Quantitative Structure – Antioxidant Activity Relationships of Flavonoid Compounds

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Károly Héberger

2004-12-01

Full Text Available A quantitative structure – antioxidant activity relationship (QSAR study of 36 flavonoids was performed using the partial least squares projection of latent structures (PLS method. The chemical structures of the flavonoids have been characterized by constitutional descriptors, two-dimensional topological and connectivity indices. Our PLS model gave a proper description and a suitable prediction of the antioxidant activities of a diverse set of flavonoids having clustering tendency.

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

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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.

Quantitative structure-activity relationship of some 1-benzylbenzimidazole derivatives as antifungal agents

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Podunavac-Kuzmanović Sanja O.

2007-01-01

Full Text Available In the present study, the antifungal activity of some 1-benzylbenzimidazole derivatives against yeast Saccharomyces cerevisiae was investigated. The tested benzimidazoles displayed in vitro antifungal activity and minimum inhibitory concentration (MIC was determined for all the compounds. Quantitative structure-activity relationship (QSAR has been used to study the relationships between the antifungal activity and lipophilicity parameter, logP, calculated by using CS Chem-Office Software version 7.0. The results are discussed on the basis of statistical data. The best QSAR model for prediction of antifungal activity of the investigated series of benzimidazoles was developed. High agreement between experimental and predicted inhibitory values was obtained. The results of this study indicate that the lipophilicity parameter has a significant effect on antifungal activity of this class of compounds, which simplify design of new biologically active molecules.

The effect of leverage and/or influential on structure-activity relationships.

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Bolboacă, Sorana D; Jäntschi, Lorentz

2013-05-01

In the spirit of reporting valid and reliable Quantitative Structure-Activity Relationship (QSAR) models, the aim of our research was to assess how the leverage (analysis with Hat matrix, h(i)) and the influential (analysis with Cook's distance, D(i)) of QSAR models may reflect the models reliability and their characteristics. The datasets included in this research were collected from previously published papers. Seven datasets which accomplished the imposed inclusion criteria were analyzed. Three models were obtained for each dataset (full-model, h(i)-model and D(i)-model) and several statistical validation criteria were applied to the models. In 5 out of 7 sets the correlation coefficient increased when compounds with either h(i) or D(i) higher than the threshold were removed. Withdrawn compounds varied from 2 to 4 for h(i)-models and from 1 to 13 for D(i)-models. Validation statistics showed that D(i)-models possess systematically better agreement than both full-models and h(i)-models. Removal of influential compounds from training set significantly improves the model and is recommended to be conducted in the process of quantitative structure-activity relationships developing. Cook's distance approach should be combined with hat matrix analysis in order to identify the compounds candidates for removal.

Anti-trypanosomal activities and structural chemical properties of selected compound classes.

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Ponte-Sucre, Alicia; Bruhn, Heike; Schirmeister, Tanja; Cecil, Alexander; Albert, Christian R; Buechold, Christian; Tischer, Maximilian; Schlesinger, Susanne; Goebel, Tim; Fuß, Antje; Mathein, Daniela; Merget, Benjamin; Sotriffer, Christoph A; Stich, August; Krohne, Georg; Engstler, Markus; Bringmann, Gerhard; Holzgrabe, Ulrike

2015-02-01

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.

Current data regarding the structure-toxicity relationship of boron-containing compounds.

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Farfán-García, E D; Castillo-Mendieta, N T; Ciprés-Flores, F J; Padilla-Martínez, I I; Trujillo-Ferrara, J G; Soriano-Ursúa, M A

2016-09-06

Boron is ubiquitous in nature, being an essential element of diverse cells. As a result, humans have had contact with boron containing compounds (BCCs) for a long time. During the 20th century, BCCs were developed as antiseptics, antibiotics, cosmetics and insecticides. Boric acid was freely used in the nosocomial environment as an antiseptic and sedative salt, leading to the death of patients and an important discovery about its critical toxicology for humans. Since then the many toxicological studies done in relation to BCCs have helped to establish the proper limits of their use. During the last 15 years, there has been a boom of research on the design and use of new, potent and efficient boron containing drugs, finding that the addition of boron to some known drugs increases their affinity and selectivity. This mini-review summarizes two aspects of BCCs: toxicological data found with experimental models, and the scarce but increasing data about the structure-activity relationship for toxicity and therapeutic use. As is the case with boron-free compounds, the biological activity of BCCs is related to their chemical structure. We discuss the use of new technology to discover potent and efficient BCCs for medicinal therapy by avoiding toxic effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Compound Structure-Independent Activity Prediction in High-Dimensional Target Space.

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Balfer, Jenny; Hu, Ye; Bajorath, Jürgen

2014-08-01

Profiling of compound libraries against arrays of targets has become an important approach in pharmaceutical research. The prediction of multi-target compound activities also represents an attractive task for machine learning with potential for drug discovery applications. Herein, we have explored activity prediction in high-dimensional target space. Different types of models were derived to predict multi-target activities. The models included naïve Bayesian (NB) and support vector machine (SVM) classifiers based upon compound structure information and NB models derived on the basis of activity profiles, without considering compound structure. Because the latter approach can be applied to incomplete training data and principally depends on the feature independence assumption, SVM modeling was not applicable in this case. Furthermore, iterative hybrid NB models making use of both activity profiles and compound structure information were built. In high-dimensional target space, NB models utilizing activity profile data were found to yield more accurate activity predictions than structure-based NB and SVM models or hybrid models. An in-depth analysis of activity profile-based models revealed the presence of correlation effects across different targets and rationalized prediction accuracy. Taken together, the results indicate that activity profile information can be effectively used to predict the activity of test compounds against novel targets. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities.

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Akhtar, Jawaid; Khan, Ahsan Ahmed; Ali, Zulphikar; Haider, Rafi; Shahar Yar, M

2017-01-05

The present review article offers a detailed account of the design strategies employed for the synthesis of nitrogen-containing anticancer agents. The results of different studies describe the N-heterocyclic ring system is a core structure in many synthetic compounds exhibiting a broad range of biological activities. Benzimidazole, benzothiazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines including others drugs containing pyridazine, pyridine and pyrimidines are covered. The following studies of these compounds suggested that these compounds showed their antitumor activities through multiple mechanisms including inhibiting protein kinase (CDK, MK-2, PLK1, kinesin-like protein Eg5 and IKK), topoisomerase I and II, microtubule inhibition, and many others. Our concise representation exploits the design and anticancer potency of these compounds. The direct comparison of anticancer activities with the standard enables a systematic analysis of the structure-activity relationship among the series. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

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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.

Aspartate and glutamate mimetic structures in biologically active compounds.

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Stefanic, Peter; Dolenc, Marija Sollner

2004-04-01

Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.

Relationship between electronic structure and radioprotective activity of some indazoles

International Nuclear Information System (INIS)

Sokolov, Yu.A.

2000-01-01

The quantum-chemical study of electronic structure of 29 indasoles with complete optimization of geometry and search of quantitative link between the established characteristics and radioprotective activity (RPA) was carried out through the MNDO method with application of multiple linear and nonlinear regression analysis and the basic component method. The equations of correlation relationship between the RPA and electronic characteristics are presented. 10 indasole structures, the forecasted RPA values whereof (survival rate, %) equal 50% and above, are selected. The statistic significance of the obtained correlation equations and their regression coefficients make it possible to conclude, that the established relationships are not accidental and are prospective for forecasting RPA of other close compounds of the indasole series [ru

Chemistry and Structure-Activity Relationships of Psychedelics.

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Nichols, David E

2018-01-01

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT 2A receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT 2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT 2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT 2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

Toxic effects on and structure-toxicity relationships of phenylpropanoids, terpenes, and related compounds in Aedes aegypti larvae.

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Santos, Sandra R L; Silva, Viviane B; Melo, Manuela A; Barbosa, Juliana D F; Santos, Roseli L C; de Sousa, Damião P; Cavalcanti, Sócrates C H

2010-12-01

In the search for toxic compounds against Aedes aegypti L. (Diptera: Culicidae) larvae, a collection of commercially available aromatic and aliphatic diversely substituted compounds were selected and evaluated. p-Cymene exhibited the highest larvicidal potency LC₅₀ = 51 ppm, whereas 1,8-cineole exhibited the lowest activity value LC₅₀ = 1419 ppm. To aid future work on the search for larvicidal compounds, the structure-toxicity relationships of this collection have been evaluated. The presence of lipophilic groups results in an overall increase in potency. In general, the presence of hydroxyl groups resulted in less potent compounds. However, methylation of such hydroxyls led to an overall increase in potency. The most potent compounds showed comparably good larvicidal activity in A. aegypti larvae as other terpenes, which we assume to be the result of the increased lipophilicity.

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

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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.

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

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Sharifuddin M. Zain

2011-11-01

Full Text Available 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.

Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

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Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

2014-12-15

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

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.

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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.

Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.

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Van Baelen, Gitte; Hostyn, Steven; Dhooghe, Liene; Tapolcsányi, Pál; Mátyus, Péter; Lemière, Guy; Dommisse, Roger; Kaiser, Marcel; Brun, Reto; Cos, Paul; Maes, Louis; Hajós, György; Riedl, Zsuzsanna; Nagy, Ildikó; Maes, Bert U W; Pieters, Luc

2009-10-15

Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.

Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

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André Luiz Lourenço

2015-04-01

Full Text Available The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.

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

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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.

Antileishmanial activities of dihydrochalcones from piper elongatum and synthetic related compounds. Structural requirements for activity.

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Hermoso, Alicia; Jiménez, Ignacio A; Mamani, Zulma A; Bazzocchi, Isabel L; Piñero, José E; Ravelo, Angel G; Valladares, Basilio

2003-09-01

Two dihydrochalcones (1 and 2) were isolated from Piper elongatum Vahl by activity-guided fractionation against extracellular promastigotes of Leishmania braziliensis in vitro. Their structures were elucidated by spectral analysis, including homonuclear and heteronuclear correlation NMR experiments. Derivatives 3-7 and 20 synthetic related compounds (8-27) were also assayed to establish the structural requirements for antileishmanial activity. Compounds 1-11 that proved to be more active that ketoconazol, used as positive control, were further assayed against promastigotes of Leishmania tropica and Leishmania infantum. Compounds 7 and 11, with a C(6)-C(3)-C(6) system, proved to be the most promising compounds, with IC(50) values of 2.98 and 3.65 microg/mL, respectively, and exhibited no toxic effect on macrophages (around 90% viability). Correlation between the molecular structures and antileishmanial activity is discussed in detail.

Molecular Descriptors Family on Structure Activity Relationships 2. Insecticidal Activity of Neonicotinoid Compounds

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Sorana BOLBOACĂ

2005-01-01

Full Text Available The neonicotinoids are the newest major class of insecticides modeled after the basic nicotine molecule having improved insecticide activity and generally low toxicity. The insecticidal activities of neonicotinoids were previous studied using 3D and standard partial least squares regression models. The paper describes the ability of the MDF SAR methodology in prediction of insecticidal activities of neonicotinoid compounds. The best MDF SAR bi-varied model was validated on training and test sets and its ability on prediction of insecticidal activity was compared with previous reported models. Even if the MDF SAR methodology is complex and time consuming the results worth the effort because they are statistical significant better then previous reported results.

