (United States)

    Wang, Nina Ching Yi; Venkatapathy, Raghuraman; Bruce, Robert Mark; Moudgal, Chandrika

    2011-03-01

    The overall risk associated with exposure to a chemical is determined by combining quantitative estimates of exposure to the chemical with their known health effects. For chemicals that cause carcinogenicity, oral slope factors (OSFs) and inhalation unit risks are used to quantitatively estimate the carcinogenic potency or the risk associated with exposure to the chemical by oral or inhalation route, respectively. Frequently, there is a lack of animal or human studies in the literature to determine OSFs. This study aims to circumvent this problem by developing quantitative structure-activity relationship (QSAR) models to predict the OSFs of chemicals. The OSFs of 70 chemicals based on male/female human, rat, and mouse bioassay data were obtained from the United States Environmental Protection Agency's Integrated Risk Information System (IRIS) database. A global QSAR model that considered all 70 chemicals as well as species and/or sex-specific QSARs were developed in this study. Study results indicate that the species and sex-specific QSARs (r(2)>0.8, q(2)>0.7) had a better predictive abilities than the global QSAR developed using data from all species and sexes (r(2)=0.77, q(2)=0.73). The QSARs developed in this study were externally validated, and demonstrated reasonable predictive abilities. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. 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.

  3. Two-dimensional quantitative structure-activity relationship study of 1,4-naphthoquinone derivatives tested against HL-60 human promyelocytic leukaemia cells.

    Science.gov (United States)

    Costa, M C A; Ferreira, M M C

    2017-04-01

    A series of 50 derivatives of 1,4-naphthoquinone tested against human HL-60 leukaemic cells showed activity at a wide range of concentrations. A multivariate quantitative structure-activity relationship (QSAR) study of 45 compounds was performed through principal component analysis (PCA) and partial least squares (PLS) regression. A good PLS regression model was obtained with two factors describing 60.1% of the total variance, and the selected descriptors were partial atomic charge at carbons 1 and 10 (C1 and C10) and total dipole moment (DIP). The calibration model exhibited the determination coefficient r 2 = 0.78 and the standard error of calibration = 0.29. For external validation, r 2 and the standard error of prediction were 0.74 and 0.32, respectively. DIP and C1 were the main descriptors for PCA, as well as for PLS, such that the pIC 50 value increases when C1 increases and DIP diminishes. The selected descriptors are in accordance with the literature, once C10 and C1 are bound or close to the quinone oxygens involved in the production of radical anions (O 2 -∙). From the QSAR analysis, the structures of two new naphthoquinones were proposed and their estimated IC 50 values were 1.42 and 1.13 μmol L -1 .

  4. A quantitative structure-activity relationship (QSAR) study on glycan array data to determine the specificities of glycan-binding proteins.

    Science.gov (United States)

    Xuan, Pengfei; Zhang, Yuehua; Tzeng, Tzuen-rong Jeremy; Wan, Xiu-Feng; Luo, Feng

    2012-04-01

    Advances in glycan array technology have provided opportunities to automatically and systematically characterize the binding specificities of glycan-binding proteins. However, there is still a lack of robust methods for such analyses. In this study, we developed a novel quantitative structure-activity relationship (QSAR) method to analyze glycan array data. We first decomposed glycan chains into mono-, di-, tri- or tetrasaccharide subtrees. The bond information was incorporated into subtrees to help distinguish glycan chain structures. Then, we performed partial least-squares (PLS) regression on glycan array data using the subtrees as features. The application of QSAR to the glycan array data of different glycan-binding proteins demonstrated that PLS regression using subtree features can obtain higher R(2) values and a higher percentage of variance explained in glycan array intensities. Based on the regression coefficients of PLS, we were able to effectively identify subtrees that indicate the binding specificities of a glycan-binding protein. Our approach will facilitate the glycan-binding specificity analysis using the glycan array. A user-friendly web tool of the QSAR method is available at http://bci.clemson.edu/tools/glycan_array.

  5. Investigating mutation-specific biological activities of small molecules using quantitative structure-activity relationship for epidermal growth factor receptor in cancer.

    Science.gov (United States)

    Anoosha, P; Sakthivel, R; Gromiha, M Michael

    2017-12-01

    Epidermal Growth Factor Receptor (EGFR) is a potential drug target in cancer therapy. Missense mutations play major roles in influencing the protein function, leading to abnormal cell proliferation and tumorigenesis. A number of EGFR inhibitor molecules targeting ATP binding domain were developed for the past two decades. Unfortunately, they become inactive due to resistance caused by new mutations in patients, and previous studies have also reported noticeable differences in inhibitor binding to distinct known driver mutants as well. Hence, there is a high demand for identification of EGFR mutation-specific inhibitors. In our present study, we derived a set of anti-cancer compounds with biological activities against eight typical EGFR known driver mutations and developed quantitative structure-activity relationship (QSAR) models for each separately. The compounds are grouped based on their functional scaffolds, which enhanced the correlation between compound features and respective biological activities. The models for different mutants performed well with a correlation coefficient, (r) in the range of 0.72-0.91 on jack-knife test. Further, we analyzed the selected features in different models and observed that hydrogen bond and aromaticity-related features play important roles in predicting the biological activity of a compound. This analysis is complimented with docking studies, which showed the binding patterns and interactions of ligands with EGFR mutants that could influence their activities. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses.

    Science.gov (United States)

    Elfiky, Abdo A; Mahdy, Samah M; Elshemey, Wael M

    2017-06-01

    A number of human coronaviruses (HCoVs) were reported in the last and present centuries. Some outbreaks of which (eg, SARS and MERS CoVs) caused the mortality of hundreds of people worldwide. The problem of finding a potent drug against HCoV strains lies in the inability of finding a drug that stops the viral replication through inhibiting its important proteins. In spite of its limited efficacy and potential side effects, Ribavirin is extensively used as a first choice against HCoVs. Therefore, scientists reverted towards the investigation of different drugs that can more specifically target proteins. In this study, four anti-HCV drugs (one approved by FDA and others under clinical trials) are tested against HCoV polymerases. Quantitative Structure-Activity Relationship (QSAR) and molecular docking are both used to compare the performance of the selected nucleotide inhibitors to their parent nucleotides and Ribavirin. Both QSAR and molecular docking showed that IDX-184 is superior compared to Ribavirin against MERS CoV, a result that was also reported for HCV. MK-0608 showed a performance that is comparable to Ribavirin. We strongly suggest an in vitro study on the potency of these two drugs against MERS CoV. © 2017 Wiley Periodicals, Inc.

  7. Quantitative structure-activity relationship (QSAR) analysis of plant-derived compounds with larvicidal activity against Zika Aedes aegypti (Diptera: Culicidae) vector using freely available descriptors.

    Science.gov (United States)

    Saavedra, Laura M; Romanelli, Gustavo P; Duchowicz, Pablo R

    2018-01-04

    We have developed a quantitative structure-activity relationship (QSAR) model for predicting the larvicidal activity of 60 plant-derived molecules against Aedes aegypti L. (Diptera: Culicidae), a vector of several diseases such as dengue, yellow fever, chikungunya and Zika. The balanced subsets method (BSM) based on k-means cluster analysis (k-MCA) was employed to split the data set. The replacement method (RM) variable subset selection technique coupled with multivariable linear regression (MLR) proved to be successful for exploring 18 326 molecular descriptors and fingerprints calculated with PaDEL, Mold 2 and EPI Suite open-source softwares. A robust QSAR model (Rtrain2=0.84, S train  = 0.20 and Rtest2=0.92, S test  = 0.23) involving five non-conformational descriptors was established. The model was validated and tested through the use of an external test set of compounds, the leave-one-out (LOO) and leave-more-out (LMO) cross-validation methods, Y-randomization and applicability domain (AD) analysis. The QSAR model surpasses previously published models based on geometrical descriptors, thereby representing a suitable tool for predicting larvicidal activity against the vector A. aegypti using a conformation-independent approach. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

  8. Docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) predicts binding affinities to aryl hydrocarbon receptor for polychlorinated dibenzodioxins, dibenzofurans, and biphenyls.

    Science.gov (United States)

    Yuan, Jintao; Pu, Yuepu; Yin, Lihong

    2013-07-01

    Polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) cause toxic effects after binding to an intracellular cytosolic receptor called the aryl hydrocarbon receptor (AhR). Thymic atrophy, weight loss, immunotoxicity, acute lethality, and induction of cytochrome P4501A1 have all been correlated with the binding affinity to AhR. To study the key molecular features for determining binding affinity to AhR, a homology model of AhR ligand-binding domains was developed, a molecular docking approach was employed to obtain docking-based conformations of all molecules in the whole set, and 3-dimensional quantitative structure-activity relationship (3D-QSAR) methodology, namely, comparative molecular field analysis (CoMFA), was applied. A partial least square analysis was performed, and QSAR models were generated for a training set of 59 compounds. The generated QSAR model showed good internal and external statistical reliability, and in a comparison with other reported CoMFA models using different alignment methods, the docking-based CoMFA model showed some advantages. Copyright © 2013 SETAC.

  9. Cellular quantitative structure-activity relationship (Cell-QSAR): conceptual dissection of receptor binding and intracellular disposition in antifilarial activities of Selwood antimycins.

    Science.gov (United States)

    Natesan, Senthil; Wang, Tiansheng; Lukacova, Viera; Bartus, Vladimir; Khandelwal, Akash; Subramaniam, Rajesh; Balaz, Stefan

    2012-04-26

    We present the cellular quantitative structure-activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug's lipophilicity, acidity, and other properties. We conceptually combined the DF with our multispecies, multimode version of the frequently used ligand-based comparative molecular field analysis (CoMFA) method, forming a single correlation function for fitting the cell-level activities. The resulting cell-QSAR model was applied to the Selwood data on filaricidal activities of antimycin analogues. Their molecules are flexible, ionize under physiologic conditions, form different intramolecular H-bonds for neutral and ionized species, and cross several membranes to reach unknown receptors. The calibrated cell-QSAR model is significantly more predictive than other models lacking the disposition part and provides valuable structure optimization clues by factorizing the cell-level activity of each compound into the contributions of the receptor binding and disposition.

  10. A Structure-Activity Relationship Study of Imidazole-5-Carboxylic Acid Derivatives as Angiotensin II Receptor Antagonists Combining 2D and 3D QSAR Methods.

    Science.gov (United States)

    Sharma, Mukesh C

    2016-03-01

    Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies were performed for correlating the chemical composition of imidazole-5-carboxylic acid analogs and their angiotensin II [Formula: see text] receptor antagonist activity using partial least squares and k-nearest neighbor, respectively. For comparing the three different feature selection methods of 2D-QSAR, k-nearest neighbor models were used in conjunction with simulated annealing (SA), genetic algorithm and stepwise coupled with partial least square (PLS) showed variation in biological activity. The statistically significant best 2D-QSAR model having good predictive ability with statistical values of [Formula: see text] and [Formula: see text] was developed by SA-partial least square with the descriptors like [Formula: see text]count, 5Chain count, SdsCHE-index, and H-acceptor count, showing that increase in the values of these descriptors is beneficial to the activity. The 3D-QSAR studies were performed using the SA-PLS. A leave-one-out cross-validated correlation coefficient [Formula: see text] and predicate activity [Formula: see text] = 0.7226 were obtained. The information rendered by QSAR models may lead to a better understanding of structural requirements of substituted imidazole-5-carboxylic acid derivatives and also aid in designing novel potent antihypertensive molecules.

  11. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

    Science.gov (United States)

    Brackman, Gilles; Celen, Shari; Hillaert, Ulrik; Van Calenbergh, Serge; Cos, Paul; Maes, Louis; Nelis, Hans J; Coenye, Tom

    2011-01-13

    Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

  12. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

    Directory of Open Access Journals (Sweden)

    Gilles Brackman

    Full Text Available BACKGROUND: Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS. Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. METHODOLOGY/PRINCIPAL FINDINGS: By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. CONCLUSIONS/SIGNIFICANCE: Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

  13. Evaluating Molecular Properties Involved in Transport of Small Molecules in Stratum Corneum: A Quantitative Structure-Activity Relationship for Skin Permeability.

    Science.gov (United States)

    Chen, Chen-Peng; Chen, Chan-Cheng; Huang, Chia-Wen; Chang, Yen-Ching

    2018-04-15

    The skin permeability ( Kp ) defines the rate of a chemical penetrating across the stratum corneum. This value is widely used to quantitatively describe the transport of molecules in the outermost layer of epidermal skin and indicate the significance of skin absorption. This study defined a Kp quantitative structure-activity relationship (QSAR) based on 106 chemical substances of Kp measured using human skin and interpreted the molecular interactions underlying transport behavior of small molecules in the stratum corneum. The Kp QSAR developed in this study identified four molecular descriptors that described the molecular cyclicity in the molecule reflecting local geometrical environments, topological distances between pairs of oxygen and chlorine atoms, lipophilicity, and similarity to antineoplastics in molecular properties. This Kp QSAR considered the octanol-water partition coefficient to be a direct influence on transdermal movement of molecules. Moreover, the Kp QSAR identified a sub-domain of molecular properties initially defined to describe the antineoplastic resemblance of a compound as a significant factor in affecting transdermal permeation of solutes. This finding suggests that the influence of molecular size on the chemical's skin-permeating capability should be interpreted with other relevant physicochemical properties rather than being represented by molecular weight alone.

  14. Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety.

    Science.gov (United States)

    Wu, Zengxue; Zhang, Jian; Chen, Jixiang; Pan, Jianke; Zhao, Lei; Liu, Dengyue; Zhang, Awei; Chen, Jin; Hu, Deyu; Song, Baoan

    2017-10-01

    Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC 50 values of 162.14, 114.61 and 255.49, 138.81 mg L -1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L -1 ). The values of q 2 and r 2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  15. 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)

    Hirano, T.; Oka, K.; Akiba, M.

    1989-01-01

    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 IC 50 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 [ 3 H] 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

  16. Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

    Science.gov (United States)

    Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

    2017-03-01

    We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  17. 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.

  18. 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

    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 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

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

    Energy Technology Data Exchange (ETDEWEB)

    Hirano, T.; Oka, K.; Akiba, M. (Tokyo College of Pharmacy (Japan))

    1989-01-01

    A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na{sup +}, K{sup +} -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na{sup +}, K{sup +} -ATPase from dog kidney cortex when present at concentrations from 40-1000 {mu}M. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC{sub 50} at 257-320 {mu}M. 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 {gt} 2-cyclohexyl-6-hydroxy-benzopyran-4-one {gt} 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 ({sup 3}H) ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na{sup +}, K{sup +} -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme.

  20. Synthesis of 9,9-dialkyl-4,5-diazafluorene derivatives and their structure-activity relationships toward human carcinoma cell lines.

    Science.gov (United States)

    Wang, Qiwei; Yuen, Marcus Chun-Wah; Lu, Guo-Liang; Ho, Cheuk-Lam; Zhou, Gui-Jiang; Keung, Oi-Mei; Lam, Kim-Hung; Gambari, Roberto; Tao, Xiao-Ming; Wong, Raymond Siu-Ming; Tong, See-Wai; Chan, Kit-Wah; Lau, Fung-Yi; Cheung, Filly; Cheng, Gregory Yin-Ming; Chui, Chung-Hin; Wong, Wai-Yeung

    2010-04-06

    A homologous set of 9,9-dialkyl-4,5-diazafluorene compounds were prepared by alkylation of 4,5-diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB-231 breast carcinoma, and SKHep-1 hepatoma cells, were investigated; a structure-activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC(50))] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9-dihexyl-4,5-diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in vitro cytotoxicity was not observed at clinically relevant concentrations.