Multivariate characterisation and quantitative structure-property relationship modelling of nitroaromatic compounds

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Joensson, S. [Man-Technology-Environment Research Centre, Department of Natural Sciences, Orebro University, 701 82 Orebro (Sweden)], E-mail: sofie.jonsson@nat.oru.se; Eriksson, L.A. [Department of Natural Sciences and Orebro Life Science Center, Orebro University, 701 82 Orebro (Sweden); Bavel, B. van [Man-Technology-Environment Research Centre, Department of Natural Sciences, Orebro University, 701 82 Orebro (Sweden)

2008-07-28

A multivariate model to characterise nitroaromatics and related compounds based on molecular descriptors was calculated. Descriptors were collected from literature and through empirical, semi-empirical and density functional theory-based calculations. Principal components were used to describe the distribution of the compounds in a multidimensional space. Four components described 76% of the variation in the dataset. PC1 separated the compounds due to molecular weight, PC2 separated the different isomers, PC3 arranged the compounds according to different functional groups such as nitrobenzoic acids, nitrobenzenes, nitrotoluenes and nitroesters and PC4 differentiated the compounds containing chlorine from other compounds. Quantitative structure-property relationship models were calculated using partial least squares (PLS) projection to latent structures to predict gas chromatographic (GC) retention times and the distribution between the water phase and air using solid-phase microextraction (SPME). GC retention time was found to be dependent on the presence of polar amine groups, electronic descriptors including highest occupied molecular orbital, dipole moments and the melting point. The model of GC retention time was good, but the precision was not precise enough for practical use. An important environmental parameter was measured using SPME, the distribution between headspace (air) and the water phase. This parameter was mainly dependent on Henry's law constant, vapour pressure, log P, content of hydroxyl groups and atmospheric OH rate constant. The predictive capacity of the model substantially improved when recalculating a model using these five descriptors only.

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

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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.

A Quantitative Structure-Activity Relationships (QSAR Study of Piperine Based Derivatives with Leishmanicidal Activity

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Edilson Beserra Alencar Filho

2017-04-01

Full Text Available Leishmaniasis is a parasitic disease which represents a serious public health problem in developing countries. It is considered a neglected tropical disease, for which there is little initiative in the search for therapeutic alternatives by pharmaceutical industry. Natural products remain a great source of inspiration for obtaining bioactive molecules. In 2010, Singh and co-workers published the synthesis and in vitro biological activity of piperoyl-aminoacid conjugates, as well as of piperine, against cellular cultures of Leishmania donovani. The piperine is an alkaloid isolated from Piper nigrum that has many activities described in the literature. In this work, we present a Quantitative Structure-Activity Study of piperine derivatives tested by Singh and co-workers, aiming to highlight important molecular features for leishmanicidal activity, obtaining a mathematical model to predict the activity of new analogs. Compounds were submitted to a geometry optimization computational procedure at semiempirical level of quantum theory. Molecular descriptors for the set of compounds were calculated by E-Dragon online plataform, followed by a variable selection procedure using Ordered Predictors Selection algorithm. Validation parameters obtained showed that a good QSAR model, based on multiple linear regression, was obtained (R2 = 0.85; Q2 = 0.69, and the following conclusions regarding the structure-activity relationship were elucidated: Compounds with electronegative atoms on different substituent groups of analogs, absence of unsaturation on lateral chain, presence of ester instead of carboxyl, and large volumes (due the presence of additional aromatic rings trends to increase the activity against promastigote forms of leishmania. DOI: http://dx.doi.org/10.17807/orbital.v9i1.893

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

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Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was

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)

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

International Nuclear Information System (INIS)

Fernandes, João Paulo dos Santos; Savino, Giovanna; Amarante, André Cortinas Gonçalves; Sousa, Milena Rodrigues de; Silva, Geane Ramos da; Cianciulli, Maria Eliza; Corrêa, Michelle Fidelis; Ferrarini, Márcio

2013-01-01

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)

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.

Structure-activity relationship of prenyl-substituted polyphenols from Artocarpus heterophyllus as inhibitors of melanin biosynthesis in cultured melanoma cells.

Science.gov (United States)

Arung, Enos Tangke; Shimizu, Kuniyoshi; Kondo, Ryuichiro

2007-09-01

A series of prenylated, flavone-based polyphenols, compounds 1-8, were isolated from the wood of Artocarpus heterophyllus. These compounds, which have previously been shown not to inhibit tyrosinase activity, were found to be active inhibitors of the in vivo melanin biosynthesis in B16 melanoma cells, with little or no cytotoxicity. To clarify the structural requirement for inhibition, some structure-activity relationships were studied, in comparison with related compounds lacking prenyl side chains. Our experiments indicate that both prenyl and OH groups, as well as the type of substitution pattern, are crucial for the inhibition of melanin production in B16 melanoma cells.

Synthesis, quantitative structure-property relationship study of novel fluorescence active 2-pyrazolines and application

Science.gov (United States)

Girgis, Adel S.; Basta, Altaf H.; El-Saied, Houssni; Mohamed, Mohamed A.; Bedair, Ahmad H.; Salim, Ahmad S.

2018-03-01

A variety of fluorescence-active fluorinated pyrazolines 13-33 was synthesized in good yields through cyclocondensation reaction of propenones 1-9 with aryl hydrazines 10-12. Some of the synthesized compounds provided promising fluorescence properties with quantum yield (Φ) higher than that of quinine sulfate (standard reference). Quantitative structure-property relationship studies were undertaken supporting the exhibited fluorescence properties and estimating the parameters governing properties. Five synthesized fluorescence-active pyrazolines (13, 15, 18, 19 and 23) with variable Φ were selected for treating two types of paper sheets (Fabriano and Bible paper). These investigated fluorescence compounds, especially compounds 19 and 23, provide improvements in strength properties of paper sheets. Based on the observed performance they can be used as markers in security documents.

Relationship between structure and antiproliferative activity of polymethoxyflavones towards HL60 cells.

Science.gov (United States)

Kawaii, Satoru; Ikuina, Tomoyasu; Hikima, Takeshi; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-12-01

As part of our continuing investigation of polymethoxyflavone (PMF) derivatives as potential anticancer substances, a series of PMF derivatives was synthesized. The synthesized compounds were evaluated for cytotoxicity against the promyelocytic leukemic HL60 cell line, and structure-activity relationship correlations were investigated along with previously isolated PMFs from the peel of king orange (Citrus nobilis). 7,3'-Dimethoxyflavone demonstrated the most potent activity among the synthetic PMFs. Consideration of correlation between the methoxylation pattern and antiproliferative activity revealed the importance of the 3'-methoxyl group and the higher degree of methoxylation on the A-ring moiety of PMFs.

Chemical structure of bismuth compounds determines their gastric ulcer healing efficacy and anti-Helicobacter pylori activity.

Science.gov (United States)

Sandha, G S; LeBlanc, R; Van Zanten, S J; Sitland, T D; Agocs, L; Burford, N; Best, L; Mahoney, D; Hoffman, P; Leddin, D J

1998-12-01

The recognition of the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has led to renewed interest in bismuth pharmacology since bismuth compounds have both anti-Helicobacter pylori and ulcer healing properties. The precise chemical structure of current bismuth compounds is not known. This has hindered the development of new and potentially more efficacious formulations. We have created two new compounds, 2-chloro-1,3-dithia-2-bismolane (CDTB) and 1,2-[bis(1,3-dithia-2-bismolane)thio]ethane (BTBT), with known structure. In a rat model of gastric ulceration, BTBT was comparable to, and CDTB was significantly less effective than colloidal bismuth subcitrate in healing cryoprobe-induced ulcers. However, both BTBT and CDTB inhibited H. pylori growth in vitro at concentrations <1/10 that of colloidal bismuth subcitrate. The effects on ulcer healing are not mediated by suppression of acid secretion, pepsin inhibition, or prostaglandin production. Since all treated animals received the same amount of elemental bismuth, it appears that the efficacy of bismuth compounds varies with compound structure and is not simply dependent on the delivery of bismuth ion. Because the structure of the novel compounds is known, our understanding of the relationship of bismuth compound structure and to biologic activity will increase. In the future it may be possible to design other novel bismuth compounds with more potent anti-H. pylori and ulcer healing effects.

6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

Science.gov (United States)

Khan, K M; Shah, Zarbad; Ahmad, V U; Ambreen, N; Khan, M; Taha, M; Rahim, F; Noreen, S; Perveen, S; Choudhary, M I; Voelter, W

2012-02-15

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC(50) values between 1.5±0.043 and 294.0±16.7 μM. Compounds 30 (IC(50)=1.5±0.043 μM), 1 (IC(50)=2.4±0.049 μM), 11 (IC(50)=5.7±0.113 μM), 13 (IC(50)=6.4±0.148 μM), 14 (IC(50)=10.5±0.51 μM), 9 (IC(50)=11.49±0.08 μM), 3 (IC(50)=63.1±1.48 μM), 10 (IC(50)=120.0±4.47 μM), and 6 (IC(50)=153.2±5.6 μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC(50)=274±0.007 μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters. Copyright © 2011 Elsevier Ltd. All rights reserved.

Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.

Science.gov (United States)

Murgatroyd, Christopher; Pirrie, Lisa; Tran, Fanny; Smith, Terry K; Westwood, Nicholas J; Adamson, Catherine S

2016-09-15

HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they

Phenolic Compounds and Antioxidant Activities of Liriope muscari

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Shu Shan Du

2012-02-01

Full Text Available Five phenolic compounds, namely N-trans-coumaroyltyramine (1, N-trans-feruloyltyramine (2, N-trans-feruloyloctopamine (3, 5,7-dihydroxy-8-methoxyflavone (4 and (3S3,5,4′-trihydroxy-7-methoxy-6-methylhomoisoflavanone (5, were isolated from the fibrous roots of Liriope muscari (Liliaceae. Compounds 2–5 were isolated for the first time from the Liriope genus. Their in vitro antioxidant activities were assessed by the DPPH and ABTS scavenging methods with microplate assays. The structure-activity relationships of compounds 1–3 are discussed.

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.

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%

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

DEFF Research Database (Denmark)

Zhang, Hang; Xiong, Xiao-feng; Boesgaard, Michael W

2017-01-01

that specifically inhibit signaling mediated by the Gq 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...

Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling.

Science.gov (United States)

Wodtke, Robert; Hauser, Christoph; Ruiz-Gómez, Gloria; Jäckel, Elisabeth; Bauer, David; Lohse, Martin; Wong, Alan; Pufe, Johanna; Ludwig, Friedrich-Alexander; Fischer, Steffen; Hauser, Sandra; Greif, Dieter; Pisabarro, M Teresa; Pietzsch, Jens; Pietsch, Markus; Löser, Reik

2018-05-24

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N ε -acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M -1 s -1 , which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.

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

Science.gov (United States)

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

2016-07-28

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

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

Science.gov (United States)

Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

2015-09-01

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF DITERPENES FOR TREATMENT OF ALZHEIMER'S DISEASE

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Gabriel F. dos Santos

Full Text Available Alzheimer's disease is an irreversible, degenerative and age-related disease which is growing more and more with the increase in life expectancy. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide. In the present work¸ twenty-seven kaurane diterpenes of natural origin and some readily available derivatives were assayed for acetylcholinesterase inhibition and the structure-activity relationship was analyzed. The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition. In addition, presence of free hydroxyl groups at C-17 and C-19, furnished a diol especially active, able to completely inhibit AChE.

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.

Quantitative structure activity relationship (QSAR) of piperine analogs for bacterial NorA efflux pump inhibitors.

Science.gov (United States)

Nargotra, Amit; Sharma, Sujata; Koul, Jawahir Lal; Sangwan, Pyare Lal; Khan, Inshad Ali; Kumar, Ashwani; Taneja, Subhash Chander; Koul, Surrinder

2009-10-01

Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.

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.

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

Science.gov (United States)

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.

1998-01-01

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential. PMID:9756747

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.

Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.

Science.gov (United States)

Chen, Yuzhen; Xiao, Huizhi; Zheng, Jie; Liang, Guizhao

2015-01-01

Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media.

An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents.

Science.gov (United States)

Arshad, Laiba; Haque, Md Areeful; Abbas Bukhari, Syed Nasir; Jantan, Ibrahim

2017-04-01

Curcumin, extracted mainly from Curcuma longa rhizomes, has been reported to possess potent anti-inflammatory and anti-oxidant activities. Although safe at higher doses and exhibiting multiple biological activities, curcumin still has the problem of poor bioavailability which has been an attractive area of research over the last few years. A number of efforts have been made by modifying structural features of curcumin. This review highlights the structurally modified and more stable newly synthesized curcumin analogs that have been screened against antioxidant and anti-inflammatory activities. Also the structure-activity relationship to gain insight into future guidelines for scheming new compounds has been discussed, and further these analogs being more stable may serve as promising agents for use in different pathological conditions.

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.

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

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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.

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

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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.

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

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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.

Structure–kinetic relationship study of CDK8/CycC specific compounds

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Schneider, Elisabeth V.; Böttcher, Jark; Huber, Robert; Maskos, Klaus; Neumann, Lars

2013-01-01

In contrast with the very well explored concept of structure–activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure–kinetic relationship. Here, we present a structure–kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif (“DMG” in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket. PMID:23630251

Trichothecenes: structure-toxic activity relationships.

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Wu, Qinghua; Dohnal, Vlastimil; Kuca, Kamil; Yuan, Zonghui

2013-07-01

Trichothecenes comprise a large family of structurally related toxins mainly produced by fungi belonging to the genus Fusarium. Among trichothecenes, type A and type B are of the most concern due to their broad and highly toxic nature. In order to address structure-activity relationships (SAR) of trichothecenes, relationships between structural features and biological effects of trichothecene mycotoxins in mammalian systems are summarized in this paper. The double bond between C-9-C-10 and the 12,13-epoxide ring are essential structural features for trichothecene toxicity. Removal of these groups results in a complete loss of toxicity. A hydroxyl group at C-3 enhances trichothecene toxicity, while this activity decreases gradually when C-3 is substituted with either hydrogen or an acetoxy group. The presence of a hydroxyl group at C-4 promotes slightly lower toxicity than an acetoxy group at the same position. The toxicity for type B trichothecenes decreases if the substituent at C-4 is changed from acetoxy to hydroxyl or hydrogen at C-4 position. The presence of hydroxyl and hydrogen groups on C-15 decreases the trichothecene toxicity in comparison with an acetoxy group attached to this carbon. Trichothecenes toxicity increases when a macrocyclic ring exists between the C-4 and C-15. At C-8 position, an oxygenated substitution at C-8 is essential for trichothecene toxicity, indicating a decrease in the toxicity if substituent change from isovaleryloxy through hydrogen to the hydroxyl group. The presence of a second epoxy ring at C-7-C-8 reduces the toxicity, whereas epoxidation at C-9-C-10 of some macrocyclic trichothecenes increases the activity. Conjugated trichothecenes could release their toxic precursors after hydrolysis in animals, and present an additional potential risk. The SAR study of trichothecenes should provide some crucial information for a better understanding of trichothecene chemical and biological properties in food contamination.

Quantitative Structure-Activity Relationship Analysis of the ...

African Journals Online (AJOL)

Erah

Quantitative Structure-Activity Relationship Analysis of the Anticonvulsant ... Two types of molecular descriptors, including the 2D autocorrelation ..... It is based on the simulation of natural .... clustering anticonvulsant, antidepressant, and.

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.

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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.

Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

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Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

2005-10-06

US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

Boiling points of halogenated aliphatic compounds: a quantitative structure-property relationship for prediction and validation.

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Oberg, Tomas

2004-01-01

Halogenated aliphatic compounds have many technical uses, but substances within this group are also ubiquitous environmental pollutants that can affect the ozone layer and contribute to global warming. The establishment of quantitative structure-property relationships is of interest not only to fill in gaps in the available database but also to validate experimental data already acquired. The three-dimensional structures of 240 compounds were modeled with molecular mechanics prior to the generation of empirical descriptors. Two bilinear projection methods, principal component analysis (PCA) and partial-least-squares regression (PLSR), were used to identify outliers. PLSR was subsequently used to build a multivariate calibration model by extracting the latent variables that describe most of the covariation between the molecular structure and the boiling point. Boiling points were also estimated with an extension of the group contribution method of Stein and Brown.

Electrochemical quantification of the structure/antioxidant activity relationship of flavonoids

International Nuclear Information System (INIS)

Ferreira, Rafael de Queiroz; Greco, Sandro José; Delarmelina, Maicon; Weber, Karen Cacilda

2015-01-01

Highlights: • CRAC assay simply and rapidly quantifies the reducing capacity of antioxidant compounds based on the consumption of a standard oxidizer (Ce 4+ ). • The electronic properties of studied flavonoid compounds and their antioxidant activity can be well correlated by this three variables: (i) polarizability, (ii) change at carbon 3’ (iii) change at carbon 5. • Hierarchical antioxidant classification generated by CRAC assay: morin > kaempferol ≅ quercetin > fisetin > apigenin > luteolin > catechin > chrysin. • Antioxidant hierarchy for groups present in the studied flavonoids compound generated by CRAC assay: OH(C2′C4′) > OH(C4′) ≅ OH(C3′C4′) > C2=C3 + 4-oxo > OH(C3,C5) + 4-oxo > OH(C3) + 4-oxo > OH(C5) + 4-oxo > OH(C3,C5). - Abstract: Ceric Reducing/Antioxidant Capacity (CRAC) is an electrochemical test that has recently emerged as an alternative to the spectrophotometric tests employed in the determination of antioxidant capacity. CRAC simply and rapidly quantifies the reducing capacity of antioxidant compounds based on the consumption of a standard oxidizer (Ce 4+ ). In this study, eight samples of flavonoids from three distinct groups were evaluated and showed the following antioxidant hierarchy: morin > kaempferol ≅ quercetin > fisetin > apigenin > luteolin > catechin > chrysin. This hierarchy is correlated with the behavior expected according to the structure/antioxidant activity relationship (SAR) of these polyphenolic compounds. Additionally, other correlations were established using SAR to explain the antioxidant behavior of the compounds with unrelated groups: OH(C2′C4′) > OH(C4′) ≅ OH(C3′C4′) > C2 = C3 + 4-oxo > OH(C3,C5) + 4-oxo > OH(C3) + 4-oxo > OH(C5) + 4-oxo > OH(C3,C5). Therefore, the use of these two tools together is very important for the study of the antioxidant behavior of flavonoids, contributing uniquely to the understanding of electronic transfer mechanisms involved in the antioxidant processes

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

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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.

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

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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.

A comparative study of aroma-active compounds between dark and milk chocolate: relationship to sensory perception.

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Liu, Jianbin; Liu, Mengya; He, Congcong; Song, Huanlu; Guo, Jia; Wang, Ye; Yang, Haiying; Su, Xiaoxia

2015-04-01

The most important aroma-active compounds of two types of chocolate and cocoa liquor used for their production were analysed by gas chromatography-olfactometry-mass spectrometry (GC-O-MS) and aroma extract dilution analysis (AEDA). Furthermore, the relationship between odorants and sensory perception of chocolate was measured by quantitative analysis, sensory evaluation and correlation analysis. In addition, some chemicals were added to the original dark or milk chocolate to validate their roles in the aroma property of chocolate. A total of 32 major aroma-active compounds were identified in the chocolate with the flavour dilution factors of 27-729 by AEDA, including seven aldehydes, six pyrazines, three pyrroles, four carboxylic acids, four lactones, two alcohols, two ketones, one ester, one pyrone, one furan and one sulfur-containing compound. Further quantitative analysis showed that dark chocolate had higher contents of pyrazine, pyrrole, carboxylic acids, alcohols and Strecker aldehydes, whereas the concentration of lactones, esters, long chain aldehydes and ketones were higher in the milk type. Differences in volatile composition and descriptive flavour attributes between the dark and milk chocolate were observed. The relationship between aroma-active compounds and sensory perception in the chocolate was verified. © 2014 Society of Chemical Industry.

Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

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Reto Brun

2009-06-01

Full Text Available Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness, we have now conducted a structure-(in-vitro-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC50-values of 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity. It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are a,b-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors.

Structure-activity relationship studies of citalopram derivatives

DEFF Research Database (Denmark)

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

2016-01-01

towards the S2 site. EXPERIMENTAL APPROACH: We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, that shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which distinguish...... citalopram from talopram in conferring selectivity towards the S1 and S2 site, respectively, was assessed by determining the binding of 14 citalopram/talopram analogous to the S1 and S2 binding sites in SERT using membranes of COS7 cells transiently expressing SERT. KEY RESULTS: The structure-activity...

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.

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

Energy Technology Data Exchange (ETDEWEB)

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

2011-01-15

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

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.

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.

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.

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.

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

Science.gov (United States)

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

2006-11-01

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

Molecular Descriptors Family on Structure Activity Relationships 1. Review of the Methodology

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Lorentz JÄNTSCHI

2005-01-01

Full Text Available This review cumulates the knowledge about the use of Molecular Descriptors Family usage on Structure Activity Relationships. The methodology is augmented through the general Structure Activity Relationships methodology. The obtained models in a series of five papers are quantitatively analyzed by comparing with previous reported results by using of the correlated correlations tests. The scores for a series of 13 data sets unpublished yet results are presented. Two unrestricted online access portals to the Molecular Descriptors Family Structure Activity Relationship models results are given.

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.

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

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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.

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.

Varic acid analogues from fungus as PTP1B inhibitors: Biological evaluation and structure-activity relationships.

Science.gov (United States)

Sun, Wenlong; Zhuang, Chunlin; Li, Xia; Zhang, Bowei; Lu, Xinhua; Zheng, Zhihui; Dong, Yuesheng

2017-08-01

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

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

Science.gov (United States)

Du, Shijie; Tian, Zaimin; Yang, Dongyan; Li, Xiuyun; Li, Hong; Jia, Changqing; Che, Chuanliang; Wang, Mian; Qin, Zhaohai

2015-05-08

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-yl)phenyl)-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.

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

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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.

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

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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.

The Ghosts of Acetylcholine : structure-activity relationships of ...

African Journals Online (AJOL)

The Ghosts of Acetylcholine : structure-activity relationships of muscle relaxants : registrar communication. ... AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL · AJOL's ...

Relationship between Structural Characteristics of Activated Carbons and Their Concentrating Efficiency with Respect to Nitroorganics.

Science.gov (United States)

Leboda, R.; Gun'ko, V. M.; Tomaszewski, W.; Trznadel, B. J.

2001-07-15

The relationships between structural properties of activated microporous, micro-mesoporous, mesoporous, and graphitized carbons determined on the basis of nitrogen adsorption at 77.4 K and the efficiency of concentrating (solid-phase extraction (SPE) technique) several nitroorganic compounds from polar solvents were investigated. Microporosity, mesoporosity, fractality, and other characteristics of adsorbents were analyzed to evaluate the dependence of the effectiveness of the SPE technique with respect to nitrate esters, cyclic nitroamines, and nitroaromatics on the origin and texture of carbons. The values of the free energy of solvation and dipole moment of nitroorganic compounds in polar liquids computed with the SM5.42/PM3 method with consideration of geometry relaxation in solution were utilized to elucidate features of their concentration of carbon adsorbents. Copyright 2001 Academic Press.