  1. Synthesis and evaluation of 8,4'-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin.

    Science.gov (United States)

    Liu, Tao; Ma, Ming; Ge, Hui-Ming; Yang, Chunying; Cleveland, John; Shen, Ben

    2015-11-01

    Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor activity via an episulfonium ion-mediated DNA alkylation upon reductive activation in the presence of cellular thiols. We recently isolated leinamycin E1 (LNM E1, 2) from an engineered strain S. atroolivaceus SB3033, which lacks the 1,3-dioxo-1,2-dithiolane moiety. Here we report the chemical synthesis of 8,4'-dideshydroxy-LNM (5) from 2 and determination of the cytotoxicity of 5 against selected cancer cell lines in comparison with 1; 5 exhibits comparable activity as 1 with the EC50 values between 8.21 and 275 nM. This work reveals new insight into the structure-activity relationship of LNM and highlights the synergy between metabolic pathway engineering and medicinal chemistry for natural product drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

    Science.gov (United States)

    Tran, Hai L; Lexa, Katrina W; Julien, Olivier; Young, Travis S; Walsh, Christopher T; Jacobson, Matthew P; Wells, James A

    2017-02-22

    Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

  3. Structure-Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells.

    Science.gov (United States)

    Robles, Andrew J; McCowen, Shelby; Cai, Shengxin; Glassman, Michaels; Ruiz, Francisco; Cichewicz, Robert H; McHardy, Stanton F; Mooberry, Susan L

    2017-11-22

    Targeted therapies for ER+/PR+ and HER2-amplified breast cancers have improved patient survival, but there are no therapies for triple negative breast cancers (TNBC) that lack expression of estrogen and progesterone receptors (ER/PR), or amplification or overexpression of HER2. Gene expression profiling of TNBC has identified molecular subtypes and representative cell lines. An extract of the Texas native plant Amyris texana was found to have selective activity against MDA-MB-453 cells, a model of the luminal androgen receptor (LAR) subtype of TNBC. Bioassay-guided fractionation identified two oxazole natural products with selective activity against this cell line. Conducted analog synthesis and structure-activity relationship studies provided analogs with more potent and selective activity against two LAR subtype cell line models, culminating in the discovery of compound 30 (CIDD-0067106). Lead compounds discovered have potent and selective antiproliferative activities, and mechanisms of action studies show they inhibit the activity of the mTORC1 pathway.

  4. The use of quantitative structure-activity relationship models to develop optimized processes for the removal of tobacco host cell proteins during biopharmaceutical production.

    Science.gov (United States)

    Buyel, J F; Woo, J A; Cramer, S M; Fischer, R

    2013-12-27

    The production of recombinant pharmaceutical proteins in plants benefits from the low cost of upstream production and the greater scalability of plants compared to fermenter-based systems. Now that manufacturing processes that comply with current good manufacturing practices have been developed, plants can compete with established platforms on equal terms. However, the costs of downstream processing remain high, in part because of the dedicated process steps required to remove plant-specific process-related impurities. We therefore investigated whether the ideal strategy for the chromatographic removal of tobacco host cell proteins can be predicted by quantitative structure-activity relationship (QSAR) modeling to reduce the process development time and overall costs. We identified more than 100 tobacco proteins by mass spectrometry and their structures were reconstructed from X-ray crystallography, nuclear magnetic resonance spectroscopy and/or homology modeling data. The resulting three-dimensional models were used to calculate protein descriptors, and significant descriptors were selected based on recently-published retention data for model proteins to develop QSAR models for protein retention on anion, cation and mixed-mode resins. The predicted protein retention profiles were compared with experimental results using crude tobacco protein extracts. Because of the generic nature of the method, it can easily be transferred to other expression systems such as mammalian cells. The quality of the models and potential improvements are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus.

    Science.gov (United States)

    Li, Sumei; Jia, Xiuhua; Shen, Xintian; Wei, Zhuwen; Jiang, Zhiyan; Liao, Yixian; Guo, Yiming; Zheng, Xiaojun; Zhong, Guohua; Song, Gaopeng

    2017-08-15

    Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC 50 values of 4.05μM and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3β- to 3α-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro. Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Synthesis and structure-activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors.

    Science.gov (United States)

    Solorzano, Carlos; Antonietti, Francesca; Duranti, Andrea; Tontini, Andrea; Rivara, Silvia; Lodola, Alessio; Vacondio, Federica; Tarzia, Giorgio; Piomelli, Daniele; Mor, Marco

    2010-08-12

    The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-alpha, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of beta-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC(50) = 420 nM; 7h, IC(50) = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.

  7. Quantitative structure-activity relationship analysis of human neutrophil elastase inhibitors using shuffling classification and regression trees and adaptive neuro-fuzzy inference systems.

    Science.gov (United States)

    Asadollahi-Baboli, M

    2012-07-01

    The purpose of this study was to develop quantitative structure-activity relationship models for N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. These models were developed with the aid of classification and regression trees (CART) and an adaptive neuro-fuzzy inference system (ANFIS) combined with a shuffling cross-validation technique using interpretable descriptors. More than one hundred meaningful descriptors, representing various structural characteristics for all 51 N-benzoylindazole derivatives in the data set, were calculated and used as the original variables for shuffling CART modelling. Five descriptors of average Wiener index, Kier benzene-likeliness index, subpolarity parameter, average shape profile index of order 2 and folding degree index selected by the shuffling CART technique have been used as inputs of the ANFIS for prediction of inhibition behaviour of N-benzoylindazole derivatives. The results of the developed shuffling CART-ANFIS model compared to other techniques, such as genetic algorithm (GA)-partial least square (PLS)-ANFIS and stepwise multiple linear regression (MLR)-ANFIS, are promising and descriptive. The satisfactory results r2p = 0.845, Q2(LOO) = 0.861, r2(L25%O) = 0.829, RMSE(LOO)  = 0.305 and RMSE(L25%O)  = 0.336) demonstrate that shuffling CART-ANFIS models present the relationship between human neutrophil elastase inhibitor activity and molecular descriptors, and they yield predictions in excellent agreement with the experimental values.

  8. Rational design of novel anti-microtubule agent (9-azido-noscapine) from quantitative structure activity relationship (QSAR) evaluation of noscapinoids.

    Science.gov (United States)

    Santoshi, Seneha; Naik, Pradeep K; Joshi, Harish C

    2011-10-01

    An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors' laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC(50) values of these analogs vary from 1.2 to 56.0 µM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model (R(2) = 0.942) was analyzed by values of the internal cross-validated regression coefficient (R(2) (LOO) = 0.815) for the training set and determination coefficient (R(2) (test) = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC(50) for both the compounds (5.585 M) turned out to be very close to predicted pIC(50) (5.731 and 5.710 M).

  9. Biological origins of color categorization

    OpenAIRE

    Skelton, Alice E.; Catchpole, Gemma; Abbott, Joshua T.; Bosten, Jenny M.; Franklin, Anna

    2017-01-01

    The biological basis of the commonality in color lexicons across languages has been hotly debated for decades. Prior evidence that infants categorize color could provide support for the hypothesis that color categorization systems are not purely constructed by communication and culture. Here, we investigate the relationship between infants’ categorization of color and the commonality across color lexicons, and the potential biological origin of infant color categories. We systematically mappe...

  10. Toxicity Assessment of Atrazine and Related Triazine Compounds in the Microtox Assay, and Computational Modeling for Their Structure-Activity Relationship

    Directory of Open Access Journals (Sweden)

    Jerzy Leszczynski

    2000-10-01

    Full Text Available The triazines are a group of chemically similar herbicides including atrazine, cyanazine, and propazine, primarily used to control broadleaf weeds. About 64 to 80 million lbs of atrazine alone are used each year in the United States, making it one of the two most widely used pesticides in the country. All triazines are somewhat persistent in water and mobile in soil. They are among the most frequently detected pesticides in groundwater. They are considered as possible human carcinogens (Group C based on an increase in mammary gland tumors in female laboratory animals. In this research, we performed the Microtox Assay to investigate the acute toxicity of a significant number of triazines including atrazine, atraton, ametryne, bladex, prometryne, and propazine, and some of their degradation products including atrazine desethyl, atrazine deisopropyl, and didealkyled triazine. Tests were carried out as described by Azur Environmental [1]. The procedure measured the relative acute toxicity of triazines, producing data for the calculation of triazine concentrations effecting 50% reduction in bioluminescence (EC50s. Quantitative structure-activity relationships (QSAR were examined based on the molecular properties obtained from quantum mechanical predictions performed for each compound. Toxicity tests yielded EC50 values of 39.87, 273.20, 226.80, 36.96, 81.86, 82.68, 12.74, 11.80, and 78.50 mg/L for atrazine, propazine, prometryne, atraton, atrazine desethyl, atrazine deisopropyl, didealkylated triazine, ametryne, and bladex, respectively; indicating that ametryne was the most toxic chemical while propazine was the least toxic. QSAR evaluation resulted in a coefficient of determination (r2 of 0.86, indicating a good value of toxicity prediction based on the chemical structures/properties of tested triazines.

  11. Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2',3',4'-trihydroxyflavone (2-D08).

    Science.gov (United States)

    Marsh, Dylan T; Das, Sukanya; Ridell, Jessica; Smid, Scott D

    2017-07-15

    Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer's disease, amyloid β (Aβ). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the Aβ protein. In the present study we have characterised the Aβ binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human Aβ 1-42 for 48h in vitro and effects on Aβ fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited Aβ 1-42 aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against β amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease. Crown Copyright © 2017

  12. Quantitative structure-activity relationships for chronic toxicity of alkyl-chrysenes and alkyl-benz[a]anthracenes to Japanese medaka embryos (Oryzias latipes).

    Science.gov (United States)

    Lin, Hongkang; Morandi, Garrett D; Brown, R Stephen; Snieckus, Victor; Rantanen, Toni; Jørgensen, Kåre B; Hodson, Peter V

    2015-02-01

    Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are a class of compounds found at significant concentrations in crude oils, and likely the main constituents responsible for the chronic toxicity of oil to fish. Alkyl substituents at different locations on the aromatic rings change the size and shape of PAH molecules, which results in different interactions with tissue receptors and different severities of toxicity. The present study is the first to report the toxicity of several alkylated derivatives of chrysene and benz[a]anthracene to the embryos of Japanese medaka (Oryzias latipes) using the partition controlled delivery (PCD) method of exposure. The PCD method maintained the desired exposure concentrations by equilibrium partitioning of hydrophobic test compounds from polydimethylsiloxane (PDMS) films. Test concentrations declined by only 13% over a period of 17 days. Based on the prevalence of signs of blue sac disease (BSD), as expressed by median effective concentrations (EC50s), benz[a]anthracene (B[a]A) was more toxic than chrysene. Alkylation generally increased toxicity, except at position 2 of B[a]A. Alkyl-PAHs substituted in the middle region had a lower EC50 than those substituted at the distal region. Except for B[a]A and 7-methylbenz[a]anthracene (7-MB), estimated EC50 values were higher than their solubility limits, which resulted in limited toxicity within the range of test concentrations. The regression between log EC50s and logKow values provided a rough estimation of structure-activity relationships for alkyl-PAHs, but Kow alone did not provide a complete explanation of the chronic toxicity of alkyl PAHs. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Characterizing microbiota-independent effects of oligosaccharides on intestinal epithelial cells: insight into the role of structure and size : Structure-activity relationships of non-digestible oligosaccharides.

    Science.gov (United States)

    Akbari, Peyman; Fink-Gremmels, Johanna; Willems, Rianne H A M; Difilippo, Elisabetta; Schols, Henk A; Schoterman, Margriet H C; Garssen, Johan; Braber, Saskia

    2017-08-01

    The direct effects of galacto-oligosaccharides (GOS), including Vivinal ® GOS syrup (VGOS) and purified Vivinal ® GOS (PGOS), on the epithelial integrity and corresponding interleukin-8 (IL-8/CXCL8) release were examined in a Caco-2 cell model for intestinal barrier dysfunction. To investigate structure-activity relationships, the effects of individual DP fractions of VGOS were evaluated. Moreover, the obtained results with GOS were compared with Caco-2 monolayers incubated with fructo-oligosaccharides (FOS) and inulin. Caco-2 monolayers were pretreated (24 h) with or without specific oligosaccharides or DP fractions of VGOS (DP2 to DP6) before being exposed for 12 or 24 h to the fungal toxin deoxynivalenol (DON). Transepithelial electrical resistance and lucifer yellow permeability were measured to investigate barrier integrity. A calcium switch assay was used to study the reassembly of tight junction proteins. Release of CXCL8, a typical marker for inflammation, was quantified by ELISA. In comparison with PGOS, FOS and inulin, VGOS showed the most pronounced protective effect on the DON-induced impairment of the monolayer integrity, acceleration of the tight junction reassembly and the subsequent CXCL8 release. DP2 and DP3 in concentrations occurring in VGOS prevented the DON-induced epithelial barrier disruption, which could be related to their high prevalence in VGOS. However, no effects of the separate DP GOS fractions were observed on CXCL8 release. This comparative study demonstrates the direct, microbiota-independent effects of oligosaccharides on the intestinal barrier function and shows the differences between individual galacto- and fructo-oligosaccharides. This microbiota-independent effect of oligosaccharides depends on the oligosaccharide structure, DP length and concentration.

  14. Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. Synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids.

    Science.gov (United States)

    Nagaoka, Masao; Watari, Yoko; Yajima, Hiromi; Tsukioka, Kaoru; Muroi, Yasuyo; Yamada, Keiko; Numazawa, Mitsuteru

    2003-08-01

    As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, two series of 3-deoxy androgens, androst-5-en-17-ones with a non-polar alkoxy (5 and 6), alkyl (20-22), or phenylalkyl (23 and 24) group at C-4beta and 4-acyloxyandrost-4-en-17-ones (29-32, and 34) were synthesized and evaluated. The 4beta-alkyl and 4beta-phenylalkyl compounds were obtained through reaction of 4alpha,5alpha-epoxy steroid (8) with RMgBr (R: alkyl and phenylalkyl) followed by dehydration of the 4beta-substituted 5alpha-hydroxy products (15-19) with SOCl(2) as key reactions. Acylation of 4alpha,5alpha-diol (25) with (RCO)(2)O in pyridine and subsequent dehydration with SOCl(2) gave the 4-acyloxy steroids. All of the steroids studied, except for 4-acetoxy-19-ol (34) that was a non-competitive inhibitor of human placental aromatase, blocked aromatase activity in a competitive manner. 4-Benzoyloxy- and 4-acetoxy steroids (31) and (32) were the most powerful inhibitors of aromatase (K(i)=70 and 60nM, respectively). Elongation of an acetoxy group in a series of 4-acyloxy steroids or a methyl group in a series of 4beta-alkyl steroids decreased affinity for aromatase principally in relation to carbon number of the acyl or alkyl function. The present findings are potentially useful for understanding the spatial and electronic nature of the binding site of aromatase as well as for developing effective aromatase inhibitors.

  15. Drug interaction study of natural steroids from herbs specifically toward human UDP-glucuronosyltransferase (UGT) 1A4 and their quantitative structure activity relationship (QSAR) analysis for prediction.

    Science.gov (United States)

    Xu, Min; Dong, Peipei; Tian, Xiangge; Wang, Chao; Huo, Xiaokui; Zhang, Baojing; Wu, Lijun; Deng, Sa; Ma, Xiaochi

    2016-08-01

    The wide application of herbal medicines and foods containing steroids has resulted in the high risk of herb-drug interactions (HDIs). The present study aims to evaluate the inhibition potential of 43 natural steroids from herb medicines toward human UDP- glucuronosyltransferases (UGTs). A remarkable structure-dependent inhibition toward UGT1A4 was observed in vitro. Some natural steroids such as gitogenin, tigogenin, and solasodine were found to be the novel selective inhibitors of UGT1A4, and did not inhibit the activities of major human CYP isoforms. To clarify the possibility of the in vivo interaction of common steroids and clinical drugs, the kinetic inhibition type and related kinetic parameters (Ki) were measured. The target compounds 2-6 and 15, competitively inhibited the UGT1A4-catalyzed trifluoperazine glucuronidation reaction, with Ki values of 0.6, 0.18, 1.1, 0.7, 0.8, and 12.3μM, respectively. And this inhibition of steroids towards UGT1A4 was also verified in human primary hepatocytes. Furthermore, a quantitative structure-activity relationship (QSAR) of steroids with inhibitory effects toward human UGT1A4 isoform was established using the computational methods. Our findings elucidate the potential for in vivo HDI effects of steroids in herbal medicine and foods, with the clinical dr ugs eliminated by UGT1A4, and reveal the vital pharamcophoric requirement of natural steroids for UGT1A4 inhibition activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Precise prediction of activators for the human constitutive androstane receptor using structure-based three-dimensional quantitative structure-activity relationship methods.

    Science.gov (United States)

    Kato, Harutoshi; Yamaotsu, Noriyuki; Iwazaki, Norihiko; Okamura, Shigeaki; Kume, Toshiyuki; Hirono, Shuichi

    2017-06-01

    The constitutive androstane receptor (CAR, NR1I3) regulates the expression of numerous drug-metabolizing enzymes and transporters. The upregulation of various enzymes, including CYP2B6, by CAR activators is a critical problem leading to clinically severe drug-drug interactions (DDIs). To date, however, few effective computational approaches for identifying CAR activators exist. In this study, we aimed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict the CAR activating potency of compounds emerging in the drug-discovery process. Models were constructed using comparative molecular field analysis (CoMFA) based on the molecular alignments of ligands binding to CAR, which were obtained from ensemble ligand-docking using 28 compounds as a training set. The CoMFA model, modified by adding a lipophilic parameter with calculated logD 7.4 (S+logD 7.4 ), demonstrated statistically good predictive ability (r 2  = 0.99, q 2  = 0.74). We also confirmed the excellent predictability of the 3D-QSAR model for CAR activation (r 2 pred  = 0.71) using seven compounds as a test set for external validation. Collectively, our results indicate that the 3D-QSAR model developed in this study provides precise prediction of CAR activating potency and, thus, should be useful for selecting drug candidates with minimized DDI risk related to enzyme-induction in the early drug-discovery stage. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  17. 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.