Structural relationships and vasorelaxant activity of monoterpenes

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Cardoso Lima Tamires

2012-09-01

Full Text Available Abstract Background and purpose of the study The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure-activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. Methods Contractions of the vessels were induced with 10 μM of phenylephine (Phe in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. Results The results from the present study showed that both oxygenated terpenes (rotundifolone, (+-limonene epoxide, pulegone epoxide, carvone epoxide, and (+-pulegone and non-oxygenated terpene ((+-limonene exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. Major conclusion The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity.

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.

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

Science.gov (United States)

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

2006-06-01

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

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

Science.gov (United States)

Li, Minyong; Xia, Lin

2007-11-01

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

Science.gov (United States)

Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

2018-05-25

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Structure-Activity Relationship Study on the Ethyl p-Methoxycinnamate as an Anti-Inflammatory Agent

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Ismiarni Komala

2018-02-01

Full Text Available Ethyl p-methoxycinnamate (EPMC (1 has been isolated as a major compound from the rhizome of Kaempferia galanga together with the other compound ethyl cinnamate (2. As reported in the literature, EPMC (1 exhibited a significant in vitro and in vivo anti-inflammatory activity. In this research, we investigated the anti-inflammatory activity of compounds 1 and 2 by using anti-denaturation of heat bovine serum albumin (BSA method. In order to analyze active sites that are responsible for the anti-inflammatory activity, therefore, it is necessary to conduct structural modification of EPMC (1. The structural modification was performed through re-esterification reaction by using conventional and assistance of the unmodified microwave oven. Evaluation of the results of the bioassay indicated that the ester and methoxy functional groups of EPMC (1 play an important role for the anti-inflammatory activity.

Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

Science.gov (United States)

Marjanović, Marko; Kralj, Marijeta; Supek, Fran; Frkanec, Leo; Piantanida, Ivo; Smuc, Tomislav; Tusek-Bozić, Ljerka

2007-03-08

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

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. ...

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

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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.

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

Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range...... 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...

Synthesis and Antifungal Activity of Musa Phytoalexins and Structural Analogs

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Adriana Gallego

2000-07-01

Full Text Available Several perinaphthenone/phenylphenalenone compounds were synthesized to establish a relationship between structure and antifungal activity against Mycosphaerella fijiensis. Substitutions on the unsaturated carbonyl system or addition of a phenyl group reduced antibiotic activity.

Anticancer and reversing multidrug resistance activities of natural isoquinoline alkaloids and their structure-activity relationship.

Science.gov (United States)

Qing, Zhi-Xing; Huang, Jia-Lu; Yang, Xue-Yi; Liu, Jing-Hong; Cao, Hua-Liang; Xiang, Feng; Cheng, Pi; Zeng, Jian-Guo

2017-09-20

The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloid (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

A New Structure-Activity Relationship (SAR) Model for Predicting Drug-Induced Liver Injury, Based on Statistical and Expert-Based Structural Alerts

Science.gov (United States)

Pizzo, Fabiola; Lombardo, Anna; Manganaro, Alberto; Benfenati, Emilio

2016-01-01

The prompt identification of chemical molecules with potential effects on liver may help in drug discovery and in raising the levels of protection for human health. Besides in vitro approaches, computational methods in toxicology are drawing attention. We built a structure-activity relationship (SAR) model for evaluating hepatotoxicity. After compiling a data set of 950 compounds using data from the literature, we randomly split it into training (80%) and test sets (20%). We also compiled an external validation set (101 compounds) for evaluating the performance of the model. To extract structural alerts (SAs) related to hepatotoxicity and non-hepatotoxicity we used SARpy, a statistical application that automatically identifies and extracts chemical fragments related to a specific activity. We also applied the chemical grouping approach for manually identifying other SAs. We calculated accuracy, specificity, sensitivity and Matthews correlation coefficient (MCC) on the training, test and external validation sets. Considering the complexity of the endpoint, the model performed well. In the training, test and external validation sets the accuracy was respectively 81, 63, and 68%, specificity 89, 33, and 33%, sensitivity 93, 88, and 80% and MCC 0.63, 0.27, and 0.13. Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the model's architecture followed a conservative approach. As it was built using human data, it might be applied without any need for extrapolation from other species. This model will be freely available in the VEGA platform. PMID:27920722

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.

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

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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.

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.

Sulfur-containing heterocyclic compounds with potential antidiabetic activity

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E. A. Savateeva

2014-12-01

Full Text Available The essential link in the pathogenesis of diabetes mellitus and its complications is a non-enzymatic glycosylation of proteins. However, modern endocrinology lacks of clinically effective pharmaceuticals for its correction. The screening of 23 derivatives of 1,3,4-thiadiazine the ability to inhibit the reaction of non-enzymatic glycosylation of proteins in vitro was held, and 11 the most active compounds of them were selected, also the relationship «structure – activity» was investigated. An essential part of the pathogenesis of diabetes mellitus and its complications is non-enzymatic glycosylation of proteins. However, modern endocrinology lacks clinically effective medicines for its correction.

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

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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.

Structural optimization and evaluation of butenolides as potent antifouling agents: modification of the side chain affects the biological activities of compounds

KAUST Repository

Li, Yongxin

2012-09-01

A recent global ban on the use of organotin compounds as antifouling agents has increased the need for safe and effective antifouling compounds. In this study, a series of new butenolide derivatives with various amine side chains was synthesized and evaluated for their anti-larval settlement activities in the barnacle, Balanus amphitrite. Side chain modification of butenolide resulted in butenolides 3c-3d, which possessed desirable physico-chemical properties and demonstrated highly effective non-toxic anti-larval settlement efficacy. A structure-activity relationship analysis revealed that varying the alkyl side chain had a notable effect on anti-larval settlement activity and that seven to eight carbon alkyl side chains with a tert-butyloxycarbonyl (Boc) substituent on an amine terminal were optimal in terms of bioactivity. Analysis of the physico-chemical profile of butenolide analogues indicated that lipophilicity is a very important physico-chemical parameter contributing to bioactivity. © 2012 Copyright Taylor and Francis Group, LLC.

Structural optimization and evaluation of butenolides as potent antifouling agents: modification of the side chain affects the biological activities of compounds

KAUST Repository

Li, Yongxin; Zhang, Fengying; Xu, Ying; Matsumura, Kiyotaka; Han, Zhuang; Liu, Lingli; Lin, Wenhan; Jia, Yanxing; Qian, Pei Yuan

2012-01-01

A recent global ban on the use of organotin compounds as antifouling agents has increased the need for safe and effective antifouling compounds. In this study, a series of new butenolide derivatives with various amine side chains was synthesized and evaluated for their anti-larval settlement activities in the barnacle, Balanus amphitrite. Side chain modification of butenolide resulted in butenolides 3c-3d, which possessed desirable physico-chemical properties and demonstrated highly effective non-toxic anti-larval settlement efficacy. A structure-activity relationship analysis revealed that varying the alkyl side chain had a notable effect on anti-larval settlement activity and that seven to eight carbon alkyl side chains with a tert-butyloxycarbonyl (Boc) substituent on an amine terminal were optimal in terms of bioactivity. Analysis of the physico-chemical profile of butenolide analogues indicated that lipophilicity is a very important physico-chemical parameter contributing to bioactivity. © 2012 Copyright Taylor and Francis Group, LLC.

Rare-earth transition-metal intermetallics: Structure-bonding-property relationships

Energy Technology Data Exchange (ETDEWEB)

Han, M. K. [Iowa State Univ., Ames, IA (United States)

2006-01-01

The explorations of rare-earth, transition metal intermetallics have resulted in the synthesis and characterization, and electronic structure investigation, as well as understanding the structure-bonding property relationships. The work has presented the following results: (1) Understanding the relationship between compositions and properties in LaFe_13-xSi_x system: A detailed structural and theoretical investigation provided the understanding of the role of a third element on stabilizing the structure and controlling the transformation of cubic NaZn{sub 13}-type structures to the tetragonal derivative, as well as the relationship between the structures and properties. (2) Synthesis of new ternary rare-earth iron silicides Re_2-xFe₄Si_14-y and proposed superstructure: This compound offers complex structural challenges such as fractional occupancies and their ordering in superstructure. (3) Electronic structure calculation of FeSi₂: This shows that the metal-semiconductor phase transition depends on the structure. The mechanism of band gap opening is described in terms of bonding and structural distortion. This result shows that the electronic structure calculations are an essential tool for understanding the relationship between structure and chemical bonding in these compounds. (4) Synthesis of new ternary rare-earth Zinc aluminides Tb₃Zn_3.6Al_7.4: Partially ordered structure of Tb₃Zn_3.6Al_7.4 compound provides new insights into the formation, composition and structure of rare-earth transition-metal intermetallics. Electronic structure calculations attribute the observed composition to optimizing metal-metal bonding in the electronegative (Zn, Al) framework, while the specific ordering is strongly influenced by specific orbital interactions. (5) Synthesis of new structure type of Zn₃₉(Cr_xAl_1-x)₈₁

Rare-Earth Transition-Metal Intermetallics: Structure-bonding-Property Relationships

Energy Technology Data Exchange (ETDEWEB)

Han, Mi-Kyung [Iowa State Univ., Ames, IA (United States)

2006-01-01

Our explorations of rare-earth, transition metal intermetallics have resulted in the synthesis and characterization, and electronic structure investigation, as well as understanding the structure-bonding-property relationships. Our work has presented the following results: (1) Understanding the relationship between compositions and properties in LaFe_13-xSi_x system: A detailed structural and theoretical investigation provided the understanding of the role of a third element on stabilizing the structure and controlling the transformation of cubic NaZn₁₃-type structures to the tetragonal derivative, as well as the relationship between the structures and properties. (2) Synthesis of new ternary rare-earth iron silicides RE_2-xFe₄Si_14-y and proposed superstructure: This compound offers complex structural challenges such as fractional occupancies and their ordering in superstructure. (3) Electronic structure calculation of FeSi₂: This shows that the metal-semiconductor phase transition depends on the structure. The mechanism of band gap opening is described in terms of bonding and structural distortion. This result shows that the electronic structure calculations are an essential tool for understanding the relationship between structure and chemical bonding in these compounds. (4) Synthesis of new ternary rare-earth Zinc aluminides Tb₃Zn_3.6Al_7.4: Partially ordered structure of Tb_3.6Zn_13-xAl_7.4 compound provides new insights into the formation, composition and structure of rare-earth transition-metal intermetallics. Electronic structure calculations attribute the observed composition to optimizing metal-metal bonding in the electronegative (Zn, Al) framework, while the specific ordering is strongly influenced by specific orbital interactions. (5) Synthesis of new structure type of Zn₃₉(Cr_xAl_1-x

Anoxic degradation of nitrogenous heterocyclic compounds by activated sludge and their active sites.

Science.gov (United States)

Xu, Peng; Han, Hongjun; Zhuang, Haifeng; Hou, Baolin; Jia, Shengyong; Wang, Dexin; Li, Kun; Zhao, Qian

2015-05-01

The potential for degradation of five nitrogenous heterocyclic compounds (NHCs), i.e., imidazole, pyridine, indole, quinoline, and carbazole, was investigated under anoxic conditions with acclimated activated sludge. Results showed that NHCs with initial concentration of 50 mg/L could be completely degraded within 60 hr. The degradation of five NHCs was dependent upon the chemical structures with the following sequence: imidazole>pyridine>indole>quinoline>carbazole in terms of their degradation rates. Quantitative structure-biodegradability relationship studies of the five NHCs showed that the anoxic degradation rates were correlated well with highest occupied molecular orbital. Additionally, the active sites of NHCs identified by calculation were confirmed by analysis of intermediates using gas chromatography and mass spectrometry. Copyright © 2015. Published by Elsevier B.V.

Cytotoxic constituents from Brazilian red propolis and their structure-activity relationship.

Science.gov (United States)

Li, Feng; Awale, Suresh; Tezuka, Yasuhiro; Kadota, Shigetoshi

2008-05-15

Several classes of flavonoids [flavanoids (1-10), flavonol (11), isoflavones (12-18), isoflavanones (19-22), isoflavans (23-26), chalcones (27-30), auronol (31), pterocarpans (32-37), 2-arylbenzofuran (38), and neoflavonoid (39)] and lignans (40-42) isolated from the MeOH extract of Brazilian red propolis were investigated for their cytotoxic activity against a panel of six different cancer cell lines including murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma, and human HT-1080 fibrosarcoma cell lines. Based on the observed results, structure-activity relationships were discussed. Among the tested compounds, 7-hydroxy-6-methoxyflavanone (3) exhibited the most potent activity against B16-BL6 (IC(50), 6.66microM), LLC (IC(50), 9.29microM), A549 (IC(50), 8.63microM), and HT-1080 (IC(50), 7.94microM) cancer cell lines, and mucronulatol (26) against LLC (IC(50), 8.38microM) and A549 (IC(50), 9.9microM) cancer cell lines. These activity data were comparable to those of the clinically used anticancer drugs, 5-fluorouracil and doxorubicin, against the tested cell lines, suggesting that 3 and 26 are the good candidates for future anticancer drug development.

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

International Nuclear Information System (INIS)

Li Jiazhong; Liu Huanxiang; Yao Xiaojun; Liu Mancang; Hu Zhide; Fan Botao

2007-01-01

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

Molecular structure descriptors in the computer-aided design of biologically active compounds

International Nuclear Information System (INIS)

Raevsky, Oleg A

1999-01-01

The current state of description of molecular structure in computer-aided molecular design of biologically active compounds by means of descriptors is analysed. The information contents of descriptors increases in the following sequence: element-level descriptors-structural formulae descriptors-electronic structure descriptors-molecular shape descriptors-intermolecular interaction descriptors. Each subsequent class of descriptors normally covers information contained in the previous-level ones. It is emphasised that it is practically impossible to describe all the features of a molecular structure in terms of any single class of descriptors. It is recommended to optimise the number of descriptors used by means of appropriate statistical procedures and characteristics of structure-property models based on these descriptors. The bibliography includes 371 references.

Potent antifouling compounds produced by marine Streptomyces

KAUST Repository

Xu, Ying

2010-02-01

Biofouling causes huge economic loss and a recent global ban on organotin compounds as antifouling agents has increased the need for safe and effective antifouling compounds. Five structurally similar compounds were isolated from the crude extract of a marine Streptomyces strain obtained from deep-sea sediments. Antifouling activities of these five compounds and four other structurally-related compounds isolated from a North Sea Streptomyces strain against major fouling organisms were compared to probe structure-activity relationships of compounds. The functional moiety responsible for antifouling activity lies in the 2-furanone ring and that the lipophilicity of compounds substantially affects their antifouling activities. Based on these findings, a compound with a straight alkyl side-chain was synthesized and proved itself as a very effective non-toxic, anti-larval settlement agent against three major fouling organisms. The strong antifouling activity, relatively low toxicity, and simple structures of these compounds make them promising candidates for new antifouling additives. © 2009 Elsevier Ltd. All rights reserved.

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.

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR OF VINCADIFFORMINE ANALOGUES AS THE ANTIPLASMODIAL COMPOUNDS OF THE CHLOROQUINOSENSIBLE STRAIN

Directory of Open Access Journals (Sweden)

Iqmal Tahir

2010-06-01

Full Text Available Quantitative Structure-Activity Relationship (QSAR analysis of vincadifformine analogs as an antimalarial drug has been conducted using atomic net charges (q, moment dipole (, LUMO (Lowest Unoccupied Molecular Orbital and HOMO (Highest Occupied Molecular Orbital energies, molecular mass (m as well as surface area (A as the predictors to their activity. Data of predictors are obtained from computational chemistry method using semi-empirical molecular orbital AM1 calculation. Antimalarial activities were taken as the activity of the drugs against chloroquine-sensitive Plasmodium falciparum (Nigerian Cell strain and were presented as the value of ln(1/IC50 where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best QSAR model has been determined by multiple linier regression analysis giving QSAR equation: Log (1/IC50 = 9.602.qC1 -17.012.qC2 +6.084.qC3 -19.758.qC5 -6.517.qC6 +2.746.qC7 -6.795.qN +6.59.qC8 -0.190. -0.974.ELUMO +0.515.EHOMO -0.274. +0.029.A -1.673 (n = 16; r = 0.995; SD = 0.099; F = 2.682   Keywords: QSAR analysis, antimalaria, vincadifformine.

Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

Science.gov (United States)

Kim, In-Hae; Park, Yong-Kyu; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

2015-11-15

Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structure-activity relationship of pentacylic triterpene esters from Uncaria rhynchophylla as inhibitors of phospholipase Cgamma1.

Science.gov (United States)

Lee, Ji Suk; Yoo, Hunseung; Suh, Young Ger; Jung, Jae Kyung; Kim, Jinwoong

2008-10-01

A systematic structure-activity relationship of 3beta-hydroxy-27- P- E-coumaroyloxyurs-12-en-28-oic acid ( 7), a triterpene ester isolated from UNCARIA RHYNCHOPHYLLA as a phospholipase Cgamma1 inhibitor, was undertaken with a view toward elucidating its chemical mode of action on PLCgamma1. Related derivatives and analogues of 7 were synthesized and their inhibitory activities against PLCgamma1 were evaluated IN VITRO. The results indicate that 3-OH and 27-esterification may be essential, and that 28-COOH and the 2' double bond appear to be important for activity. Furthermore, the compound possessing a P-coumaroyloxy at position 27 rather than at the 3 and 28 positions shows the greatest inhibitory activity against PLCgamma1. Therefore, this inhibitor will be providing a chemical lead for the further development of cancer chemopreventive or cancer chemotherapeutic agents that have lower toxicity against normal tissues.

Biochemical studies on certain biologically active nitrogenous compounds

International Nuclear Information System (INIS)

Abdel kader, S.M.; El Sayed, M.M.; El Malt, E.A.; Shaker, E.S.; Abdel Aziz, H.G.

2010-01-01

Certain biologically active nitrogenous compounds such as alkaloids are widely distributed in many wild and medicinal plants such as peganum harmala L. (Phycophyllaceae). However, less literature cited on the natural compounds was extracted from the aerial parts of this plant; therefore this study was conducted on harmal leaves using several solvents. Data indicated that methanol extract was the inhibitoriest effect against some pathogenic bacteria, particularly Streptococcus pyogenus. Chromatographic separation illustrated that presence of four compounds; the most active one was the third compound (3). Elementary analysis (C, H, N) revealed that the primary chemical structure of the active antibacterial compound (C3) was: C17 H21 N3 O7 S with molecular weight 411. Spectroscopic analysis proved that coninical structure was = 1- thioformyl, 8?- D glucoperanoside- Bis- 2, 3 dihydroisopyridino pyrrol. This new compound is represented as a noval ?- carboline alkaloid compound

Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

Directory of Open Access Journals (Sweden)

Jambalsuren Bayarmaa

2008-06-01

Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

Structure-activity relationships in a new series of insecticidally active dioxatricycloalkenes derived by structural comparison of the GABA [γ-aminobutyric acid] antagonists bicycloorthocarboxylates and endosulfan

International Nuclear Information System (INIS)

Ozoe, Yoshihisa; Sawada, Yoshihiro; Mochida, Kazuo; Nakamura, Toshiie; Matsumura, Fumio

1990-01-01

To study structural requirements for picrotoxinin-type GABA (γ-aminobutyric acid) antagonists to interact with the receptor site, 5-substituted 4,6-dioxatricyclo[7.2.1.0 2,8 ]dodec-10-enes and related compounds were prepared and examined for their insecticidal activity and potency in displacing [ 35 S]tert-butylbicyclophosphorothionate (TBPS) binding. Compounds with high insecticidal activity possessed a phenyl group with an electron-withdrawing para substituent, a cycloalkyl group, or a C 3 -C 5 straight-chain alkyl group at the 5-position. The effect of the 5-substituents on insecticidal activity was very similar to that of the 1-substituents of the bicyloorthocarboxylate GABA antagonists. Representative dioxatricycloalkenes displaced the binding of the GABA antagonist [ 35 S]TBPS to housefly head membranes by 29-53% at 10 μM. X-ray crystal structure analysis demonstrated that this class of compounds had structures superimposable on those of 4-tert-butylbicycloorthocarboxylates. These findings indicate that the dioxatricycloalkenes and some other analogues occupy the picrotoxinin binding site in such a way that the fourth interacting subsite of the receptor site accommodates the 5-substituent

Structure-activity relationship of surfactant for preparing DMFC anodic catalyst

International Nuclear Information System (INIS)

Su Yi; Xue Xinzhong; Xu Weilin; Liu Changpeng; Xing Wei; Zhou Xiaochun; Tian Tian; Lu Tianhong

2006-01-01

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

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.

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.

An automated pulse labelling method for structure-activity relationship studies with antibacterial oxazolidinones.

Science.gov (United States)

Eustice, D C; Brittelli, D R; Feldman, P A; Brown, L J; Borkowski, J J; Slee, A M

1990-01-01

The 3-aryl-2-oxooxazolidinones are a new class of synthetic antibacterial agents that potently inhibit protein synthesis. An automated pulse labelling method with [3H]-lysine was developed with Bacillus subtilis to obtain additional quantitative activity data for structure-activity relationship studies with the oxazolidinones. Inhibition constants were calculated after a Logit fit of the data into the formula: % of control = 100/(1 + e[-B(X - A)]), where B is the slope of the model, X is the natural log of the inhibitor concentration and A is the natural log of the inhibitor concentration required to inhibit protein synthesis by 50% (ln IC50). When substituents at the 5-methyl position of the heterocyclic ring (B-substituent) were NHCOCH3, OH or Cl, the correlation coefficient was 0.87 between the MIC and IC50 values (for all compounds with MICs less than or equal to 16 micrograms/ml). The D-isomers of DuP 721 (A-substituent = CH3CO) and DuP 105 (A-substituent = CH3SO) gave MICs of 128 micrograms/ml and IC50s of greater than or equal to 50 micrograms/ml for protein synthesis, showing that only the L-isomers were active. By MIC testing, oxazolidinones with the B-substituent of NHCOCH3 and the A-substituent of CH3CO, NO2, CH3S, CH3SO2 or (CH3)2CH had comparable antibacterial potency; however, pulse labelling analysis showed that compounds with an A-substituent of CH3CO or NO2 were more potent inhibitors of protein synthesis.

Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

Science.gov (United States)

Myint, Melissa; Bucki, Robert; Janmey, Paul A; Diamond, Scott L

2015-07-15

Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene-1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages.