  18. An orientation sensitive approach in biomolecule interaction quantitative structure-activity relationship modeling and its application in ion-exchange chromatography.

    Science.gov (United States)

    Kittelmann, Jörg; Lang, Katharina M H; Ottens, Marcel; Hubbuch, Jürgen

    2017-01-27

    Quantitative structure-activity relationship (QSAR) modeling for prediction of biomolecule parameters has become an established technique in chromatographic purification process design. Unfortunately available descriptor sets fail to describe the orientation of biomolecules and the effects of ionic strength in the mobile phase on the interaction with the stationary phase. The literature describes several special descriptors used for chromatographic retention modeling, all of these do not describe the screening of electrostatic potential by the mobile phase in use. In this work we introduce two new approaches of descriptor calculations, namely surface patches and plane projection, which capture an oriented binding to charged surfaces and steric hindrance of the interaction with chromatographic ligands with regard to electrostatic potential screening by mobile phase ions. We present the use of the developed descriptor sets for predictive modeling of Langmuir isotherms for proteins at different pH values between pH 5 and 10 and varying ionic strength in the range of 10-100mM. The resulting model has a high correlation of calculated descriptors and experimental results, with a coefficient of determination of 0.82 and a predictive coefficient of determination of 0.92 for unknown molecular structures and conditions. The agreement of calculated molecular interaction orientations with both, experimental results as well as molecular dynamic simulations from literature is shown. The developed descriptors provide the means for improved QSAR models of chromatographic processes, as they reflect the complex interactions of biomolecules with chromatographic phases. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.

    Science.gov (United States)

    Noha, Stefan M; Schmidhammer, Helmut; Spetea, Mariana

    2017-06-21

    Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

  20. 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.

  1. Anti-HIV-1 activity and structure-activity-relationship study of a fucosylated glycosaminoglycan from an echinoderm by targeting the conserved CD4 induced epitope.

    Science.gov (United States)

    Lian, Wu; Wu, Mingyi; Huang, Ning; Gao, Na; Xiao, Chuang; Li, Zi; Zhang, Zhigang; Zheng, Yongtang; Peng, Wenlie; Zhao, Jinhua

    2013-10-01

    Fucosylated glycosaminoglycan (FG) is a novel glycosaminoglycan with a chondroitin sulfate-like backbone and fucose sulfate branches. The aim of this study is to investigate the mechanism and structure-activity relationships (SAR) of FG for combating HIV-1 infection. Anti-HIV activities of FGs were assessed by a cytopathic effect assay and an HIV-1 p24 detection assay. The biomolecule interactions were explored via biolayer interferometry technology. The SAR was established by comparing its anti-HIV-1 activities, conserved CD4 induced (CD4i) epitope-dependent interactions and anticoagulant activities. FG efficiently and selectively inhibited the X4- and R5X4-tropic HIV-1 infections in C8166 cells with little cytotoxicity against C8166 cells and PBMCs. Our data indicated that FG bound to gp120 with nanomolar affinity and may interact with CD4i of gp120. Additionally, the CD4i binding affinity of FG was higher than that of dextran sulfate. SAR studies suggested that the unique sulfated fucose branches account for the anti-HIV-1 activity. The molecular size and present carboxyl groups of FG may also play important roles in various activities. Notably, several FG derivatives showed higher anti-HIV-1 activities and much lower anticoagulant activities than those of heparin. FG exhibits strong activity against X4- and R5X4-tropic HIV-1 infections. The mechanism may be related to targeting CD4i of gp120, which results in inhibition of HIV-1 entry. The carboxyl group substituted derivatives of FG (8.5-12.8kDa), might display high anti-HIV-1 activity and low anticoagulant activity. Our data supports further the investigation of FG derivatives as novel HIV-1 entry inhibitors targeting CD4i. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. 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.

  3. Support vector regression-guided unravelling: antioxidant capacity and quantitative structure-activity relationship predict reduction and promotion effects of flavonoids on acrylamide formation

    Science.gov (United States)

    Huang, Mengmeng; Wei, Yan; Wang, Jun; Zhang, Yu

    2016-09-01

    We used the support vector regression (SVR) approach to predict and unravel reduction/promotion effect of characteristic flavonoids on the acrylamide formation under a low-moisture Maillard reaction system. Results demonstrated the reduction/promotion effects by flavonoids at addition levels of 1-10000 μmol/L. The maximal inhibition rates (51.7%, 68.8% and 26.1%) and promote rates (57.7%, 178.8% and 27.5%) caused by flavones, flavonols and isoflavones were observed at addition levels of 100 μmol/L and 10000 μmol/L, respectively. The reduction/promotion effects were closely related to the change of trolox equivalent antioxidant capacity (ΔTEAC) and well predicted by triple ΔTEAC measurements via SVR models (R: 0.633-0.900). Flavonols exhibit stronger effects on the acrylamide formation than flavones and isoflavones as well as their O-glycosides derivatives, which may be attributed to the number and position of phenolic and 3-enolic hydroxyls. The reduction/promotion effects were well predicted by using optimized quantitative structure-activity relationship (QSAR) descriptors and SVR models (R: 0.926-0.994). Compared to artificial neural network and multi-linear regression models, SVR models exhibited better fitting performance for both TEAC-dependent and QSAR descriptor-dependent predicting work. These observations demonstrated that the SVR models are competent for predicting our understanding on the future use of natural antioxidants for decreasing the acrylamide formation.

  4. Identification and characterization of the structure-activity relationships involved in UGT1A1 inhibition by anthraquinone and dianthrone constituents of Polygonum multiflorum.

    Science.gov (United States)

    Wang, Qi; Wang, Yadan; Li, Yong; Wen, Binyu; Dai, Zhong; Ma, Shuangcheng; Zhang, Yujie

    2017-12-20

    The adverse effects of Polygonum (P.) multiflorum, including abnormal bilirubin metabolism, are a serious public health issue. As uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme responsible for bilirubin metabolism, we investigated the inhibitory effect of a P. multiflorum extract and 10 anthraquinone and dianthrone compounds on UGT1A1 in rat liver microsomes in vitro. The P. multiflorum extract exhibited the strongest inhibitory effect on UGT1A1 activity (inhibition constant [K i ] = 0.3257 μM, 1422 μg of material/mL), followed by cis-emodin dianthrones (K i  = 0.8630 μM), trans-emodin dianthrones (K i  = 1.083 μM), emodin-8-O-glc (K i  = 3.425 μM), and polygonumnolide C2 (K i  = 4.291 μM). Analysis of the structure-activity relationships of these compounds suggested that the spatial orientation of the molecules and the presence of particular functional groups affect UGT1A1 inhibition. A mechanistic analysis showed that all the tested compounds docked into two of the nine active sites of UGT1A1 and suggested that hydrophobic interactions and hydrogen bonds are important for the affinity of the tested compounds for UGT1A1; moreover, their interaction energies were generally in agreement with the K i values. These findings provide insight into adverse reactions to P. multiflorum and identify the pharmacophores involved in inhibition of UGT1A1.

  5. Optimization and structure-activity relationships of a series of potent inhibitor/span>s of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents.

    Science.gov (United States)

    Kumar, Nag S; Amandoron, Emily A; Cherkasov, Artem; Finlay, B Brett; Gong, Huansheng; Jackson, Linda; Kaur, Sukhbir; Lian, Tian; Moreau, Anne; Labrière, Christophe; Reiner, Neil E; See, Raymond H; Strynadka, Natalie C; Thorson, Lisa; Wong, Edwin W Y; Worrall, Liam; Zoraghi, Roya; Young, Robert N

    2012-12-15

    A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected 'hub proteins' in MRSA. PK has been shown to be critical for bacterial survival which makes it a potential target for development of novel antibiotics and the high degree of connectivity implies it should be very sensitive to mutations and thus less able to develop resistance. PK is not unique to bacteria and thus a critical requirement for such a PK inhibitor would be that it does not inhibit the homologous human enzyme(s) at therapeutic concentrations. Several MRSA PK inhibitors (including 8d) were identified using in silico screening combined with enzyme assays and were found to be selective for bacterial enzyme compared to four human PK isoforms (M1, M2, R and L). However these lead compounds did not show significant inhibitory activity for MRSA growth presumably due to poor bacterial cell penetration. Structure-activity relationship (SAR) studies were carried out on 8d and led us to discover more potent compounds with enzyme inhibiting activities in the low nanomolar range and some were found to effectively inhibit bacteria growth in culture with minimum inhibitory concentrations (MIC) as low as 1 μg/mL. These inhibitors bind in two elongated flat clefts found at the minor interfaces in the homo-tetrameric enzyme complex and the observed SAR is in keeping with the size and electronic constraints of these binding sites. Access to the corresponding sites in the human enzyme is blocked. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Prediction of cross-recognition of peptide-HLA A2 by Melan-A-specific cytotoxic T lymphocytes using three-dimensional quantitative structure-activity relationships.

    Science.gov (United States)

    Fagerberg, Theres; Zoete, Vincent; Viatte, Sebastien; Baumgaertner, Petra; Alves, Pedro M; Romero, Pedro; Speiser, Daniel E; Michielin, Olivier

    2013-01-01

    The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D) quantitative structure-activity relationships (QSARs) to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2). First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006)]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997)] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2)) is used as the fitness criterion and all obtained models are evaluated based on their q (2) values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set). The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to determine the

  7. Prediction of cross-recognition of peptide-HLA A2 by Melan-A-specific cytotoxic T lymphocytes using three-dimensional quantitative structure-activity relationships.

    Directory of Open Access Journals (Sweden)

    Theres Fagerberg

    Full Text Available The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D quantitative structure-activity relationships (QSARs to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2. First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2 is used as the fitness criterion and all obtained models are evaluated based on their q (2 values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set. The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to

  8. 2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors.

    Science.gov (United States)

    Ozola, Vita; Thorand, Mark; Diekmann, Martina; Qurishi, Ramatullah; Schumacher, Britta; Jacobson, Kenneth A; Müller, Christa E

    2003-02-06

    Structure-activity relationships of 2-phenyl-imidazo[2,1-i]purin-5-ones as ligands for human A(3) adenosine receptors (ARs) were investigated. An ethyl group in the 8-position of the imidazoline ring of 4-methyl-2-phenyl-imidazopurinone leading to chiral compounds was found to increase affinity for human A(3) ARs by several thousand-fold. Propyl substitution instead of methyl at N4 decreased A(3) affinity but increased A(1) affinity leading to potent A(1)-selective AR antagonists. The most potent A(1) antagonist of the present series was (S)-8-ethyl-2-phenyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (S-3) exhibiting a K(i) value of 7.4 nM at rat A(1) ARs and greater than 100-fold selectivity versus rat A(2A) and human A(3) ARs. At human A(1) ARs 2-phenylimidazo[2,1-i]purin-5-ones were generally less potent and therefore less A(1)-selective (S-3: K(i)=98 nM). 2-, 3-, or 4-Mono-chlorination of the 2-phenyl ring reduced A(3) affinity but led to an increase in affinity for A(1) ARs, whereas di- (3,4-dichloro) or polychlorination (2,3,5-trichloro) increased A(3) affinity. The most potent and selective A(3) antagonist of the present series was the trichlorophenyl derivative (R)-8-ethyl-4-methyl-2-(2,3,5-trichlorophenyl)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (R-8) exhibiting a subnanomolar K(i) value at human A(3) ARs and greater than 800-fold selectivity versus the other AR subtypes. Methylation of 4-alkyl-2-phenyl-substituted imidazo[2,1-i]purin-5-ones led exclusively to the N9-methyl derivatives, which exhibited largely reduced AR affinities as compared to the unmethylated compounds. [35S]GTP gamma S binding studies of the most potent 2-phenyl-imidazo[2,1-i]purin-5-ones at membranes of Chinese hamster ovary cells expressing the human A(3) AR revealed that the compounds were inverse agonists at A(3) receptors under standard test conditions. Due to their high A(3) affinity, selectivity, and relatively high water-solubility, 2-phenyl-imidazo[2,1-i

  9. Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure-Activity Relationship Study.

    Science.gov (United States)

    Yellol, Jyoti; Pérez, Sergio A; Buceta, Alicia; Yellol, Gorakh; Donaire, Antonio; Szumlas, Piotr; Bednarski, Patrick J; Makhloufi, Gamall; Janiak, Christoph; Espinosa, Arturo; Ruiz, José

    2015-09-24

    A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 μM, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.

  10. Biological origins of color categorization.

    Science.gov (United States)

    Skelton, Alice E; Catchpole, Gemma; Abbott, Joshua T; Bosten, Jenny M; Franklin, Anna

    2017-05-23

    The biological basis of the commonality in color lexicons across languages has been hotly debated for decades. Prior evidence that infants categorize color could provide support for the hypothesis that color categorization systems are not purely constructed by communication and culture. Here, we investigate the relationship between infants' categorization of color and the commonality across color lexicons, and the potential biological origin of infant color categories. We systematically mapped infants' categorical recognition memory for hue onto a stimulus array used previously to document the color lexicons of 110 nonindustrialized languages. Following familiarization to a given hue, infants' response to a novel hue indicated that their recognition memory parses the hue continuum into red, yellow, green, blue, and purple categories. Infants' categorical distinctions aligned with common distinctions in color lexicons and are organized around hues that are commonly central to lexical categories across languages. The boundaries between infants' categorical distinctions also aligned, relative to the adaptation point, with the cardinal axes that describe the early stages of color representation in retinogeniculate pathways, indicating that infant color categorization may be partly organized by biological mechanisms of color vision. The findings suggest that color categorization in language and thought is partially biologically constrained and have implications for broader debate on how biology, culture, and communication interact in human cognition.

  11. 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...... to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration...

  12. New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

    DEFF Research Database (Denmark)

    Hansen, Stinne Wessel; Erichsen, Mette Norman; Huynh, T.H.V.

    2016-01-01

    In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 diffe...... as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism....

  13. The dynamics of categorization: Unraveling rapid categorization.

    Science.gov (United States)

    Mack, Michael L; Palmeri, Thomas J

    2015-06-01

    We explore a puzzle of visual object categorization: Under normal viewing conditions, you spot something as a dog fastest, but at a glance, you spot it faster as an animal. During speeded category verification, a classic basic-level advantage is commonly observed (Rosch, Mervis, Gray, Johnson, & Boyes-Braem, 1976), with categorization as a dog faster than as an animal (superordinate) or Golden Retriever (subordinate). A different story emerges during ultra-rapid categorization with limited exposure duration (<30 ms), with superordinate categorization faster than basic or subordinate categorization (Thorpe, Fize, & Marlot, 1996). These two widely cited findings paint contrary theoretical pictures about the time course of categorization, yet no previous study has investigated them together. We systematically examined two experimental factors that could explain the qualitative difference in categorization across the two paradigms: exposure duration and category trial context. Mapping out the time course of object categorization by manipulating exposure duration and the timing of a post-stimulus mask revealed that brief exposure durations favor superordinate-level categorization, but with more time a basic-level advantage emerges. However, these advantages were modulated by category trial context. With randomized target categories, the superordinate advantage was eliminated; and with only four repetitions of superordinate categorization within an otherwise randomized context, the basic-level advantage was eliminated. Contrary to theoretical accounts that dictate a fixed priority for certain levels of abstraction in visual processing and access to semantic knowledge, the dynamics of object categorization are flexible, depending jointly on the level of abstraction, time for perceptual encoding, and category context. (c) 2015 APA, all rights reserved).

  14. The Relationship Between the Stanford Leisure-Time Activity Categorical Item and the Godin Leisure-Time Exercise Questionnaire Among Rural Intervention Participants of Varying Health Literacy Status.