Science.gov (United States)

Shrestha, Aarajana; Jin Oh, Hye; Kim, Mi Jin; Pun, Nirmala Tilija; Magar, Til Bahadur Thapa; Bist, Ganesh; Choi, Hongseok; Park, Pil-Hoon; Lee, Eung-Seok

2017-06-16

As a continuous effort to discover new potential anti-inflammatory agents, we systematically designed and synthesized sixty-one 2-benzylidene-1-indanone derivatives with structural modification of chalcone, and evaluated their inhibitory activity on LPS-stimulated ROS production in RAW 264.7 macrophages. Systematic structure-activity relationship study revealed that hydroxyl group in C-5, C-6, or C-7 position of indanone moiety, and ortho-, meta-, or para-fluorine, trifluoromethyl, trifluoromethoxy, and bromine functionalities in phenyl ring are important for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. Among all the tested compounds, 6-hydroxy-2-(2-(trifluoromethoxy) benzylidene)-2,3-dihydro-1H-inden-1-one (compound 44) showed the strongest inhibitory activity of ROS production. Further studies on the mode of action revealed that compound 44 potently suppressed LPS-stimulated ROS production via modulation of NADPH oxidase. The findings of this work could be useful to design 2-benzylidene-indanone based lead compounds as novel anti-inflammatory agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis, crystal structure and biological activity of a novel 1,2,3-thidiazole compound

International Nuclear Information System (INIS)

Ke, W.

2013-01-01

A new 1,2,3-thiadiazole compound was synthesized and characterized by 1H NMR, MS and HRMS. The crystal structure of the title compound (C/sub 12/H/sub 11/ClN/sub 2/O/sub 4/S/sub 2/, Mr = 346.80) has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group P-1 with a = 8.4425(17) A, b = 8.9801(18) A, c = 9.859(2) A, alpha = 84.36(3) degree, beta = 86.71(3)degree, lambda = 83.25(3) degree, V = 737.9(3)A3, Z 2, F(000) = 356, Dc = 1.561 g/cm/sup 3/, mu = 0.557 mm-1, the final R1 0.0380 and wR2 = 0.0982 for 2160 observed reflections with I > 2sigma(I). A total of 12585 reflections were collected, of which 2601 were independent (Rint 0.0364). The herbicidal activity of title compound was determined, the results showed the title compound displayed excellent herbicidal activity against Brassica campestris. (author)

Structure–Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities

Directory of Open Access Journals (Sweden)

Yoshitomo Hamada

2015-10-01

Full Text Available Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4–8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (−-epigallocatechin-[4,8]-(+-catechin, (−-epigallocatechin-[4,8]-(−-epigallocatechin, (−-epigallocatechin-[4,8]-(−-epigallocatechin-3-O-gallate, and (+-catechin-[4,8]-(−-epigallocatechin and performed structure–activity relationship (SAR studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity.

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.

Structure-activity relationships in a new series of insecticidally active dioxatricycloalkenes derived by structural comparison of the GABA (. gamma. -aminobutyric acid) antagonists bicycloorthocarboxylates and endosulfan

Energy Technology Data Exchange (ETDEWEB)

Ozoe, Yoshihisa; Sawada, Yoshihiro; Mochida, Kazuo; Nakamura, Toshiie (Shimane Univ. (Japan)); Matsumura, Fumio (Univ. of California, Davis (USA))

1990-05-01

To study structural requirements for picrotoxinin-type GABA ({gamma}-aminobutyric acid) antagonists to interact with the receptor site, 5-substituted 4,6-dioxatricyclo(7.2.1.0{sup 2,8})dodec-10-enes and related compounds were prepared and examined for their insecticidal activity and potency in displacing ({sup 35}S)tert-butylbicyclophosphorothionate (TBPS) binding. Compounds with high insecticidal activity possessed a phenyl group with an electron-withdrawing para substituent, a cycloalkyl group, or a C{sub 3}-C{sub 5} straight-chain alkyl group at the 5-position. The effect of the 5-substituents on insecticidal activity was very similar to that of the 1-substituents of the bicyloorthocarboxylate GABA antagonists. Representative dioxatricycloalkenes displaced the binding of the GABA antagonist ({sup 35}S)TBPS to housefly head membranes by 29-53% at 10 {mu}M. X-ray crystal structure analysis demonstrated that this class of compounds had structures superimposable on those of 4-tert-butylbicycloorthocarboxylates. These findings indicate that the dioxatricycloalkenes and some other analogues occupy the picrotoxinin binding site in such a way that the fourth interacting subsite of the receptor site accommodates the 5-substituent.

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

Science.gov (United States)

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

2016-05-17

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

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

Science.gov (United States)

Giardina, G; Clarke, G D; Dondio, G; Petrone, G; Sbacchi, M; Vecchietti, V

1994-10-14

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

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

Science.gov (United States)

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

2018-07-01

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

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

Science.gov (United States)

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

2016-08-01

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

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.

Biochemical interpretation of quantitative structure-activity relationships (QSAR) for biodegradation of N-heterocycles: a complementary approach to predict biodegradability.

Science.gov (United States)

Philipp, Bodo; Hoff, Malte; Germa, Florence; Schink, Bernhard; Beimborn, Dieter; Mersch-Sundermann, Volker

2007-02-15

Prediction of the biodegradability of organic compounds is an ecologically desirable and economically feasible tool for estimating the environmental fate of chemicals. We combined quantitative structure-activity relationships (QSAR) with the systematic collection of biochemical knowledge to establish rules for the prediction of aerobic biodegradation of N-heterocycles. Validated biodegradation data of 194 N-heterocyclic compounds were analyzed using the MULTICASE-method which delivered two QSAR models based on 17 activating (OSAR 1) and on 16 inactivating molecular fragments (GSAR 2), which were statistically significantly linked to efficient or poor biodegradability, respectively. The percentages of correct classifications were over 99% for both models, and cross-validation resulted in 67.9% (GSAR 1) and 70.4% (OSAR 2) correct predictions. Biochemical interpretation of the activating and inactivating characteristics of the molecular fragments delivered plausible mechanistic interpretations and enabled us to establish the following biodegradation rules: (1) Target sites for amidohydrolases and for cytochrome P450 monooxygenases enhance biodegradation of nonaromatic N-heterocycles. (2) Target sites for molybdenum hydroxylases enhance biodegradation of aromatic N-heterocycles. (3) Target sites for hydratation by an urocanase-like mechanism enhance biodegradation of imidazoles. Our complementary approach represents a feasible strategy for generating concrete rules for the prediction of biodegradability of organic compounds.

Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

Science.gov (United States)

Nandi, Sisir; Monesi, Alessandro; Drgan, Viktor; Merzel, Franci; Novič, Marjana

2013-10-30

In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation.

Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity

Directory of Open Access Journals (Sweden)

Hui Wang

2016-11-01

Full Text Available Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF, induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d, three bromo-substituted products of crebanine (2a, 2b, 2c, N-methylcrebanine (2d, and dehydrostephanine (4a displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05, increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01, and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01. Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice, simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

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

Directory of Open Access Journals (Sweden)

Eliška Potůčková

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

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

, 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......) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr(5) was only 13-fold less...

Effect of green tea catechins and hydrolyzable tannins on benzo[a]pyrene-induced DNA adducts and structure-activity relationship.

Science.gov (United States)

Cao, Pengxiao; Cai, Jian; Gupta, Ramesh C

2010-04-19

Green tea catechins and hydrolyzable tannins are gaining increasing attention as chemopreventive agents. However, their mechanism of action is poorly understood. We investigated the effects of four green tea catechins and two hydrolyzable tannins on microsome-induced benzo[a]pyrene (BP)-DNA adducts and the possible structure-activity relationship. BP (1 microM) was incubated with rat liver microsomes and DNA in the presence of the test compound (1-200 microM) or vehicle. The purified DNA was analyzed by (32)P-postlabeling. The inhibitory activity of the catechins was in the following descending order: epigallocatechin gallate (IC(50) = 16 microM) > epicatechin gallate (24 microM) > epigallocatechin (146 microM) > epicatechin (462 microM), suggesting a correlation between the number of adjacent aromatic hydroxyl groups in the molecular structure and their potencies. Tannic acid (IC(50) = 4 microM) and pentagalloglucose (IC(50) = 26 microM) elicited as much DNA adduct inhibitory activity as the catechins or higher presumably due to the presence of more functional hydroxyl groups. To determine if the activity of these compounds was due to direct interaction of phenolic groups with electrophilic metabolite(s) of BP, DNA was incubated with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) (0.5 microM) in the presence of test compounds (200 microM) or vehicle. Significant inhibition of DNA adduct formation was found (tannic acid > pentagalloglucose > epigallocatechin gallate > epicatechin gallate). This notion was confirmed by analysis of the reaction products of anti-BPDE with the catechins and pentagalloglucose by electrospray ionization mass spectrometry and liquid chromatography-mass spectrometry. In conclusion, our data demonstrate that green tea catechins and the hydrolyzable tannins are highly effective in inhibiting BP-DNA adduct formation at least, in part, due to direct interaction of adjacent hydroxyl groups in their structures and that the activity is

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

Attraction Pheromone of The Benthic Diatom Seminavis robusta: Studies on Structure-Activity Relationships.

Science.gov (United States)

Lembke, Christine; Stettin, Daniel; Speck, Franziska; Ueberschaar, Nico; De Decker, Sam; Vyverman, Wim; Pohnert, Georg

2018-04-01

Recently the first pheromone of a marine diatom was identified to be the diketopiperazine (S,S)-diproline. This compound facilitates attraction between mating partners in the benthic diatom Seminavis robusta. Interestingly, sexualized S. robusta cells are attracted to both the natural pheromone (S,S)-diproline as well as to its enantiomer (R,R)-diproline. Usually stereospecificity is a prerequisite for successful substrate-receptor interactions, and especially pheromone perception is often highly enantioselective. Here we introduce a structure-activity relationship study, to learn more about the principles of pheromone reception in diatoms. We analyzed the activity of nine different diketopiperazines in attraction and interference assays. The pheromone diproline itself, as well as a pipecolic acid derived diketopiperazine with two expanded aliphatic ring systems, showed the highest attractivity. Hydroxylatoin of the aliphatic rings abolished any bioactivity. Diketopiperazines derived from acyclic amino acids were not attrative as well. All stereoisomers of both the diproline and the pipecolic acid derived diketopiperazine were purified by enantioselective high-performance liquid chromatography, and application in bioactivity tests confirmed that attraction pheromone perception in this diatom is indeed not stereospecific. However, the lack of activity of diketopiperazines derived from acyclic amino acids suggests a specificity that prevents misguidance to sources of other naturally occurring diketopiperazines.

MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition.

Science.gov (United States)

Usuki, Hirokazu; Yamamoto, Yukihiro; Kumagai, Yuya; Nitoda, Teruhiko; Kanzaki, Hiroshi; Hatanaka, Tadashi

2011-04-21

The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.