    Science.gov (United States)

    Kružliaková, Natalie; Estabrooks, Paul A; You, Wen; Hedrick, Valisa; Porter, Kathleen; Kiernan, Michaela; Zoellner, Jamie

    2018-02-09

    A pragmatic, self-reported physical activity measure is needed for individuals of varying health literacy status. This study is a secondary analysis of a 6-month behavioral intervention for rural Appalachian adults developed using health literacy strategies. We examined the relationship and responsiveness of the Stanford Leisure-Time Activity Categorical Item (L-Cat) and adapted Godin Leisure-Time Exercise Questionnaire (GLTEQ) and determined if baseline health literacy status moderates intervention effects. Of 301 enrolled participants, 289 completed the L-Cat at baseline and 212 at 6 months. Approximately 33% were low health literate and 43% reported annual income of ≤$14,999. There was high agreement (84.1%) between the L-Cat and adapted GLTEQ for classifying individuals as meeting physical activity recommendations with little differences by health literacy level (low literacy 80.4% and high literacy 85.9%). The primary source of incongruent classification was the adapted GLTEQ classified almost 20% of individuals as meeting recommendations, whereas the L-Cat classified them as not meeting recommendations. There were differences in responsiveness between measures, but baseline health literacy status did not moderate change in any L-Cat or adapted GLTEQ measures. Implications and recommendations for using the L-Cat 2.3 and GLTEQ among individuals of varying health literacy status are discussed.

  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. 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.

  17. 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.

  18. Hydrogen Production by Ethanol Steam Reforming (ESR over CeO2 Supported Transition Metal (Fe, Co, Ni, Cu Catalysts: Insight into the Structure-Activity Relationship

    Directory of Open Access Journals (Sweden)

    Michalis Konsolakis

    2016-03-01

    Full Text Available The aim of the present work was to investigate steam reforming of ethanol with regard to H2 production over transition metal catalysts supported on CeO2. Various parameters concerning the effect of temperature (400–800 °C, steam-to-carbon (S/C feed ratio (0.5, 1.5, 3, 6, metal entity (Fe, Co, Ni, Cu and metal loading (15–30 wt.% on the catalytic performance, were thoroughly studied. The optimal performance was obtained for the 20 wt.% Co/CeO2 catalyst, achieving a H2 yield of up to 66% at 400 °C. In addition, the Co/CeO2 catalyst demonstrated excellent stability performance in the whole examined temperature range of 400–800 °C. In contrast, a notable stability degradation, especially at low temperatures, was observed for Ni-, Cu-, and Fe-based catalysts, ascribed mainly to carbon deposition. An extensive characterization study, involving N2 adsorption-desorption (BET, X-ray diffraction (XRD, Scanning Electron Microscopy (SEM/EDS, X-ray Photoelectron Spectroscopy (XPS, and Temperature Programmed Reduction (H2-TPR was undertaken to gain insight into the structure-activity correlation. The excellent reforming performance of Co/CeO2 catalysts could be attributed to their intrinsic reactivity towards ethanol reforming in combination to their high surface oxygen concentration, which hinders the deposition of carbonaceous species.

  19. Structure-activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter.

    Science.gov (United States)

    Lykke, Kasper; Töllner, Kathrin; Römermann, Kerstin; Feit, Peter W; Erker, Thomas; MacAulay, Nanna; Löscher, Wolfgang

    2015-06-23

    The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na + , K + and Cl - ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of 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. 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. Bumetanide blocked hNKCC2A transport with an IC 50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r 2 = 0.817; P human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. © 2015 The British Pharmacological Society.

  20. Categorization by Groups

    NARCIS (Netherlands)

    R.W. Hamilton (Rebecca); S. Puntoni (Stefano); N.T. Tavassoli (Nader)

    2006-01-01

    textabstractCategorization is a core psychological process central to consumer and managerial decision-making. While a substantial amount of research has been conducted to examine individual categorization behaviors, relatively little is known about the group categorization process. In two

  1. Biases in categorization

    NARCIS (Netherlands)

    Das-Smaal, E.A.

    1990-01-01

    On what grounds can we conclude that an act of categorization is biased? In this chapter, it is contended that in the absence of objective norms of what categories actually are, biases in categorization can only be specified in relation to theoretical understandings of categorization. Therefore, the

  2. 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

  3. Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work.

    Science.gov (United States)

    Pang, Siu-Kwong

    2017-03-30

    Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

    Science.gov (United States)

    Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

    2018-03-01

    We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

  5. Structure-activity relationship of benzoxazinones and related compounds with respect to the growth inhibition and alpha-amylase activity in cress seedlings.

    Science.gov (United States)

    Kato-Noguchi, Hisashi; Macías, Francisco A; Molinillo, José M G

    2010-10-15

    Benzoxazinones and their degradation compounds inhibited root growth and alpha-amylase activity in cress seedlings. The inhibitory activity of these compounds was divided into three groups: the high active group; 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one, 4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, 4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one, the moderate active group; 7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, (2H)-1,4-benzoxazin-3(4H)-one, 6-methoxy-benzoxazolin-2(3H)-one, benzoxazolin-2(3H)-one and 2-amino-phenoxazine-3-one, and the low active group; 2-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one, 2-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, 2-amino-7-hydroxyphenoxazine-3-one and 2-amino-7-methoxyphenoxazine-3-one. The structure-activity of these compounds suggests that compounds that have benzoxazinone skeletons are the most active structure, and a hydroxyl group at position C-2 on the benzoxazinone skeleton may not affect inhibitory activity, whereas a hydroxyl group at position N-4 on the skeleton is essential for inhibitory activity. However, the concentration-response curves of these compounds and the I(50) values (the concentrations required for 50% inhibition) for root growth and alpha-amylase indicated that root growth was positively correlated with the alpha-amylase activity in the seedlings. alpha-Amylase is required not only for seed germination, but also subsequent seedling growth until photosynthesis is sufficient to support seedling growth. Therefore, these results suggest that the compounds studied here may inhibit the root growth of cress seedlings by inhibiting alpha-amylase activity. Copyright (c) 2010 Elsevier GmbH. All rights reserved.

  6. Quantitative structure-activity relationship of phenoxyphenyl-methanamine compounds with 5HT2A, SERT, and hERG activities.

    Science.gov (United States)

    Mente, Scot; Gallaschun, Randall; Schmidt, Anne; Lebel, Lorrie; Vanase-Frawley, Michelle; Fliri, Anton

    2008-12-01

    QSAR models have been used to evaluate activities for compounds in the phenoxyphenyl-methanamine (PPMA) class of compounds. These models utilize Hammett-type donating-withdrawing substituent values as well as simple parameters to describe substituent size and elucidate the SAR of the 'A' and 'B' rings. Using this methodology, intuitive QSAR relationships were found for the three biological activities with R(2) values of 0.73, 0.45, and 0.58 for 5HT(2A), SerT, and hERG activities.

  7. 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....

  8. White ash (Fraxinus americana) health in the Allegheny plateau region, Pennsylvania: Evaluating the relationship between FIA phase 3 crown variables and a categorical rating system

    Science.gov (United States)

    Alejandro A. Royo; Kathleen S. Knight; Jamie M. Himes; Ashley N. Will

    2012-01-01

    Following the detection of white ash (Fraxinus americana) decline in the Allegheny National Forest (ANF) of Pennsylvania, we established an intensified white ash monitoring network throughout the ANF. We rated crowns using both a categorical system as well as Forest Inventory and Analyses (FIA) Phase 3 measures of uncompacted live crown ratio,...

  9. Structure-activity relationship of imidazolidine derivatives related to clonidine at histamine H2-receptors in guinea-pig isolated atria

    Science.gov (United States)

    McCulloch, M.W.; Medgett, I.C.; Rand, M.J.; Story, D.F.

    1980-01-01

    1 Cumulative concentration-response relationships for the chronotropic effects of histamine, oxymetazoline, clonidine and thirteen clonidine-like imidazolidine derivatives were examined in isolated spontaneously beating guinea-pig atria. 2 The following compounds induced positive chronotropic effects: histamine, clonidine (2,6-dichloro-phenyliminoimidazolidine) and the 2,6-dibromo, 2,6-dimethyl, 2,6-diethyl, 2,6-dihydroxy, 2,4,6-trimethyl, 3,4-dihydroxy and 2-methyl-5-fluoro analogues of clonidine. These compounds appeared to act as partial agonists on histamine H2-receptors, with potencies ranging from one tenth to one hundredth and intrinsic activities from approximately 20% to 75% of those of histamine. 3 The following compounds did not induce positive chronotropic effects but rather decreased the atrial rate, usually at high concentrations: oxymetazoline and the 2,3-dichloro, 4-dichloro, 5-dichloro, 2-chloro-4-methyl, 2-methyl-5-chloro, 2,4,6-trichloro analogues of clonidine. 4 The effects of histamine were antagonized by cimetidine, the pA2 value being 6.68 (s.e. mean = 0.16, n = 3), and also in a concentration-dependent manner by clonidine. Cimetidine antagonized the response to clonidine in a concentration-dependent manner; however, high concentrations of cimetidine depressed the maximal response to clonidine and the slope of the concentration-response curve was no longer parallel to the control curve. 5 The effects of the other compounds which induced positive chronotropic effects were also antagonized by cimetidine (1 μmol/l); however, the effect of the 3,4-dihydroxy derivative was unaffected by cimetidine (1 μmol/l) but was abolished by propranolol (0.3 μmol/l). 6 In general, phenyliminoimidazolidine derivatives with 2,6-substitution on the phenyl ring are active on histamine H2-receptors, whereas derivatives with 2,3-, 2,4- or 2,5-substitutions are weakly active or inactive. Thus the restriction imposed on the free rotation of the phenyl ring about

  10. 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.

  11. Structure Activity Relationship of Heparin Mimicking Polymer p(SS-co-PEGMA): Effect of Sulfonation and Polymer Size on FGF2-Receptor Binding.

    Science.gov (United States)

    Paluck, Samantha J; Maynard, Heather D

    2017-08-20

    Fibroblast growth factor-2 (FGF2) is a heparin binding protein that plays a role in a range of biological functions such as wound healing and bone regeneration. Heparin, a highly sulfated glycosaminoglycan, is required for FGF2 to bind to its receptor. Therefore, polymeric mimics of heparin are widely studied for their ability to manipulate FGF2-induced biological interactions. It is known that altering the degree of sulfonated monomer incorporation and size of heparin-mimicking polymers can affect protein-receptor binding. To elucidate the relationship between degree of sulfonation and receptor binding for the heparin-mimicking polymer, poly(styrene sulfonate- co -poly(ethylene glycol) methyl ether methacrylate) (p(SS- co -PEGMA)) a library was synthesized to contain nine polymers with degrees of sulfonation ranging from 0-100%. Kinetics of the polymerization was evaluated and reactivity ratios compared to literature results. These polymers were then tested for their ability to enhance FGF2 binding with its receptor as both covalent conjugates and as excipients. In a receptor based enzyme-linked immunosorbant assay (ELISA), as well as a cell-based study, the polymer with 81% SS incorporation enhanced receptor binding compared to FGF2 alone, and to a greater extent than the other polymers. Therefore, another library of polymers was prepared maintaining the degree of sulfonation at 81% and changing the size from 41 to 390 monomer repeat units. The polymers were again tested in receptor based ELISA and cell studies, and all of the different sizes performed similarly, except for degree of polymerization 295 and 390, which had reduced response in the cellular assay. These results provide important information for the use of pSS- co -PEGMA as a potential heparin-mimicking therapeutic.

  12. Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program.

    Science.gov (United States)

    Zhang, Ting; Liu, Yong; Yang, Xianshu; Martin, Gary E; Yao, Huifang; Shang, Jackie; Bugianesi, Randal M; Ellsworth, Kenneth P; Sonatore, Lisa M; Nizner, Peter; Sherer, Edward C; Hill, Susan E; Knemeyer, Ian W; Geissler, Wayne M; Dandliker, Peter J; Helmy, Roy; Wood, Harold B

    2016-03-10

    A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated a number of metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities to the FIXa protein. Microgram quantities of the metabolites of interest were then isolated through microisolation analytical capabilities, and structurally characterized using MicroCryoProbe heteronuclear 2D NMR techniques. The isolated metabolites recovered from the NMR experiments were then submitted directly to an in vitro FIXa enzymatic assay. The order of the metabolites' binding affinity to the Factor IXa protein from the ALIS assay was completely consistent with the enzymatic assay results. This work showcases an innovative and efficient approach to uncover structure-activity relationships (SARs) and guide drug design via microisolation-structural characterization and ALIS capabilities.

  13. 1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

    Science.gov (United States)

    La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

    2008-07-10

    New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC

  14. Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

    Science.gov (United States)

    Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele

    2017-03-09

    Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

  15. Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A critical role played by the conjugated trienyl lactone moiety.

    Science.gov (United States)

    Qian, Shan; Shah, Aashay K; Head, Sarah A; Liu, Jun O; Jin, Zhendong

    2016-08-01

    Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, two new analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated trienyl lactone moiety of the molecule by replacing the C2-C3 double bond in ZJ-101 with a single bond and switching the geometry of the C4-C5 double bond in ZJ-101 from Z to E, respectively. Biological evaluation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of the molecule is critical for its anticancer activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. 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...

  17. Speech perception as categorization.

    Science.gov (United States)

    Holt, Lori L; Lotto, Andrew J

    2010-07-01

    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 resulted from these challenges. We focus here on issues and experiments that define open research questions relevant to phoneme categorization, arguing that SP is best understood as perceptual categorization, a position that places SP in direct contact with research from other areas of perception and cognition.

  18. Structure-activity relationship studies of argiotoxins

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Lucas, Simon; Bach, Tinna B

    2013-01-01

    receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors...... developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA...

  19. Structure-activity relationships of bumetanide derivatives

    DEFF Research Database (Denmark)

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

    2015-01-01

    , 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 and its...... derivatives in dogs and their inhibition of hNKCC2A (r(2) = 0.817; P ... of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics....

  20. Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

    Science.gov (United States)

    Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

    2016-08-01

    The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect. © 2016 Institute of Food Technologists®

  1. Quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines as potent Na/H exchange inhibitors.

    Science.gov (United States)

    Yamamoto, T; Hori, M; Watanabe, I; Harada, K; Ikeda, S; Ohtaka, H

    2000-06-01

    We have previously reported that N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-car bonyl)guanidine (4b) methanesulfonate salt (KB-R9032) is a potent and highly water-soluble Na/H exchange inhibitor. In a series of studies on Na/H exchange inhibitors, we designed and synthesized N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines (5) as more potent inhibitors with high water-solubility. The design strategy for 5 was based on a quantitative structure-activity relationship (QSAR) study, involving the proportional relationship between the biological activity and hydrophobicity of the ring structure of compounds 4. As expected, compounds 5 showed more potent activity than 4. It was found by using the QSAR analysis that 5 were about five-fold more potent than 4. The increase in potency of compounds 5 well agreed with our previous QSAR analysis result. The most potent derivative was the methanesulfonate salt 5d of the 4-isopropyl derivative (IC50=0.0091 microM). And in addition to the in vitro study, 5d showed significant protective activity against a rat acute myocardial infraction model.

  2. Categorization of radiation sources

    International Nuclear Information System (INIS)

    2000-12-01

    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

  3. Categorization of radiation sources

    International Nuclear Information System (INIS)

    Antonova, M.