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

International Nuclear Information System (INIS)

Salter-Blanc, Alexandra J.; Lyon, Molly A.; Science University, Portland, OR; Ness, Stuart C.; Science University, Portland, OR; Tratnyek, Paul G.; Science University, Portland, OR

2016-01-01

New energetic compounds are designed to minimize their potential environmental impacts, which includes their transformation and the fate and effects of their transformation products. The nitro groups of energetic compounds are readily reduced to amines, and the resulting aromatic amines are subject to oxidation and coupling reactions. Manganese dioxide (MnO 2 ) is a common environmental oxidant and model system for kinetic studies of aromatic amine oxidation. Here in this study, a training set of new and previously reported kinetic data for the oxidation of model and energetic-derived aromatic amines was assembled and subjected to correlation analysis against descriptor variables that ranged from general purpose [Hammett σ constants (σ − ), pK a s of the amines, and energies of the highest occupied molecular orbital (E HOMO )] to specific for the likely rate-limiting step [one-electron oxidation potentials (E ox )]. The selection of calculated descriptors (pK a ), E HOMO , and E ox ) was based on validation with experimental data. All of the correlations gave satisfactory quantitative structure-activity relationships (QSARs), but they improved with the specificity of the descriptor. The scope of correlation analysis was extended beyond MnO 2 to include literature data on aromatic amine oxidation by other environmentally relevant oxidants (ozone, chlorine dioxide, and phosphate and carbonate radicals) by correlating relative rate constants (normalized to 4-chloroaniline) to E HOMO (calculated with a modest level of theory).

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.

Syntheses and absorption-structure relationships of some new ...

Indian Academy of Sciences (India)

New biheterocyclic compound was synthesized as starting material to prepare new photosensitizers mono-, tri-, substituted tri-, azadimethine and mixed cyanine dyes. Absorption-structure relationship of the synthesized cyanine dyes were determined by studying their electronic spectral behaviour in ethanol. The structure of ...

Larvicidal activity and structure activity relationship of cinnamoyl amides from Zanthoxylum armatum and their synthetic analogues against diamondback moth, Plutella xylostella.

Science.gov (United States)

Kumar, Vishal; Reddy, S G Eswara; Bhardwaj, Anuja; Dolma, Shudh Kirti; Kumar, Neeraj

2016-01-01

Cinnamoyl amides isolated from Zanthoxylum armatum (Rutaceae) and their synthetic analogues were tested for their insecticidal activity against the second instar larvae of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Yponomeutidae) to determine the promising structures with insecticidal activity. Most of the test compounds showed promising activity against larvae of P. xylostella. However, the activities of different compounds varied depending on the presence of different substituents at various positions of both the aromatic rings A and B. Among the tested compounds, 8, N-(3-bromo-4-methoxyphenethyl)cinnamamide showed best larvicidal activity with an LC50 = 62.13 mg/L followed by 6, N-(3׳-bromophenethyl)cinnamamide (LC50=128.49 mg/L) and 2 N-(4׳-methoxyphenylethyl)cinnamamide (LC50 = 225.65 mg/L).

Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

Science.gov (United States)

Das, Jagabandhu; Kimball, S David; Hall, Steven E; Han, Wen Ching; Iwanowicz, Edwin; Lin, James; Moquin, Robert V; Reid, Joyce A; Sack, John S; Malley, Mary F; Chang, Chiehying Y; Chong, Saeho; Wang-Iverson, David B; Roberts, Daniel G M; Seiler, Steven M; Schumacher, William A; Ogletree, Martin L

2002-01-07

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Bayesian screening for active compounds in high-dimensional chemical spaces combining property descriptors and molecular fingerprints.

Science.gov (United States)

Vogt, Martin; Bajorath, Jürgen

2008-01-01

Bayesian classifiers are increasingly being used to distinguish active from inactive compounds and search large databases for novel active molecules. We introduce an approach to directly combine the contributions of property descriptors and molecular fingerprints in the search for active compounds that is based on a Bayesian framework. Conventionally, property descriptors and fingerprints are used as alternative features for virtual screening methods. Following the approach introduced here, probability distributions of descriptor values and fingerprint bit settings are calculated for active and database molecules and the divergence between the resulting combined distributions is determined as a measure of biological activity. In test calculations on a large number of compound activity classes, this methodology was found to consistently perform better than similarity searching using fingerprints and multiple reference compounds or Bayesian screening calculations using probability distributions calculated only from property descriptors. These findings demonstrate that there is considerable synergy between different types of property descriptors and fingerprints in recognizing diverse structure-activity relationships, at least in the context of Bayesian modeling.

Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1.

Science.gov (United States)

Xie, Meng; Zhang, Hai-Jing; Deng, An-Jun; Wu, Lian-Qiu; Zhang, Zhi-Hui; Li, Zhi-Hong; Wang, Wen-Jie; Qin, Hai-Lin

2016-04-22

In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.

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.

A quantitative structure- property relationship of gas chromatographic/mass spectrometric retention data of 85 volatile organic compounds as air pollutant materials by multivariate methods

Directory of Open Access Journals (Sweden)

Sarkhosh Maryam

2012-05-01

Full Text Available Abstract A quantitative structure-property relationship (QSPR study is suggested for the prediction of retention times of volatile organic compounds. Various kinds of molecular descriptors were calculated to represent the molecular structure of compounds. Modeling of retention times of these compounds as a function of the theoretically derived descriptors was established by multiple linear regression (MLR and artificial neural network (ANN. The stepwise regression was used for the selection of the variables which gives the best-fitted models. After variable selection ANN, MLR methods were used with leave-one-out cross validation for building the regression models. The prediction results are in very good agreement with the experimental values. MLR as the linear regression method shows good ability in the prediction of the retention times of the prediction set. This provided a new and effective method for predicting the chromatography retention index for the volatile organic compounds.

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.

A new structure-activity relationship (SAR model for predicting drug-induced liver injury, based on statistical and expert-basedstructural alerts.

Directory of Open Access Journals (Sweden)

Fabiola Pizzo

2016-11-01

Full Text Available The prompt identification of chemical molecules with potential effects on liver may help in drug discovery and in raising the levels of protection for human health. Besides in vitro approaches, computational methods in toxicology are drawing attention. We built a structure-activity relationship (SAR model for evaluating hepatotoxicity. After compiling a data set of 950 compounds using data from the literature, we randomly split it into training (80% and test sets (20%. We also compiled an external validation set (101 compounds for evaluating the performance of the model. To extract structural alerts (SAs related to hepatotoxicity and non-hepatotoxicity we used SARpy, a statistical application that automatically identifies and extracts chemical fragments related to a specific activity. We also applied the chemical grouping approach for manually identifying other SAs. We calculated accuracy, specificity, sensitivity and Matthews correlation coefficient (MCC on the training, test and external validation sets. Considering the complexity of the endpoint, the model performed well. In the training, test and external validation sets the accuracy was respectively 81%, 63% and 68%, specificity 89%, 33% and 33%, sensitivity 93%, 88% and 80% and MCC 0.63, 0.27 and 0.13. Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the model’s architecture followed a conservative approach. As it was built using human data, it might be applied without any need for extrapolation from other species. This model will be freely available in the VEGA platform.

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.

Structural and Electronic Investigations of Complex Intermetallic Compounds

Energy Technology Data Exchange (ETDEWEB)

Ko, Hyunjin [Iowa State Univ., Ames, IA (United States)

2008-01-01

In solid state chemistry, numerous investigations have been attempted to address the relationships between chemical structure and physical properties. Such questions include: (1) How can we understand the driving forces of the atomic arrangements in complex solids that exhibit interesting chemical and physical properties? (2) How do different elements distribute themselves in a solid-state structure? (3) Can we develop a chemical understanding to predict the effects of valence electron concentration on the structures and magnetic ordering of systems by both experimental and theoretical means? Although these issues are relevant to various compound classes, intermetallic compounds are especially interesting and well suited for a joint experimental and theoretical effort. For intermetallic compounds, the questions listed above are difficult to answer since many of the constituent atoms simply do not crystallize in the same manner as in their separate, elemental structures. Also, theoretical studies suggest that the energy differences between various structural alternatives are small. For example, Al and Ga both belong in the same group on the Periodic Table of Elements and share many similar chemical properties. Al crystallizes in the fcc lattice with 4 atoms per unit cell and Ga crystallizes in an orthorhombic unit cell lattice with 8 atoms per unit cell, which are both fairly simple structures (Figure 1). However, when combined with Mn, which itself has a very complex cubic crystal structure with 58 atoms per unit cell, the resulting intermetallic compounds crystallize in a completely different fashion. At the 1:1 stoichiometry, MnAl forms a very simple tetragonal lattice with two atoms per primitive unit cell, while MnGa crystallizes in a complicated rhombohedral unit cell with 26 atoms within the primitive unit cell. The mechanisms influencing the arrangements of atoms in numerous crystal structures have been studied theoretically by calculating electronic

Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

Science.gov (United States)

Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

1998-03-01

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

Deciphering structure-activity relationships in a series of Tat/TAR inhibitors.

Science.gov (United States)

Pascale, Lise; González, Alejandro López; Di Giorgio, Audrey; Gaysinski, Marc; Teixido Closa, Jordi; Tejedor, Roger Estrada; Azoulay, Stéphane; Patino, Nadia

2016-11-01

A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.

Structure of Thermobifida fusca DyP-type peroxidase and activity towards Kraft lignin and lignin model compounds.

Science.gov (United States)

Rahmanpour, Rahman; Rea, Dean; Jamshidi, Shirin; Fülöp, Vilmos; Bugg, Timothy D H

2016-03-15

A Dyp-type peroxidase enzyme from thermophilic cellulose degrader Thermobifida fusca (TfuDyP) was investigated for catalytic ability towards lignin oxidation. TfuDyP was characterised kinetically against a range of phenolic substrates, and a compound I reaction intermediate was observed via pre-steady state kinetic analysis at λmax 404 nm. TfuDyP showed reactivity towards Kraft lignin, and was found to oxidise a β-aryl ether lignin model compound, forming an oxidised dimer. A crystal structure of TfuDyP was determined, to 1.8 Å resolution, which was found to contain a diatomic oxygen ligand bound to the heme centre, positioned close to active site residues Asp-203 and Arg-315. The structure contains two channels providing access to the heme cofactor for organic substrates and hydrogen peroxide. Site-directed mutant D203A showed no activity towards phenolic substrates, but reduced activity towards ABTS, while mutant R315Q showed no activity towards phenolic substrates, nor ABTS. Copyright © 2016 Elsevier Inc. All rights reserved.

Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPKα2β1γ1 activators.

Science.gov (United States)

Liu, Junhua; Chen, Dakai; Liu, Peng; He, Mengna; Li, Jia; Li, Jingya; Hu, Lihong

2014-05-22

Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure-activity relationship study showed that the amine derivatives at the 24-position (groups I-VI) can improve the potency (EC50: 0.7-2.3 μM) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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.

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.

Science.gov (United States)

Yin, Donghua; He, Yali; Perera, Minoli A; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane D; Dalton, James T

2003-01-01

The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

Structural Modifications of Benzimidazoles via Multi-Step Synthesis and Their Impact on Sirtuin-Inhibitory Activity.

Science.gov (United States)

Yoon, Yeong Keng; Choon, Tan Soo

2016-01-01

Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular design chemical structure generation from the properties of pure organic compounds

CERN Document Server

Horvath, AL

1992-01-01

This book is a systematic presentation of the methods that have been developed for the interpretation of molecular modeling to the design of new chemicals. The main feature of the compilation is the co-ordination of the various scientific disciplines required for the generation of new compounds. The five chapters deal with such areas as structure and properties of organic compounds, relationships between structure and properties, and models for structure generation. The subject is covered in sufficient depth to provide readers with the necessary background to understand the modeling

Anti-Candida albicans biofilm effect of novel heterocyclic compounds.