    2000-01-01

    Through one-parameter (factor) analysis it is proved a hypothesis that the value of a radiation source (RS) activity of an application correlates with the category (the rank) given to it by the IAEA categorization although it is based on other parameters of the RS applications (practices like devices with radiation sources in industry, science, medicine and agriculture). The principles of the new IAEA categorization, taking into account the potential harm the sources may cause and the necessary regulatory control, are described. (author)

  4. A MEDLINE categorization algorithm

    Directory of Open Access Journals (Sweden)

    Gehanno Jean-Francois

    2006-02-01

    Full Text Available Abstract Background Categorization is designed to enhance resource description by organizing content description so as to enable the reader to grasp quickly and easily what are the main topics discussed in it. The objective of this work is to propose a categorization algorithm to classify a set of scientific articles indexed with the MeSH thesaurus, and in particular those of the MEDLINE bibliographic database. In a large bibliographic database such as MEDLINE, finding materials of particular interest to a specialty group, or relevant to a particular audience, can be difficult. The categorization refines the retrieval of indexed material. In the CISMeF terminology, metaterms can be considered as super-concepts. They were primarily conceived to improve recall in the CISMeF quality-controlled health gateway. Methods The MEDLINE categorization algorithm (MCA is based on semantic links existing between MeSH terms and metaterms on the one hand and between MeSH subheadings and metaterms on the other hand. These links are used to automatically infer a list of metaterms from any MeSH term/subheading indexing. Medical librarians manually select the semantic links. Results The MEDLINE categorization algorithm lists the medical specialties relevant to a MEDLINE file by decreasing order of their importance. The MEDLINE categorization algorithm is available on a Web site. It can run on any MEDLINE file in a batch mode. As an example, the top 3 medical specialties for the set of 60 articles published in BioMed Central Medical Informatics & Decision Making, which are currently indexed in MEDLINE are: information science, organization and administration and medical informatics. Conclusion We have presented a MEDLINE categorization algorithm in order to classify the medical specialties addressed in any MEDLINE file in the form of a ranked list of relevant specialties. The categorization method introduced in this paper is based on the manual indexing of resources

  5. A MEDLINE categorization algorithm

    Science.gov (United States)

    Darmoni, Stefan J; Névéol, Aurelie; Renard, Jean-Marie; Gehanno, Jean-Francois; Soualmia, Lina F; Dahamna, Badisse; Thirion, Benoit

    2006-01-01

    Background Categorization is designed to enhance resource description by organizing content description so as to enable the reader to grasp quickly and easily what are the main topics discussed in it. The objective of this work is to propose a categorization algorithm to classify a set of scientific articles indexed with the MeSH thesaurus, and in particular those of the MEDLINE bibliographic database. In a large bibliographic database such as MEDLINE, finding materials of particular interest to a specialty group, or relevant to a particular audience, can be difficult. The categorization refines the retrieval of indexed material. In the CISMeF terminology, metaterms can be considered as super-concepts. They were primarily conceived to improve recall in the CISMeF quality-controlled health gateway. Methods The MEDLINE categorization algorithm (MCA) is based on semantic links existing between MeSH terms and metaterms on the one hand and between MeSH subheadings and metaterms on the other hand. These links are used to automatically infer a list of metaterms from any MeSH term/subheading indexing. Medical librarians manually select the semantic links. Results The MEDLINE categorization algorithm lists the medical specialties relevant to a MEDLINE file by decreasing order of their importance. The MEDLINE categorization algorithm is available on a Web site. It can run on any MEDLINE file in a batch mode. As an example, the top 3 medical specialties for the set of 60 articles published in BioMed Central Medical Informatics & Decision Making, which are currently indexed in MEDLINE are: information science, organization and administration and medical informatics. Conclusion We have presented a MEDLINE categorization algorithm in order to classify the medical specialties addressed in any MEDLINE file in the form of a ranked list of relevant specialties. The categorization method introduced in this paper is based on the manual indexing of resources with MeSH (terms

  6. Synthesis and quantitative structure-activity relationships of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines as Na/H exchange inhibitors.

    Science.gov (United States)

    Yamamoto, T; Hori, M; Watanabe, I; Tsutsui, H; Harada, K; Ikeda, S; Maruo, J; Morita, T; Ohtaka, H

    1998-11-01

    N-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines 4 were prepared and tested for Na/H exchange inhibitory activities in order to clarify the structure-activity relationship (SAR). Quantitative SAR (QSAR) analysis of 6-carbonylguanidines 4 indicated that the length of the 4-substituent was parabolically related to activity and that the calculated optimum 4-substituents were propyl, ethyl and isopropyl groups. This SAR was similar to the SAR of the 2- and 4-substituents of 7-carbonylguanidine derivatives 3, although the position relative to the essential guanidinocarbonyl group was different. Larger 2-substituents, such as a phenyl group were unfavorable. The most potent derivative in this series was N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro- 2H-benzo[1,4]oxazine-6-carbonyl)guanidine 4 g, with an IC50 value of 0.12 microM. The methanesulfonate salt (KB-R9032) of 4g had excellent water-solubility and showed anti-arrhythmia activity against a rat acute myocardial infarction model. KB-R9032 was selected for further investigation as a therapy for ischemia-reperfusion induced injury.

  7. Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.

    Science.gov (United States)

    Istyastono, Enade P; Nijmeijer, Saskia; Lim, Herman D; van de Stolpe, Andrea; Roumen, Luc; Kooistra, Albert J; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

    2011-12-08

    The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

  8. Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities.

    Science.gov (United States)

    Srinivasan, Balasubramanian; Johnson, Thomas E; Lad, Rahul; Xing, Chengguo

    2009-11-26

    Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.

  9. 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

    2016-04-06

    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.

  10. Modeling human color categorization

    NARCIS (Netherlands)

    van den Broek, Egon; Schouten, Th.E.; Kisters, P.M.F.

    A unique color space segmentation method is introduced. It is founded on features of human cognition, where 11 color categories are used in processing color. In two experiments, human subjects were asked to categorize color stimuli into these 11 color categories, which resulted in markers for a

  11. Categorizing clients with disabilities

    DEFF Research Database (Denmark)

    Kjeldsen, Lena; Amby, Finn

    than that of people without disabilities for more than a decade (Larsen & Høgelund 2015). An explanation of this difference could be the limited connection between these general goals, the employment laws and the actual implementation of the goals in the job centers (Amby 2015). Earlier Danish studies...... have by large focused on employment and disability at the stage where the client already has been categorized as having a disability (e.g. Møller & Stone 2013). This study offers new insight to the field in a Danish context by exploring the process in which people with disabilities are categorized...... during their first interactions with the job center by asking two interconnected questions: a) To what extent do job centers construct categories that capture client with disabilities? b) How do caseworkers identify whether (and to what extent) the client has lasting impairments that can be considered...

  12. Interaction and observation, categorically

    Directory of Open Access Journals (Sweden)

    Vincenzo Ciancia

    2011-07-01

    Full Text Available This paper proposes to use dialgebras to specify the semantics of interactive systems in a natural way. Dialgebras are a conservative extension of coalgebras. In this categorical model, from the point of view that we provide, the notions of observation and interaction are separate features. This is useful, for example, in the specification of process equivalences, which are obtained as kernels of the homomorphisms of dialgebras. As an example we present the asynchronous semantics of the CCS.

  13. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

    Science.gov (United States)

    Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-07-20

    The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

  14. Anterior Temporal Lobe Morphometry Predicts Categorization Ability

    Directory of Open Access Journals (Sweden)

    Béatrice Garcin

    2018-02-01

    Full Text Available Categorization is the mental operation by which the brain classifies objects and events. It is classically assessed using semantic and non-semantic matching or sorting tasks. These tasks show a high variability in performance across healthy controls and the cerebral bases supporting this variability remain unknown. In this study we performed a voxel-based morphometry study to explore the relationships between semantic and shape categorization tasks and brain morphometric differences in 50 controls. We found significant correlation between categorization performance and the volume of the gray matter in the right anterior middle and inferior temporal gyri. Semantic categorization tasks were associated with more rostral temporal regions than shape categorization tasks. A significant relationship was also shown between white matter volume in the right temporal lobe and performance in the semantic tasks. Tractography revealed that this white matter region involved several projection and association fibers, including the arcuate fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, and inferior longitudinal fasciculus. These results suggest that categorization abilities are supported by the anterior portion of the right temporal lobe and its interaction with other areas.

  15. Discovery, characterization and structure-activity relationships of an inhibitor of inward rectifier potassium (Kir channels with preference for Kir2.3, Kir3.X and Kir7.1

    Directory of Open Access Journals (Sweden)

    Jerod S Denton

    2011-11-01

    Full Text Available The inward rectifier family of potassium (Kir channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that GIRK (G protein-regulated inward rectifier K channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+ flux-based high-throughput screen (HTS of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 M and 19 M, respectively and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK and Kir3.1/3.4 (cardiac GIRK channels with equal potency and preferentially inhibited GIRK, Kir2.3 and Kir7.1 over Kir1.1 and Kir2.1. Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure-activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure-function relationships of these Kir channels.

  16. New structure-activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR).

    Science.gov (United States)

    Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta

    2013-01-15

    As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure-activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis). The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I](0.5)) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a-d and 6d, showed excellent efficacy with a α(max) close to 1. Selected compounds (2d, 3a, 3b, 5a-d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells. The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site. In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,(29) are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Structure-activity relationships of acetylcholine derivatives with Lucilia cuprina nicotinic acetylcholine receptor α1 and α2 subunits in chicken β2 subunit hybrid receptors in comparison with chicken nicotinic acetylcholine receptor α4/β2.

    Science.gov (United States)

    Dederer, H; Berger, M; Meyer, T; Werr, M; Ilg, T

    2013-04-01

    Insect nicotinic acetylcholine (ACh) receptors (nAChRs) are the targets of several insecticide classes. In the present study, we report the gene identification and cloning of nAChR α1 and α2 subunits (Lcα1 and Lcα2) from the sheep blowfly Lucilia cuprina. Xenopus oocytes voltage clamp experiments as hybrids with the chicken β2 nAChR (Ggβ2) subunit resulted in ACh-gated ion channels with distinct dose-response curves for Lcα1/Ggβ2 (effective concentration 50% [EC50 ] = 80 nM; nH  = 1.05), and Lcα2/Ggβ2 (EC50  = 5.37 μM, nH  = 1.46). The neonicotinoid imidacloprid was a potent agonist for the α-bungarotoxin-sensitive Lcα1/Ggβ2 (EC50 ∼ 20 nM), while the α-bungarotoxin-resistant Lcα2/Ggβ2 showed a 30-fold lower sensitivity to this insecticide (EC50  = 0.62 μM). Thirteen close derivatives of ACh were analysed in EC50 , Hill coefficient and maximum current (relative to ACh) determinations for Lcα1/Ggβ2 and Lcα2/Ggβ2 and the chicken Ggα4/Ggβ2 nAChRs, and comparisons relative to ACh allowed the definition of novel structure-activity and structure-selectivity relationships. In the case of N-ethyl-acetylcholine, the EC50 of the chicken Ggα4/Ggβ2 rose by a factor of 1000, while for both Lcα1/Ggβ2 and Lcα2/Ggβ2, potency remained unchanged. Further derivatives with insect nAChR selectivity potential were acetyl-α-methylcholine and trimethyl-(3-methoxy-3-oxopropyl)ammonium, followed by acetylhomocholine and trimethyl-(4-oxopentyl) ammonium. Our results may provide guidance for the identification or design of insect-specific nAChR agonists using structure-based or in silico methods. © 2013 Royal Entomological Society.

  18. Advanced Structure-activity Relationships Applied to Mentha spicata L. Subsp. spicata Essential Oil Compounds as AChE and NMDA Ligands, in Comparison with Donepezil, Galantamine and Memantine - New Approach in Brain Disorders Pharmacology.

    Science.gov (United States)

    Avram, Speranta; Mernea, Maria; Bagci, Eyup; Hritcu, Lucian; Borcan, Livia-Cristina; Mihailescu, Dan Florin

    2017-01-01

    Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2). Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Categorical database generalization in GIS

    NARCIS (Netherlands)

    Liu, Y.

    2002-01-01

    Key words: Categorical database, categorical database generalization, Formal data structure, constraints, transformation unit, classification hierarchy, aggregation hierarchy, semantic similarity, data model,

  20. 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.

  1. 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

  2. Visual Analysis of Multi-Dimensional Categorical Data Sets

    NARCIS (Netherlands)

    Broeksema, Bertjan; Telea, Alexandru C.; Baudel, Thomas

    2013-01-01

    We present a set of interactive techniques for the visual analysis of multi-dimensional categorical data. Our approach is based on multiple correspondence analysis (MCA), which allows one to analyse relationships, patterns, trends and outliers among dependent categorical variables. We use MCA as a

  3. Working Memory Does Not Dissociate between Different Perceptual Categorization Tasks

    Science.gov (United States)

    Lewandowsky, Stephan; Yang, Lee-Xieng; Newell, Ben R.; Kalish, Michael L.

    2012-01-01

    Working memory is crucial for many higher level cognitive functions, ranging from mental arithmetic to reasoning and problem solving. Likewise, the ability to learn and categorize novel concepts forms an indispensable part of human cognition. However, very little is known about the relationship between working memory and categorization. This…

  4. Working Memory Capacity and Categorization: Individual Differences and Modeling

    Science.gov (United States)

    Lewandowsky, Stephan

    2011-01-01

    Working memory is crucial for many higher-level cognitive functions, ranging from mental arithmetic to reasoning and problem solving. Likewise, the ability to learn and categorize novel concepts forms an indispensable part of human cognition. However, very little is known about the relationship between working memory and categorization, and…

  5. 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…

  6. Motivation to control prejudice predicts categorization of multiracials.

    Science.gov (United States)

    Chen, Jacqueline M; Moons, Wesley G; Gaither, Sarah E; Hamilton, David L; Sherman, Jeffrey W

    2014-05-01

    Multiracial individuals often do not easily fit into existing racial categories. Perceivers may adopt a novel racial category to categorize multiracial targets, but their willingness to do so may depend on their motivations. We investigated whether perceivers' levels of internal motivation to control prejudice (IMS) and external motivation to control prejudice (EMS) predicted their likelihood of categorizing Black-White multiracial faces as Multiracial. Across four studies, IMS positively predicted perceivers' categorizations of multiracial faces as Multiracial. The association between IMS and Multiracial categorizations was strongest when faces were most racially ambiguous. Explicit prejudice, implicit prejudice, and interracial contact were ruled out as explanations for the relationship between IMS and Multiracial categorizations. EMS may be negatively associated with the use of the Multiracial category. Therefore, perceivers' motivations to control prejudice have important implications for racial categorization processes.

  7. 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

  8. Categorization of Mobile Advertising Campaigns

    OpenAIRE

    Pousttchi, Key; Wiedemann, Dietmar Georg

    2006-01-01

    The result of this contribution is a categorization and thus a description model for mobile advertising campaigns using the morphological method. For identification of the characteristics 32 case studies were analysed and relevant literature was sighted.

  9. Lectures on categorical data analysis

    CERN Document Server

    Rudas, Tamás

    2018-01-01

    This book offers a relatively self-contained presentation of the fundamental results in categorical data analysis, which plays a central role among the statistical techniques applied in the social, political and behavioral sciences, as well as in marketing and medical and biological research. The methods applied are mainly aimed at understanding the structure of associations among variables and the effects of other variables on these interactions. A great advantage of studying categorical data analysis is that many concepts in statistics become transparent when discussed in a categorical data context, and, in many places, the book takes this opportunity to comment on general principles and methods in statistics, addressing not only the “how” but also the “why.” Assuming minimal background in calculus, linear algebra, probability theory and statistics, the book is designed to be used in upper-undergraduate and graduate-level courses in the field and in more general statistical methodology courses, as w...

  10. 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...

  11. Atomic toposes and countable categoricity

    OpenAIRE

    Caramello, Olivia

    2008-01-01

    We give a model-theoretic characterization of the class of geometric theories classified by an atomic topos having enough points; in particular, we show that every complete geometric theory classified by an atomic topos is countably categorical. Some applications are also discussed.

  12. Evaluation and structure-activity relationship analysis of a new series of 4-imino-5H-pyrazolo[3,4-d]pyrimidin-5-amines as potential antibacterial agents

    Science.gov (United States)

    Beyzaei, Hamid; Aryan, Reza; Moghaddam-Manesh, Mohammadreza; Ghasemi, Behzad; Karimi, Pouya; Samareh Delarami, Hojat; Sanchooli, Mahmood

    2017-09-01

    The synthesis of pyrazolo[3,4-d]pyrimidine derivatives is important due to their presence in various biologically active compounds such as anticancer, antimicrobial, antiparasitic, anti-inflammatory and antidiabetic agents. In this project, a new and efficient approach for the synthesis of some novel 4-imino-5H-pyrazolo[3,4-d]pyrimidin-5-amines from reaction of 5-amino-pyrazole-4-carbonitrile with various hydrazides in ethanolic sodium ethoxide medium was reported. Antimicrobial activities of all synthesized derivatives were evaluated against eight Gram-positive and five Gram-negative pathogenic bacteria. The moderate to good inhibitory effects were observed based on inhibition zone diameter (IZD), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. In order to determine the reasonable relationship between antibacterial activities and physiochemical properties of the derivatives, computational studies were carried out in terms of geometry optimization, short-range van der Waals forces, dipole moments, atomic charges and frontier orbital energies. It was found that both short-range forces and covalent bonds are important in the observed inhibitory effects of the molecules. The results suggested that pyrazolo[3,4-d]pyrimidine derivatives prefer a soft nucleophilic attack on bio-macromolecular targets. Furthermore, our models proposed that the antibacterial activities of these derivatives can be improved by substituting large electron donating groups on the 6-phenyl rings.

  13. 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.

  14. Colour categorization by domestic chicks.

    OpenAIRE

    Jones, C. D.; Osorio, D.; Baddeley, R. J.

    2001-01-01

    Spectral stimuli form a physical continuum, which humans divide into discrete non-overlapping regions or categories that are designated by colour names. Little is known about whether non-verbal animals form categories on stimulus continua, but work in psychology and artificial intelligence provides models for stimulus generalization and categorization. We compare predictions of such models to the way poultry chicks (Gallus gallus) generalize to novel stimuli following appetitive training to e...

  15. Complementarity in Categorical Quantum Mechanics

    Science.gov (United States)

    Heunen, Chris

    2012-07-01

    We relate notions of complementarity in three layers of quantum mechanics: (i) von Neumann algebras, (ii) Hilbert spaces, and (iii) orthomodular lattices. Taking a more general categorical perspective of which the above are instances, we consider dagger monoidal kernel categories for (ii), so that (i) become (sub)endohomsets and (iii) become subobject lattices. By developing a `point-free' definition of copyability we link (i) commutative von Neumann subalgebras, (ii) classical structures, and (iii) Boolean subalgebras.

  16. Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors

    DEFF Research Database (Denmark)

    Larsen, Anja Probst; Francotte, Pierre; Frydenvang, Karla

    2016-01-01

    of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7-4.3 μM; concentration of compound responsible for a 2-fold increase...... the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1......, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency....

  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. Preliminary structure-activity relationship studies on some novel s ...

    African Journals Online (AJOL)

    alkyl halides in DMF medium, with NaH catalyst. Spectral characterization of each derivative was carried out with .... Different saturated/unsaturated alkyl halides (1 mmol) were added separately to the reaction mixture in the round ..... different aromatic acids [20]. New antimicrobial derivative of 1 3, 4-oxodiazole with 5 ...

  19. Structure-activity relationships of strychnine analogs at glycine receptors.

    Science.gov (United States)

    Mohsen, Amal M Y; Heller, Eberhard; Holzgrabe, Ulrike; Jensen, Anders A; Zlotos, Darius P

    2014-08-01

    Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21) = C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

  20. Quantitative structure-activity relationships of salicylamide neuroleptic agents.

    Science.gov (United States)

    Gupta, S P; Saha, R N; Singh, P

    1990-05-01

    The in vitro antidopamine activity of substituted N-[(1-alkyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides was found to be well correlated with the hydrophobic and electronic nature of substituents at the 3-position, and with the steric nature of groups replacing the hydrogen atom of the salicyl hydroxy group. In contrast, only the hydrophobic and steric characteristics were found to be important in the in vivo activity of these neuroleptics. This difference suggests that different mechanisms are probably involved in their in vitro and in vivo actions, and that the relevant receptors are slightly different in structure. The in vitro results suggest that electron donation by the 3-substituent strengthens the formation of a hydrogen bond between the carbonyl group of the amide moiety and a hydrogen of the receptor.

  1. 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.

  2. Structure-activity relationships of strychnine analogues at glycine receptors

    DEFF Research Database (Denmark)

    Mohsen, A.M.Y.; Heller, Eberhard; Holzgrabe, Ulrike

    2014-01-01

    Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best...... pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)[DOUBLE BOND]C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine...

  3. 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.

  4. Quantitative Structure-Activity Relationship Analysis of the ...

    African Journals Online (AJOL)

    Erah

    Methods: AM1 semiempirical quantum chemical calculation method was used to find the optimum 3D geometry of the studied molecules. Two types of molecular descriptors, including the 2D .... i and j respectively; w is the average value of property; L is the number of nonzero values in the sum, N is the number of atoms.

  5. Antispasmodic activity of xanthoxyline derivatives: structure-activity relationships.

    Science.gov (United States)

    Cechinel Filho, V; Miguel, O G; Nunes, R J; Calixto, J B; Yunes, R A

    1995-04-01

    The antispasmodic activity of several xanthoxyline derivatives against acetylcholine-induced contraction of the guinea pig ileum was evaluated in vitro. The acetophenones with two methoxyl groups, mainly in the 3,4 positions, exhibited potent antispasmodic activity. Modification of the hydroxyl group in xanthoxyline by the introduction of benzoyl, acetyl, or tosyl groups produced inactive compounds, whereas the introduction of benzyl or p-methoxybenzyl groups furnished compounds that were four- to eight-fold more potent than xanthoxyline. In marked contrast, the introduction of a methyl group gave a compound that caused contractant activity. Modification of the carbonyl group of xanthoxyline lead to inactive compounds, whereas the condensation of xanthoxyline with benzaldehydes gave chalkones that were about fivefold more potent than xanthoxyline. The introduction of benzyl and styrene groups, on the basis of the similarity with papaverine, improves the antispasmodic action of the xanthoxyline derivates. Our results suggest that the methoxyl and carbonyl groups are critical structural points for the antispasmodic activity of xanthoxyline derivatives. The hydroxyl group improves antispasmodic activity, but is not fundamental to its manifestation.

  6. 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

  7. Structure-activity relationships in carbohydrates revealed by their hydration.

    Science.gov (United States)

    Maugeri, Laura; Busch, Sebastian; McLain, Sylvia E; Pardo, Luis Carlos; Bruni, Fabio; Ricci, Maria Antonietta

    2017-06-01

    One of the more intriguing aspects of carbohydrate chemistry is that despite having very similar molecular structures, sugars have very different properties. For instance, there is a sensible difference in sweet taste between glucose and trehalose, even though trehalose is a disaccharide that comprised two glucose units, suggesting a different ability of these two carbohydrates to bind to sweet receptors. Here we have looked at the hydration of specific sites and at the three-dimensional configuration of water molecules around three carbohydrates (glucose, cellobiose, and trehalose), combining neutron diffraction data with computer modelling. Results indicate that identical chemical groups can have radically different hydration patterns depending on their location on a given molecule. These differences can be linked with the specific activity of glucose, cellobiose, and trehalose as a sweet substance, as building block of cellulose fiber, and as a bioprotective agent, respectively. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Developments in Quantitative Structure-Activity Relationships (QSAR). A Review

    Science.gov (United States)

    1976-07-01

    AspergiL us niger, phenyl methacrylates upon Ranse-nula awmat~a and RR’NCSS Na+ upon Botrytis cinerea conformed to the general equation 35. The equations...8217 i - •.. i i r ’: I I ----- ’ 1--- 114 isolated enzyme does not ensure high activity in in vivo tests (see page 84). Competing processes such as...log II vs log kw *79 Botrytis cinerea , 41, 64 -lg! slgý,7 Bovine hemoglobin, 36 lg Elv o .,7 Bovine serum albumin, 36 - log iI vs log P, 79 - log JE

  9. 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.

  10. Comparison and Contrast in Perceptual Categorization

    Science.gov (United States)

    Hampton, James A.; Estes, Zachary; Simmons, Claire L.

    2005-01-01

    People categorized pairs of perceptual stimuli that varied in both category membership and pairwise similarity. Experiments 1 and 2 showed categorization of 1 color of a pair to be reliably contrasted from that of the other. This similarity-based contrast effect occurred only when the context stimulus was relevant for the categorization of the…

  11. Categorical perception of animal patterns.

    Science.gov (United States)

    Goldstein, Julie; Davidoff, Jules

    2008-05-01

    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 type of visual stimulus not previously used to assess the effect of labels on perceptual judgments. For the animal patterns, the Whorfian view predicted that it would only be the Himba who showed superiority for cross-category decisions as only they have the appropriate labels. The Whorfian view was upheld and confirmed previous findings that linked perceptual differences to labelling differences.

  12. Categorical Perception of Sound Frequency by Crickets

    Science.gov (United States)

    Wyttenbach, Robert A.; May, Michael L.; Hoy, Ronald R.

    1996-09-01

    Partitioning continuously varying stimuli into categories is a fundamental problem of perception. One solution to this problem, categorical perception, is known primarily from human speech, but also occurs in other modalities and in some mammals and birds. Categorical perception was tested in crickets by using two paradigms of human psychophysics, labeling and habituation-dishabituation. The results show that crickets divide sound frequency categorically between attractive (16 kilohertz) sounds. There is sharp discrimination between these categories but no discrimination between different frequencies of ultrasound. This demonstration of categorical perception in an invertebrate suggests that categorical perception may be a basic and widespread feature of sensory systems, from humans to invertebrates.

  13. Detecting and categorizing fleeting emotions in faces.

    Science.gov (United States)

    Sweeny, Timothy D; Suzuki, Satoru; Grabowecky, Marcia; Paller, Ken A

    2013-02-01

    Expressions of emotion are often brief, providing only fleeting images from which to base important social judgments. We sought to characterize the sensitivity and mechanisms of emotion detection and expression categorization when exposure to faces is very brief, and to determine whether these processes dissociate. Observers viewed 2 backward-masked facial expressions in quick succession, 1 neutral and the other emotional (happy, fearful, or angry), in a 2-interval forced-choice task. On each trial, observers attempted to detect the emotional expression (emotion detection) and to classify the expression (expression categorization). Above-chance emotion detection was possible with extremely brief exposures of 10 ms and was most accurate for happy expressions. We compared categorization among expressions using a d' analysis, and found that categorization was usually above chance for angry versus happy and fearful versus happy, but consistently poor for fearful versus angry expressions. Fearful versus angry categorization was poor even when only negative emotions (fearful, angry, or disgusted) were used, suggesting that this categorization is poor independent of decision context. Inverting faces impaired angry versus happy categorization, but not emotion detection, suggesting that information from facial features is used differently for emotion detection and expression categorizations. Emotion detection often occurred without expression categorization, and expression categorization sometimes occurred without emotion detection. These results are consistent with the notion that emotion detection and expression categorization involve separate mechanisms. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  14. 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure-activity relationship profile.

    Science.gov (United States)

    Nawrozkij, Maxim B; Rotili, Dante; Tarantino, Domenico; Botta, Giorgia; Eremiychuk, Alexandre S; Musmuca, Ira; Ragno, Rino; Samuele, Alberta; Zanoli, Samantha; Armand-Ugón, Mercedes; Clotet-Codina, Imma; Novakov, Ivan A; Orlinson, Boris S; Maga, Giovanni; Esté, José A; Artico, Marino; Mai, Antonello

    2008-08-14

    A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl- S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L100I mutated RTs) assays, compounds carrying an ethyl/ iso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.

  15. The Timing of Visual Object Categorization

    OpenAIRE

    Mack, Michael L.; Palmeri, Thomas J.

    2011-01-01

    An object can be categorized at different levels of abstraction: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing imp...

  16. The timing of visual object categorization

    Directory of Open Access Journals (Sweden)

    Michael L. Mack

    2011-07-01

    Full Text Available An object can be categorized at different levels of abstraction: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing implies a relative timing of stages of visual processing that are tied to particular levels of object categorization: Fast categorizations are fast because they precede other categorizations within the visual processing hierarchy. By another account, the relative timing reflects when perceptual features are available over time and the quality of perceptual evidence used to drive a perceptual decision process: Fast simply means fast, it does not mean first. Understanding the short-term and long-term temporal dynamics of object categorizations is key to developing computational models of visual object recognition. We briefly review a number of models of object categorization and outline how they explain the timing of visual object categorization at different levels of abstraction.

  17. The timing of visual object categorization.

    Science.gov (United States)

    Mack, Michael L; Palmeri, Thomas J

    2011-01-01

    AN OBJECT CAN BE CATEGORIZED AT DIFFERENT LEVELS OF ABSTRACTION: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing implies a relative timing of stages of visual processing that are tied to particular levels of object categorization: Fast categorizations are fast because they precede other categorizations within the visual processing hierarchy. By another account, the relative timing reflects when perceptual features are available over time and the quality of perceptual evidence used to drive a perceptual decision process: Fast simply means fast, it does not mean first. Understanding the short-term and long-term temporal dynamics of object categorizations is key to developing computational models of visual object recognition. We briefly review a number of models of object categorization and outline how they explain the timing of visual object categorization at different levels of abstraction.

  18. Hierarchical document categorization using associative networks

    NARCIS (Netherlands)

    Bloom, Niels; Theune, Mariet; de Jong, Franciska M.G.; Klement, E.P.; Borutzky, W.; Fahringer, T.; Hamza, M.H.; Uskov, V.

    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

  19. An Intelligent System For Arabic Text Categorization

    NARCIS (Netherlands)

    Syiam, M.M.; Tolba, Mohamed F.; Fayed, Z.T.; Abdel-Wahab, Mohamed S.; Ghoniemy, Said A.; Habib, Mena Badieh

    Text Categorization (classification) is the process of classifying documents into a predefined set of categories based on their content. In this paper, an intelligent Arabic text categorization system is presented. Machine learning algorithms are used in this system. Many algorithms for stemming and

  20. Accelerating Visual Categorization with the GPU

    NARCIS (Netherlands)

    van de Sande, K.E.A.; Gevers, T.; Snoek, C.G.M.

    2012-01-01

    Visual categorization is important to manage large collections of digital images and video, where textual meta-data is often incomplete or simply unavailable. The bag-of-words model has become the most powerful method for visual categorization of images and video. Despite its high accuracy, a severe

  1. 7 CFR 520.5 - Categorical exclusions.

    Science.gov (United States)

    2010-01-01

    ... OF AGRICULTURE PROCEDURES FOR IMPLEMENTING NATIONAL ENVIRONMENTAL POLICY ACT § 520.5 Categorical...) Department of Agriculture categorical exclusions (7 CFR 1b.3). (1) Policy development, planning and... involve the use of control agents requiring containment or a special license or a permit from a regulatory...

  2. On \\omega-categorical simple theories

    OpenAIRE

    Palacin, Daniel

    2011-01-01

    In the present paper we shall prove that countable \\omega-categorical simple CM-trivial theories and countable \\omega-categorical simple theories with strong stable forking are low. In addition, we observe that simple theories of bounded finite weight are low.

  3. Three-dimensional quantitative structure-activity relationship of angiotesin-converting enzyme and thermolysin inhibitors. II. A comparison of CoMFA models incorporating molecular orbital fields and desolvation free energies based on active-analog and complementary-receptor-field alignment rules.

    Science.gov (United States)

    Waller, C L; Marshall, G R

    1993-08-06

    The utility of comparative molecular field analysis (CoMFA), a three-dimensional Quantitative Structure-Activity Relationship (3-D QSAR) paradigm, as a tool to aid in the development of predictive models has been previously addressed (Depriest, S.D. et al., J. Am. Chem. Soc. 1993, in press). Although predictive correlations were obtained for angiotensin-converting and thermolysin inhibitors, certain inadequacies of the CoMFA technique were noted. Primarily, CoMFA steric and electrostatic fields alone do not fully characterize the zinc-ligand interaction. Previously, this was partially rectified by the inclusion of indicator variables into the QSAR table to designate the class of zinc-binding ligand. Recent advances in molecular modeling technology have allowed us to further address this limitation of the preceding study. Using molecular orbital fields derived from semiempirical calculations as additional descriptors in the QSAR table, predictive correlations were produced based on CoMFA and molecular orbital fields alone--indicator variables no longer being necessary. Arbitrary information concerning the alignment of molecules under study within the active-site introduces ambiguities into the CoMFA study. Crystallographic information detailing the binding mode of several thermolysin enzyme inhibitors has previously been used as a guide for the alignment of additional, noncrystallized, inhibitors. However, this process was complicated by the lack of parameters for zinc in the molecular mechanical force field. Therefore, zinc-ligand interactions were ignored during the standard minimization procedure. The use of field-fit minimization using complementary receptor fields as templates is presented as a possible solution to the problem. Predictive correlations were obtained from analyses based on this method of molecular alignment. The availability of crystallographic data for thermolysin enzyme-inhibitor complexes allowed for an alternate definition of the CoMFA region

  4. Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants.

    Science.gov (United States)

    Yang, Jiao; Chen, Kai; Zhang, Guo; Yang, Qiu-Yuan; Li, Yue-Shan; Huang, Shen-Zhen; Wang, Yan-Lin; Yang, Wei; Jiang, Xiao-Juan; Yan, Heng-Xiu; Zhu, Jing-Qiang; Xiang, Rong; Luo, You-Fu; Li, Wei-Min; Wei, Yu-Quan; Li, Lin-Li; Yang, Sheng-Yong

    2018-01-01

    The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC 50 (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure--Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1).

    Science.gov (United States)

    Pulla, Venkat Koushik; Sriram, Dinavahi Saketh; Viswanadha, Srikant; Sriram, Dharmarajan; Yogeeswari, Perumal

    2016-01-25

    Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation.

  6. Space Structure and Clustering of Categorical Data.

    Science.gov (United States)

    Qian, Yuhua; Li, Feijiang; Liang, Jiye; Liu, Bing; Dang, Chuangyin

    2016-10-01

    Learning from categorical data plays a fundamental role in such areas as pattern recognition, machine learning, data mining, and knowledge discovery. To effectively discover the group structure inherent in a set of categorical objects, many categorical clustering algorithms have been developed in the literature, among which k -modes-type algorithms are very representative because of their good performance. Nevertheless, there is still much room for improving their clustering performance in comparison with the clustering algorithms for the numeric data. This may arise from the fact that the categorical data lack a clear space structure as that of the numeric data. To address this issue, we propose, in this paper, a novel data-representation scheme for the categorical data, which maps a set of categorical objects into a Euclidean space. Based on the data-representation scheme, a general framework for space structure based categorical clustering algorithms (SBC) is designed. This framework together with the applications of two kinds of dissimilarities leads two versions of the SBC-type algorithms. To verify the performance of the SBC-type algorithms, we employ as references four representative algorithms of the k -modes-type algorithms. Experiments show that the proposed SBC-type algorithms significantly outperform the k -modes-type algorithms.

  7. 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

  8. EFFECTS OF TALKER GENDER ON DIALECT CATEGORIZATION.

    Science.gov (United States)

    Clopper, Cynthia G; Conrey, Brianna; Pisoni, David B

    2005-06-01

    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.

  9. 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

  10. Statistical methods for categorical data analysis

    CERN Document Server

    Powers, Daniel

    2008-01-01

    This book provides a comprehensive introduction to methods and models for categorical data analysis and their applications in social science research. Companion website also available, at https://webspace.utexas.edu/dpowers/www/

  11. 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.

  12. Causal structure in categorical quantum mechanics

    Science.gov (United States)

    Lal, Raymond Ashwin

    Categorical quantum mechanics is a way of formalising the structural features of quantum theory using category theory. It uses compound systems as the primitive notion, which is formalised by using symmetric monoidal categories. This leads to an elegant formalism for describing quantum protocols such as quantum teleportation. In particular, categorical quantum mechanics provides a graphical calculus that exposes the information flow of such protocols in an intuitive way. However, the graphical calculus also reveals surprising features of these protocols; for example, in the quantum teleportation protocol, information appears to flow `backwards-in-time'. This leads to question of how causal structure can be described within categorical quantum mechanics, and how this might lead to insight regarding the structural compatibility between quantum theory and relativity. This thesis is concerned with the project of formalising causal structure in categorical quantum mechanics. We begin by studying an abstract view of Bell-type experiments, as described by `no-signalling boxes', and we show that under time-reversal no-signalling boxes generically become signalling. This conflicts with the underlying symmetry of relativistic causal structure. This leads us to consider the framework of categorical quantum mechanics from the perspective of relativistic causal structure. We derive the properties that a symmetric monoidal category must satisfy in order to describe systems in such a background causal structure. We use these properties to define a new type of category, and this provides a formal framework for describing protocols in spacetime. We explore this new structure, showing how it leads to an understanding of the counter-intuitive information flow of protocols in categorical quantum mechanics. We then find that the formal properties of our new structure are naturally related to axioms for reconstructing quantum theory, and we show how a reconstruction scheme based on

  13. 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.

  14. Visual Categorization and the Parietal Cortex

    Directory of Open Access Journals (Sweden)

    Jamie K Fitzgerald

    2012-05-01

    Full Text Available The primate brain is adept at rapidly grouping items and events into functional classes, or categories, in order to recognize the significance of stimuli and guide behavior. Higher cognitive functions have traditionally been considered the domain of frontal areas. However, increasing evidence suggests that parietal cortex is also involved in categorical and associative processes. Previous work showed that the parietal cortex is highly involved in spatial processing, attention and saccadic eye movement planning, and more recent studies have found decision-making signals in LIP. We recently found that a subdivision of parietal cortex, the lateral intraparietal area (LIP, reflects learned categories for multiple types of visual stimuli. Additionally, a comparison of categorization signals in parietal and frontal areas found stronger and earlier categorization signals in parietal cortex, arguing that parietal abstract association or category signals are unlikely to arise via feedback from prefrontal cortex (PFC.

  15. Comparing Categorical and Probabilistic Fingerprint Evidence.

    Science.gov (United States)

    Garrett, Brandon; Mitchell, Gregory; Scurich, Nicholas

    2018-04-23

    Fingerprint examiners traditionally express conclusions in categorical terms, opining that impressions do or do not originate from the same source. Recently, probabilistic conclusions have been proposed, with examiners estimating the probability of a match between recovered and known prints. This study presented a nationally representative sample of jury-eligible adults with a hypothetical robbery case in which an examiner opined on the likelihood that a defendant's fingerprints matched latent fingerprints in categorical or probabilistic terms. We studied model language developed by the U.S. Defense Forensic Science Center to summarize results of statistical analysis of the similarity between prints. Participant ratings of the likelihood the defendant left prints at the crime scene and committed the crime were similar when exposed to categorical and strong probabilistic match evidence. Participants reduced these likelihoods when exposed to the weaker probabilistic evidence, but did not otherwise discriminate among the prints assigned different match probabilities. © 2018 American Academy of Forensic Sciences.

  16. Marine Corps IT Hardware: A Method for Categorizing and Determining Technology Refreshment Cycles

    Science.gov (United States)

    2015-06-01

    the necessary data. A. CATEGORIZING ASSETS In an article concerning IT and the classification of assets, Rajakrom, Chandarasupsang, Harnpornchai and...category will illuminate a relationship of the subjects and objects of knowledge. In the article , he describes two models by which to categorize assets...assets in the inventory, it was necessary to choose between procurement cost or depreciated value of the assets. Although the ITIL recommends both

  17. 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.

  18. Local Alignments for Fine-Grained Categorization

    NARCIS (Netherlands)

    Gavves, E.; Fernando, B.; Snoek, C.G.M.; Smeulders, A.W.M.; Tuytelaars, T.

    2015-01-01

    The aim of this paper is fine-grained categorization without human interaction. Different from prior work, which relies on detectors for specific object parts, we propose to localize distinctive details by roughly aligning the objects using just the overall shape. Then, one may proceed to the

  19. A quick survey of text categorization algorithms

    Directory of Open Access Journals (Sweden)

    Dan MUNTEANU

    2007-12-01

    Full Text Available This paper contains an overview of basic formulations and approaches to text classification. This paper surveys the algorithms used in text categorization: handcrafted rules, decision trees, decision rules, on-line learning, linear classifier, Rocchio’s algorithm, k Nearest Neighbor (kNN, Support Vector Machines (SVM.

  20. 36 CFR 907.10 - Categorical exclusion.

    Science.gov (United States)

    2010-07-01

    ... human environment. Therefore, neither an environmental assessment nor an environmental impact statement... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Categorical exclusion. 907.10 Section 907.10 Parks, Forests, and Public Property PENNSYLVANIA AVENUE DEVELOPMENT CORPORATION...

  1. 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.

  2. Multivariate sensitivity to voice during auditory categorization.

    Science.gov (United States)

    Lee, Yune Sang; Peelle, Jonathan E; Kraemer, David; Lloyd, Samuel; Granger, Richard

    2015-09-01

    Past neuroimaging studies have documented discrete regions of human temporal cortex that are more strongly activated by conspecific voice sounds than by nonvoice sounds. However, the mechanisms underlying this voice sensitivity remain unclear. In the present functional MRI study, we took a novel approach to examining voice sensitivity, in which we applied a signal detection paradigm to the assessment of multivariate pattern classification among several living and nonliving categories of auditory stimuli. Within this framework, voice sensitivity can be interpreted as a distinct neural representation of brain activity that correctly distinguishes human vocalizations from other auditory object categories. Across a series of auditory categorization tests, we found that bilateral superior and middle temporal cortex consistently exhibited robust sensitivity to human vocal sounds. Although the strongest categorization was in distinguishing human voice from other categories, subsets of these regions were also able to distinguish reliably between nonhuman categories, suggesting a general role in auditory object categorization. Our findings complement the current evidence of cortical sensitivity to human vocal sounds by revealing that the greatest sensitivity during categorization tasks is devoted to distinguishing voice from nonvoice categories within human temporal cortex. Copyright © 2015 the American Physiological Society.

  3. The Education of the Categorical Imperative

    Science.gov (United States)

    Johnston, James Scott

    2006-01-01

    In this article, I examine anew the moral philosophy of Immanuel Kant and its contributions to educational theory. I make four claims. First, that Kant should be read as having the Categorical Imperative develop out of subjective maxims. Second, that moral self-perfection is the aim of moral education. Third, that moral self-perfection develops by…

  4. Bootstrapping Visual Categorization with Relevant Negatives

    NARCIS (Netherlands)

    Li, X.; Snoek, C.G.M.; Worring, M.; Koelma, D.; Smeulders, A.W.M.

    Learning classifiers for many visual concepts are important for image categorization and retrieval. As a classifier tends to misclassify negative examples which are visually similar to positive ones, inclusion of such misclassified and thus relevant negatives should be stressed during learning.

  5. Quantifier Scope in Categorical Compositional Distributional Semantics

    Directory of Open Access Journals (Sweden)

    Mehrnoosh Sadrzadeh

    2016-08-01

    Full Text Available In previous work with J. Hedges, we formalised a generalised quantifiers theory of natural language in categorical compositional distributional semantics with the help of bialgebras. In this paper, we show how quantifier scope ambiguity can be represented in that setting and how this representation can be generalised to branching quantifiers.

  6. Categorical Perception in American Sign Language.

    Science.gov (United States)

    Emmorey, Karen; McCullough, Stephen; Brentari, Diane

    2003-01-01

    Two experiments examined whether Deaf signers or hearing nonsigners exhibit categorical perception (CP) for hand configuration or for place of articulation in American Sign Language. Findings that signers and nonsigners performed similarly suggests that these categories in American Sign Language have a perceptual as well as a linguistic basis.…

  7. Information criterion for the categorization quality evaluation

    Directory of Open Access Journals (Sweden)

    Michail V. Svirkin

    2011-05-01

    Full Text Available The paper considers the possibility of using the variation of information function as a quality criterion for categorizing a collection of documents. The performance of the variation of information function is being examined subject to the number of categories and the sample volume of the test document collection.

  8. Nonparametric Bayes Modeling of Multivariate Categorical Data.

    Science.gov (United States)

    Dunson, David B; Xing, Chuanhua

    2012-01-01

    Modeling of multivariate unordered categorical (nominal) data is a challenging problem, particularly in high dimensions and cases in which one wishes to avoid strong assumptions about the dependence structure. Commonly used approaches rely on the incorporation of latent Gaussian random variables or parametric latent class models. The goal of this article is to develop a nonparametric Bayes approach, which defines a prior with full support on the space of distributions for multiple unordered categorical variables. This support condition ensures that we are not restricting the dependence structure a priori. We show this can be accomplished through a Dirichlet process mixture of product multinomial distributions, which is also a convenient form for posterior computation. Methods for nonparametric testing of violations of independence are proposed, and the methods are applied to model positional dependence within transcription factor binding motifs.

  9. Hierarchical Rhetorical Sentence Categorization for Scientific Papers

    Science.gov (United States)

    Rachman, G. H.; Khodra, M. L.; Widyantoro, D. H.

    2018-03-01

    Important information in scientific papers can be composed of rhetorical sentences that is structured from certain categories. To get this information, text categorization should be conducted. Actually, some works in this task have been completed by employing word frequency, semantic similarity words, hierarchical classification, and the others. Therefore, this paper aims to present the rhetorical sentence categorization from scientific paper by employing TF-IDF and Word2Vec to capture word frequency and semantic similarity words and employing hierarchical classification. Every experiment is tested in two classifiers, namely Naïve Bayes and SVM Linear. This paper shows that hierarchical classifier is better than flat classifier employing either TF-IDF or Word2Vec, although it increases only almost 2% from 27.82% when using flat classifier until 29.61% when using hierarchical classifier. It shows also different learning model for child-category can be built by hierarchical classifier.

  10. Categorization of radioactive sources. Safety guide

    International Nuclear Information System (INIS)

    2005-01-01

    Radioactive sources are used throughout the world in medicine, industry, agriculture, research and education; they are also used in some military applications. Many are in the form of sealed sources with the radioactive materials firmly contained or bound within a suitable capsule or housing. The risks posed by these sources vary widely, depending on such factors as the radionuclides used, the physical and chemical form and the activity. Sealed sources, unless they have been breached or are leaking, present a risk of external radiation exposure only. However, breached or leaking sealed sources, as well as unsealed radioactive materials, may give rise to contamination of the environment and the intake of radioactive materials into the human body. Until the 1950s, only radionuclides of natural origin, particularly 226 Ra, were generally available for use. Since then, radionuclides produced artificially in nuclear facilities and accelerators, including 60 Co, 90 Sr, 137 Cs and 192 Ir, have become widely used. The International Basic Safety Standards for Protection against Ionizing Radiation and for the Safety of Radiation Sources (BSS) provide an internationally harmonized basis for ensuring the safe and secure use of sources of ionizing radiation, and the Safety Requirements for Legal and Governmental Infrastructure for Nuclear, Radiation, Radioactive Waste and Transport Safety set out the essential elements of a regulatory control system. Sealed and unsealed radioactive sources are used for a variety of purposes and they incorporate a wide range of radionuclides and amounts of radioactive material. High activity sources, if not managed safely and securely, can cause severe deterministic effects to individuals in a short period of time, whereas low activity sources are unlikely to cause exposures with harmful consequences. his Safety Guide provides a risk based ranking of radioactive sources and practices in five categories. The categorization system is based on a

  11. 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)

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

    OpenAIRE

    Silva, Wender A.; Andrade, Carlos Kleber Z.; Napolitano, Hamilton B.; Vencato, Ivo; Lariucci, Carlito; Castro, Miriam. R. C. de; Camargo, Ademir J.

    2013-01-01

    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. ...

  13. Stochastic text models for music categorization

    OpenAIRE

    Pérez Sancho, Carlos; Rizo Valero, David; Iñesta Quereda, José Manuel

    2008-01-01

    Music genre meta-data is of paramount importance for the organization of music repositories. People use genre in a natural way when entering a music store or looking into music collections. Automatic genre classification has become a popular topic in music information retrieval research. This work brings to symbolic music recognition some technologies, like the stochastic language models, already successfully applied to text categorization. In this work we model chord progressions and melodie...

  14. EFFECTS OF TALKER GENDER ON DIALECT CATEGORIZATION

    OpenAIRE

    CLOPPER, CYNTHIA G.; CONREY, BRIANNA; PISONI, DAVID B.

    2005-01-01

    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 co...

  15. Auditory intensity processing: Categorization versus comparison.

    Science.gov (United States)

    Angenstein, Nicole; Brechmann, André

    2015-10-01

    Intensity is an important parameter for the perception of complex auditory stimuli like speech. The results of previous studies on the processing of intensity are diverse since left-lateralized, right-lateralized and non-lateralized processing was suggested. A clear dependence of the lateralization on the kind of stimuli and/or task is not apparent. With the present functional magnetic resonance imaging (fMRI) study, we directly investigated the differences between a categorical and comparative task. To determine hemispheric involvement we used a method with contralateral noise presentation. Harmonic complexes were presented monaurally without and with contralateral noise. Both categorization and comparison of harmonic complexes according to their intensity more strongly involved the left than the right auditory cortex shown by a stronger effect of the additional noise on the activity in the left auditory cortex. Together with previous results, this suggests that left-lateralized processing of intensity in the auditory cortex can be observed independent of task and stimuli. The comparison task more strongly engaged the left auditory cortex than the categorization task probably due the additional need for sequential comparison and the right auditory cortex probably due to capacity reasons. Comparison also more strongly engaged areas associated with attentional processes and areas responsible for motor response selection. We suggest this to be caused by a more difficult response selection and by the need for continuous update of information in reference memory during the comparison task. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Licensing criteria for particle accelerators categorization

    Energy Technology Data Exchange (ETDEWEB)

    Costa, Evaldo L.C. da, E-mail: evaldo@cnen.gov.br [Comissao Nacional de Energia Nuclear (CNEN-RJ), Rio de Janeiro, RJ (Brazil). Dir. de Radioprotecao e Seguranca; Melo, Paulo F.F. Frutuoso e, E-mail: frutuoso@nuclear.ufrj.br [Coordenacao dos Programas de Pos-Graduacao em Engenharia (COPPE/UFRJ), Rio de Janeiro, RJ (Brazil)

    2013-07-01

    From the international experience of research centers in various parts of the world, where there are particle accelerators of various sizes and energies, it was found that operating energy of particle accelerators is one of the parameters used by categorization models in the licensing of these radiation facilities, and the facility size is an important aspect to be considered in this model. A categorization based on these two key parameters is presented, also taking into account the kinds of accelerated particles and radiation produced, the operating related technology and the possible applications concerned. The categorization models of national nuclear authorities of five countries are reviewed, emphasizing the contribution of Brazil, and the new model proposed is also based on the experience of these countries, modified by those two parameter discussed above: facility size and operating energy of particle accelerators. Later, some changes are suggested, considering risk factors and safety features related to these facilities, emphasizing some analytical tools commonly used in nuclear facilities and chemical plants, such as: risk-informing decision making, layer of protection analysis (LOPRA) and safety integrity levels (SIL), the two latter ones having its origin in the broader concept of system safety. We also discuss the problem of scarcity of reliability data (common in the analyses involving risk factors and safety), due to security concerns and other factors, being the possible alternative solutions the use of generic databases and the adoption of reference facilities that provide partial data publicly. (author).

  17. Quantitative structure-activity relationships in fish toxicity studies. Part 1: relationship for 50 industrial pollutants

    Energy Technology Data Exchange (ETDEWEB)

    Koenemann, H.

    1981-01-01

    LC50-experiments have been conducted using guppies subjected to 72 industrial pollutants. The correlation of the LC50 with several expressions of the hydrophobicity of these chemicals has been studied. Calculated log Poct-values appeared to satisfy more than HPLC retention indices, solubility data or molecular connectivity indices. One QSAR, with log Poct as the only variable, gave good estimations of the toxicity of most of the tested compounds with log Poct less than 6. No LC50 could be determined for solutions of compounds with log Poct greater than 6.

  18. A complete categorization of multiscale models of infectious disease systems.

    Science.gov (United States)

    Garira, Winston

    2017-12-01

    Modelling of infectious disease systems has entered a new era in which disease modellers are increasingly turning to multiscale modelling to extend traditional modelling frameworks into new application areas and to achieve higher levels of detail and accuracy in characterizing infectious disease systems. In this paper we present a categorization framework for categorizing multiscale models of infectious disease systems. The categorization framework consists of five integration frameworks and five criteria. We use the categorization framework to give a complete categorization of host-level immuno-epidemiological models (HL-IEMs). This categorization framework is also shown to be applicable in categorizing other types of multiscale models of infectious diseases beyond HL-IEMs through modifying the initial categorization framework presented in this study. Categorization of multiscale models of infectious disease systems in this way is useful in bringing some order to the discussion on the structure of these multiscale models.

  19. What is a Planet?-Categorizing Objects

    Science.gov (United States)

    Lebofsky, Larry A.

    2009-05-01

    Observing, communicating, comparing, organizing, relating, and inferring are fundamental to scientific thinking processes. Teaching this way, rather than just teaching "the facts,” is also important for developing the critical thinking skills of our future generations of a scientifically literate society. Since the IAU started its discussions on a definition of a planet in 2005, I have been presenting a hands-on activity called "What is a Planet?” at the annual meeting of the DPS. This activity has been designed for short (20 minute) to long (two hour) presentations depending on the venue and the audience. This has been presented to elementary-grade students, middle school students, K-12 teachers, and scientists and educators. Depending on the amount of time available, I show students how people, as well as scientists group or categorize things such as plants and animals, cats and dog, etc. The students are then broken up into groups. Science is usually done by teams of scientists working together, not as individuals working alone. I assess their prior knowledge (how many planets, their names, their properties, etc.). They also do a hands-on group activity where they group/categorize ten spheres by their properties (size, color, etc.). Finally we discuss the process by which the IAU came up with a definition of a planet. I then discuss with them why some scientists, including myself, do not agree with this definition: as with the spheres, there may be more than one "right” answer. There are many ways to look at the properties of objects in the Solar System and group them into planets and other designations. This is the way that science should be done, to look at all of the properties of an object and categorize them in a meaningful way. There may be more than one right answer.

  20. EM cluster analysis for categorical data

    Czech Academy of Sciences Publication Activity Database

    Grim, Jiří

    2006-01-01

    Roč. 44, č. 4109 (2006), s. 640-648 ISSN 0302-9743. [Joint IAPR International Workshops SSPR 2006 and SPR 2006. Hong Kong , 17.08.2006-19.08.2006] R&D Projects: GA AV ČR 1ET400750407; GA MŠk 1M0572 EU Projects: European Commission(XE) 507752 - MUSCLE Institutional research plan: CEZ:AV0Z10750506 Keywords : cluster analysis * categorical data * EM algorithm Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 0.402, year: 2005

  1. Categorizing the Growth Strategies of Small Firms

    Directory of Open Access Journals (Sweden)

    Mika Westerlund

    2012-05-01

    Full Text Available This study investigates the link between a small firm’s investment in R&D and its growth strategy. A firm’s growth strategy refers to the means by which the organization plans to achieve its objective to grow in volume and turnover. We categorize firm growth strategies into eight distinctive clusters: opportunity explorers, radical innovators, business developers, business expanders, profit makers, business rebuilders, stagnators, and downsizers. We argue that understanding a firm’s growth orientation provides a way to assess the returns of its R&D investments, because an organization’s intangible growth strategies and tangible inputs are connected.

  2. Applied categorical and count data analysis

    CERN Document Server

    Tang, Wan; Tu, Xin M

    2012-01-01

    Introduction Discrete Outcomes Data Source Outline of the BookReview of Key Statistical ResultsSoftwareContingency Tables Inference for One-Way Frequency TableInference for 2 x 2 TableInference for 2 x r TablesInference for s x r TableMeasures of AssociationSets of Contingency Tables Confounding Effects Sets of 2 x 2 TablesSets of s x r TablesRegression Models for Categorical Response Logistic Regression for Binary ResponseInference about Model ParametersGoodness of FitGeneralized Linear ModelsRegression Models for Polytomous ResponseRegression Models for Count Response Poisson Regression Mode

  3. A Framework for Categorizing Important Project Variables

    Science.gov (United States)

    Parsons, Vickie S.

    2003-01-01

    While substantial research has led to theories concerning the variables that affect project success, no universal set of such variables has been acknowledged as the standard. The identification of a specific set of controllable variables is needed to minimize project failure. Much has been hypothesized about the need to match project controls and management processes to individual projects in order to increase the chance for success. However, an accepted taxonomy for facilitating this matching process does not exist. This paper surveyed existing literature on classification of project variables. After an analysis of those proposals, a simplified categorization is offered to encourage further research.

  4. Predictive Manufacturing: Classification of categorical data

    DEFF Research Database (Denmark)

    Khan, Abdul Rauf; Schiøler, Henrik; Kulahci, Murat

    2018-01-01

    and classification capabilities of our methodology (on different experimental settings) is done through a specially designed simulation experiment. Secondly, in order to demonstrate the applicability in a real life problem a data set from electronics component manufacturing is being analysed through our proposed...... processes is high volume of information about the process dynamics. In this paper we present a methodology to deal with the categorical data streams from manufacturing processes, with an objective of predicting failures on the last stage of the process. A thorough examination of the behaviour...

  5. 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.

  6. Domain learning naming game for color categorization.

    Science.gov (United States)

    Li, Doujie; Fan, Zhongyan; Tang, Wallace K S

    2017-01-01

    Naming game simulates the evolution of vocabulary in a population of agents. Through pairwise interactions in the games, agents acquire a set of vocabulary in their memory for object naming. The existing model confines to a one-to-one mapping between a name and an object. Focus is usually put onto name consensus in the population rather than knowledge learning in agents, and hence simple learning model is usually adopted. However, the cognition system of human being is much more complex and knowledge is usually presented in a complicated form. Therefore, in this work, we extend the agent learning model and design a new game to incorporate domain learning, which is essential for more complicated form of knowledge. In particular, we demonstrate the evolution of color categorization and naming in a population of agents. We incorporate the human perceptive model into the agents and introduce two new concepts, namely subjective perception and subliminal stimulation, in domain learning. Simulation results show that, even without any supervision or pre-requisition, a consensus of a color naming system can be reached in a population solely via the interactions. Our work confirms the importance of society interactions in color categorization, which is a long debate topic in human cognition. Moreover, our work also demonstrates the possibility of cognitive system development in autonomous intelligent agents.

  7. Behavioural evidence of a dissociation between voice gender categorization and phoneme categorization using auditory morphed stimuli

    Directory of Open Access Journals (Sweden)

    Cyril R Pernet

    2014-01-01

    Full Text Available Both voice gender and speech perception rely on neuronal populations located in the peri-sylvian areas. However, whilst functional imaging studies suggest a left versus right hemisphere and anterior versus posterior dissociation between voice and speech categorization, psycholinguistic studies on talker variability suggest that these two processes (voice and speech categorization share common mechanisms. In this study, we investigated the categorical perception of voice gender (male vs. female and phonemes (/pa/ vs. /ta/ using the same stimulus continua generated by morphing. This allowed the investigation of behavioural differences while controlling acoustic characteristics, since the same stimuli were used in both tasks. Despite a higher acoustic dissimilarity between items during the phoneme categorization task (a male and female voice producing the same phonemes than the gender task (the same person producing 2 phonemes, results showed that speech information is being processed much faster than voice information. In addition, f0 or timbre equalization did not affect RT, which disagrees with the classical psycholinguistic models in which voice information is stripped away or normalized to access phonetic content. Also, despite similar response (percentages and perceptual (d’ curves, a reverse correlation analysis on acoustic features revealed, as expected, that the formant frequencies of the consonant distinguished stimuli in the phoneme task, but that only the vowel formant frequencies distinguish stimuli in the gender task. The 2nd set of results thus also disagrees with models postulating that the same acoustic information is used for voice and speech. Altogether these results suggest that voice gender categorization and phoneme categorization are dissociated at an early stage on the basis of different enhanced acoustic features that are diagnostic to the task at hand.

  8. Multiracial Children's and Adults' Categorizations of Multiracial Individuals

    Science.gov (United States)

    Roberts, Steven Othello; Gelman, Susan

    2017-01-01

    Research has explored how multiracial individuals are categorized by monoracial individuals, but has not yet explored how they are categorized by multiracial individuals themselves. We examined how multiracial children (4-9 years) and adults categorized multiracial targets (presented with and without parentage information). When parentage information was provided, multiracial targets were more likely to be categorized as neither wholly black nor wholly white. However, both multiracial adults and children more often categorized multiracial targets as black than as white regardless of the absence or presence of parentage information. For multiracial children, increased contact with white people predicted the tendency to categorize multiracial targets as black. These data suggest that multiracial children's categorizations are more flexible than those of monoracial children in previous research, and that the tendency to categorize multiracial targets as black emerges early in development within multiracial samples, and is especially likely in predominantly white contexts. PMID:28890668

  9. Categorization of aortic aneurysm thrombus morphology by magnetic resonance imaging

    DEFF Research Database (Denmark)

    de la Motte, Louise; Pedersen, Mads Møller; Thomsen, Carsten

    2013-01-01

    Magnetic resonance imaging (MRI) has been proposed for qualitative categorization of intraluminal thrombus morphology. We aimed to correlate the qualitative MRI categorization previously described to quantitative measurements of signal intensity and to compare morphological characteristics...

  10. Categorization of web pages - Performance enhancement to search engine

    Digital Repository Service at National Institute of Oceanography (India)

    Lakshminarayana, S.

    search systems. Categorization of the web pages abet fairly in addressing this issue. The anatomy of the web pages, links, categorization of text and their relations are empathized with time. Search engines perform critical analysis using several inputs...

  11. A Ligand Structure-Activity Study of DNA-Based Catalytic Asymmetric Hydration and Diels-Alder Reactions

    NARCIS (Netherlands)

    Rosati, F.; Roelfes, J.G.

    A structure-activity relationship study of the first generation ligands for the DNA-based asymmetric hydration of enones and Diels-Alder reaction in water is reported. The design of the ligand was optimized resulting in a maximum ee of 83% in the hydration reaction and 75% in the Diels-Alder

  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. Equality of opportunity with categorical data

    Directory of Open Access Journals (Sweden)

    Carmen Herrero

    2014-01-01

    Full Text Available Este trabajo aborda el problema de la evaluación social cuando la equidad es un aspecto relevante. En él se propone una forma de valorar la igualdad de oportunidades aplicable en contextos donde los datos son categóricos. Este método consiste en dividir la sociedad en grupos de características similares y medir la dispersión de los resultados entre dichos grupos, a partir de la distribución de la población en diferentes categorías. El trabajo incluye una aplicación empírica sobre la igualdad de oportunidades educativas usando los datos del informe PISA 2012 sobre conocimientos matemáticos en las regiones españolas.

  14. 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....

  15. ERP signs of categorical and supra-categorical processing of visual information.

    Science.gov (United States)

    Zani, Alberto; Marsili, Giulia; Senerchia, Annapaola; Orlandi, Andrea; Citron, Francesca M M; Rizzi, Ezia; Proverbio, Alice M

    2015-01-01

    The aim of the present study was to investigate to what extent shared and distinct brain mechanisms are possibly subserving the processing of visual supra-categorical and categorical knowledge as observed with event-related potentials of the brain. Access time to these knowledge types was also investigated. Picture pairs of animals, objects, and mixed types were presented. Participants were asked to decide whether each pair contained pictures belonging to the same category (either animals or man-made objects) or to different categories by pressing one of two buttons. Response accuracy and reaction times (RTs) were also recorded. Both ERPs and RTs were grand-averaged separately for the same-different supra-categories and the animal-object categories. Behavioral performance was faster for more endomorphic pairs, i.e., animals vs. objects and same vs. different category pairs. For ERPs, a modulation of the earliest C1 and subsequent P1 responses to the same vs. different supra-category pairs, but not to the animal vs. object category pairs, was found. This finding supports the view that early afferent processing in the striate cortex can be boosted as a by-product of attention allocated to the processing of shapes and basic features that are mismatched, but not to their semantic quintessence, during same-different supra-categorical judgment. Most importantly, the fact that this processing accrual occurred independent of a traditional experimental condition requiring selective attention to a stimulus source out of the various sources addressed makes it conceivable that this processing accrual may arise from the attentional demand deriving from the alternate focusing of visual attention within and across stimulus categorical pairs' basic structural features. Additional posterior ERP reflections of the brain more prominently processing animal category and same-category pairs were observed at the N1 and N2 levels, respectively, as well as at a late positive complex level

  16. Topological and categorical properties of binary trees

    Directory of Open Access Journals (Sweden)

    H. Pajoohesh

    2008-04-01

    Full Text Available Binary trees are very useful tools in computer science for estimating the running time of so-called comparison based algorithms, algorithms in which every action is ultimately based on a prior comparison between two elements. For two given algorithms A and B where the decision tree of A is more balanced than that of B, it is known that the average and worst case times of A will be better than those of B, i.e., ₸A(n ≤₸B(n and TWA (n≤TWB (n. Thus the most balanced and the most imbalanced binary trees play a main role. Here we consider them as semilattices and characterize the most balanced and the most imbalanced binary trees by topological and categorical properties. Also we define the composition of binary trees as a commutative binary operation, *, such that for binary trees A and B, A * B is the binary tree obtained by attaching a copy of B to any leaf of A. We show that (T,* is a commutative po-monoid and investigate its properties.

  17. Complex surveys analysis of categorical data

    CERN Document Server

    Mukhopadhyay, Parimal

    2016-01-01

    The primary objective of this book is to study some of the research topics in the area of analysis of complex surveys which have not been covered in any book yet. It discusses the analysis of categorical data using three models: a full model, a log-linear model and a logistic regression model. It is a valuable resource for survey statisticians and practitioners in the field of sociology, biology, economics, psychology and other areas who have to use these procedures in their day-to-day work. It is also useful for courses on sampling and complex surveys at the upper-undergraduate and graduate levels. The importance of sample surveys today cannot be overstated. From voters’ behaviour to fields such as industry, agriculture, economics, sociology, psychology, investigators generally resort to survey sampling to obtain an assessment of the behaviour of the population they are interested in. Many large-scale sample surveys collect data using complex survey designs like multistage stratified cluster designs. The o...

  18. Vowel categorization and the critical band.

    Science.gov (United States)

    Weitzman, R S

    1992-01-01

    Using the concept formation paradigm, two series of experiments were conducted to test the hypothesis that the critical band (CB) was a factor in learning to make absolute discriminations of vowels. The specific hypothesis being examined was that the CB is a psychoacoustic boundary in learning to make vowel categorizations, and that learning absolute discriminations of pairs of vowels that differ in one of their formants by one bark or more is significantly easier than learning absolute discriminations of vowels that differ by less than one bark. Subjects were given the task of learning to identify paired sets of synthesized vowels that differed in either F1 or F2 by 0.4, 0.6, 0.8, 1.0, or 1.2 bark. The results of these experiments suggest that the critical bandwidth is not a natural psychoacoustic boundary in the learning of vowel categories, and also that subjects seem better able to learn distinctions involving differences in F1 than distinctions involving differences in F2. The discussion raises the possibility that vowels that differ by less than one bark may not be perceptually viable because of such factors as ambient noise, articulatory constraints, and coarticulatory influences. Some evidence from Dutch and French is presented in support of this conjecture.

  19. 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.

  20. 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.