Science.gov (United States)

Kagan, Sarah; Jabbour, Adel; Sionov, Edward; Alquntar, Abed A; Steinberg, Doron; Srebnik, Morris; Nir-Paz, Ran; Weiss, Aryeh; Polacheck, Itzhack

2014-02-01

The aims of this study were to develop new anti-biofilm drugs, examine their activity against Candida albicans biofilm and investigate their structure-activity relationship and mechanism of action. A series of thiazolidinedione and succinimide derivatives were synthesized and their ability to inhibit C. albicans biofilm formation and destroy pre-formed biofilm was tested. The biofilms' structure, metabolic activity and viability were determined by XTT assay and propidium iodide and SYTO 9 live/dead stains combined with confocal microscopic analysis. The effect of the most active compounds on cell morphology, sterol distribution and cell wall morphology and composition was then determined by specific fluorescent stains and transmission electron microscopy. Most of the compounds were active at sub-MICs. Elongation of the aliphatic side chain resulted in reduced anti-biofilm activity and the sulphur atom contributed to biofilm killing, indicating a structure-activity relationship. The compounds differed in their effects on biofilm viability, yeast-to-hyphal form transition, hyphal morphology, cell wall morphology and composition, and sterol distribution. The most effective anti-biofilm compounds were the thiazolidinedione S8H and the succinimide NA8. We developed novel anti-biofilm agents that both inhibited and destroyed C. albicans biofilm. With some further development, these agents might be suitable for therapeutic purposes.

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

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Lorentz JÄNTSCHI

2006-01-01

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

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.

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.

Structure-activity relationships between sterols and their thermal stability in oil matrix.

Science.gov (United States)

Hu, Yinzhou; Xu, Junli; Huang, Weisu; Zhao, Yajing; Li, Maiquan; Wang, Mengmeng; Zheng, Lufei; Lu, Baiyi

2018-08-30

Structure-activity relationships between 20 sterols and their thermal stabilities were studied in a model oil system. All sterol degradations were found to be consistent with a first-order kinetic model with determination of coefficient (R 2 ) higher than 0.9444. The number of double bonds in the sterol structure was negatively correlated with the thermal stability of sterol, whereas the length of the branch chain was positively correlated with the thermal stability of sterol. A quantitative structure-activity relationship (QSAR) model to predict thermal stability of sterol was developed by using partial least squares regression (PLSR) combined with genetic algorithm (GA). A regression model was built with R 2 of 0.806. Almost all sterol degradation constants can be predicted accurately with R 2 of cross-validation equals to 0.680. Four important variables were selected in optimal QSAR model and the selected variables were observed to be related with information indices, RDF descriptors, and 3D-MoRSE descriptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

DEFF Research Database (Denmark)

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

2000-01-01

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application......" 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...

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

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.

New compounds from acid hydrolyzed products of the fruits of Momordica charantia L. and their inhibitory activity against protein tyrosine phosphatas 1B.

Science.gov (United States)

Zeng, Ke; He, Yan-Ni; Yang, Di; Cao, Jia-Qing; Xia, Xi-Chun; Zhang, Shi-Jun; Bi, Xiu-Li; Zhao, Yu-Qing

2014-06-23

Four new cucurbitane-type triterpene sapogenins, compounds 1-4, together with other eight known compounds were isolated from the acid-hydrolyzed fruits extract of Momordica charantia L. Their chemical structures were established by NMR, mass spectrometry and X-ray crystallography. Compounds 1-7 and 9-12 were evaluated for their inhibitory activities toward protein tyrosine phosphatase 1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for therapy against type II diabetes. Compounds 1, 2, 4, 7 and 9 were shown inhibitory activities of 77%, 62%, 62% 60% and 68% against PTP1B, respectively. All of these tested compounds were exhibited higher PTP1B inhibition activities than that of the Na3VO4, a known PTP1B inhibitor used as positive control in present study. Structure activity relationship (SAR) analysis indicated that the inhibition activity of PTP1B was associated with the presence and number of -OH groups. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A categorical structure-activity relationship analysis of the developmental toxicity of antithyroid drugs.

Science.gov (United States)

Cunningham, Albert R; Carrasquer, C Alex; Mattison, Donald R

2009-01-01

The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

TOXICOPHORES AND QUANTITATIVE STRUCTURE -TOXICITY RELATIONSHIPS FOR SOME ENVIRONMENTAL POLLUTANTS

Directory of Open Access Journals (Sweden)

N. N. Gorinchoy

2008-06-01

Full Text Available The electron-conformational (EC method is employed to reveal the toxicophore and to predict aquatic toxicity quantitatively using as a training set a series of 51 compounds that have aquatic toxicity to fish. By performing conformational analysis (optimization of geometries of the low-energy conformers by the PM3 method and electronic structure calculations (by ab initio method corrected within the SM54/PM3 solvatation model, the Electron-Conformational Matrix of Congruity (ECMC was constructed for each conformation of these compounds. The toxicophore defined as the EC sub-matrix of activity (ECSA, a sub-matrix with matrix elements common to all the active compounds under consideration within minimal tolerances, is determined by an iterative procedure of comparison of their ECMC’s, gradually minimizing the tolerances. Starting with only the four most toxic compounds, their ECSA (toxicophore was found to consists of a 4x4 matrix (four sites with certain electronic and topologic characteristics which was shown to be present in 17 most active compounds. A structure-toxicity correlation between three toxicophore parameters and the activities of these 17 compounds with R2=0.94 was found. It is shown that the same toxicophore with larger tolerances satisfies the compounds with les activity, thus explicitly demonstrating how the activity is controlled by the tolerances quantitatively and which atoms (sites are most flexible in this respect. This allows for getting slightly different toxicophores for different levels of activity. For some active compounds that have no toxicophore a bimolecular mechanism of activity is suggested. Distinguished from other QSAR methods, no arbitrary descriptors and no statistics are involved in this EC structure-activity investigation.

Activity of Polyphenolic Compounds against Candida glabrata

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Ricardo Salazar-Aranda

2015-09-01

Full Text Available Opportunistic mycoses increase the morbidity and mortality of immuno-compromised patients. Five Candida species have been shown to be responsible for 97% of worldwide cases of invasive candidiasis. Resistance of C. glabrata and C. krusei to azoles has been reported, and new, improved antifungal agents are needed. The current study was designed to evaluatethe activity of various polyphenolic compounds against Candida species. Antifungal activity was evaluated following the M27-A3 protocol of the Clinical and Laboratory Standards Institute, and antioxidant activity was determined using the DPPH assay. Myricetin and baicalein inhibited the growth of all species tested. This effect was strongest against C. glabrata, for which the minimum inhibitory concentration (MIC value was lower than that of fluconazole. The MIC values against C. glabrata for myricitrin, luteolin, quercetin, 3-hydroxyflavone, and fisetin were similar to that of fluconazole. The antioxidant activity of all compounds was confirmed, and polyphenolic compounds with antioxidant activity had the greatest activity against C. glabrata. The structure and position of their hydroxyl groups appear to influence their activity against C. glabrata.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

Science.gov (United States)

Ogawa, Seiji; Watanabe, Toshihide; Moriyuki, Kazumi; Goto, Yoshikazu; Yamane, Shinsaku; Watanabe, Akio; Tsuboi, Kazuma; Kinoshita, Atsushi; Okada, Takuya; Takeda, Hiroyuki; Tani, Kousuke; Maruyama, Toru

2016-05-15

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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Katalin Prokai-Tatrai

2013-01-01

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

Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

Energy Technology Data Exchange (ETDEWEB)

Zhang, Lianying [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); College of Life Science, Dezhou University, Dezhou 253023 (China); Ren, Xiao-Min; Wan, Bin [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China)

2014-09-15

Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.

Predicting the activity of drugs for a group of imidazopyridine anticoccidial compounds.

Science.gov (United States)

Si, Hongzong; Lian, Ning; Yuan, Shuping; Fu, Aiping; Duan, Yun-Bo; Zhang, Kejun; Yao, Xiaojun

2009-10-01

Gene expression programming (GEP) is a novel machine learning technique. The GEP is used to build nonlinear quantitative structure-activity relationship model for the prediction of the IC(50) for the imidazopyridine anticoccidial compounds. This model is based on descriptors which are calculated from the molecular structure. Four descriptors are selected from the descriptors' pool by heuristic method (HM) to build multivariable linear model. The GEP method produced a nonlinear quantitative model with a correlation coefficient and a mean error of 0.96 and 0.24 for the training set, 0.91 and 0.52 for the test set, respectively. It is shown that the GEP predicted results are in good agreement with experimental ones.

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

Science.gov (United States)

Jin, Weihua; Zhang, Wenjing; Liang, Hongze; Zhang, Quanbin

2015-01-01

In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA) content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal) to fucose (Fuc) was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation. PMID:26712768

Taste-active compounds in a traditional Italian food: 'lampascioni'.

Science.gov (United States)

Borgonovo, Gigliola; Caimi, Sara; Morini, Gabriella; Scaglioni, Leonardo; Bassoli, Angela

2008-06-01

Nature is a rich source of taste-active compounds, in particular of plant origin, many of which have unusual tastes. Many of these are found in traditional food, where spontaneous plants are used as ingredients. Some taste-active compounds were identified in the bulbs of Muscari comosum, a spontaneous plant belonging to the family of the Liliaceae, very common in the Mediterranean area, and used in traditional gastronomy (called 'lampascioni' in South Italy). The bulbs were extracted with a series of solvents of different polarity. The different fractions were submitted to a preliminary sensory evaluation, and the most interesting ones, characterized by a strong bitter taste and some chemestetic properties, were submitted to further purification and structural analysis. From the ethereal extract, several 3-benzyl-4-chromanones and one stilbene derivative were isolated. Pure compounds were examined for their taste activity by means of sensory evaluation, and proved to be responsible for the characteristic taste of this food. Some of these compounds have been synthesized de novo to confirm their structure.

Development of an in Silico Model of DPPH• Free Radical Scavenging Capacity: Prediction of Antioxidant Activity of Coumarin Type Compounds

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Elizabeth Goya Jorge

2016-06-01

Full Text Available A quantitative structure-activity relationship (QSAR study of the 2,2-diphenyl-l-picrylhydrazyl (DPPH• radical scavenging ability of 1373 chemical compounds, using DRAGON molecular descriptors (MD and the neural network technique, a technique based on the multilayer multilayer perceptron (MLP, was developed. The built model demonstrated a satisfactory performance for the training ( R 2 = 0.713 and test set ( Q ext 2 = 0.654 , respectively. To gain greater insight on the relevance of the MD contained in the MLP model, sensitivity and principal component analyses were performed. Moreover, structural and mechanistic interpretation was carried out to comprehend the relationship of the variables in the model with the modeled property. The constructed MLP model was employed to predict the radical scavenging ability for a group of coumarin-type compounds. Finally, in order to validate the model’s predictions, an in vitro assay for one of the compounds (4-hydroxycoumarin was performed, showing a satisfactory proximity between the experimental and predicted pIC50 values.

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.

Science.gov (United States)

Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S; Nallaganchu, Bhaskara Rao; Olson, Gary L; Dicker, David T; Allen, Joshua E; El-Deiry, Wafik S

2014-12-30

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.

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.

Thermodynamic and structure-property study of liquid-vapor equilibrium for aroma compounds.

Science.gov (United States)

Tromelin, Anne; Andriot, Isabelle; Kopjar, Mirela; Guichard, Elisabeth

2010-04-14

Thermodynamic parameters (T, DeltaH degrees , DeltaS degrees , K) were collected from the literature and/or calculated for five esters, four ketones, two aldehydes, and three alcohols, pure compounds and compounds in aqueous solution. Examination of correlations between these parameters and the range values of DeltaH degrees and DeltaS degrees puts forward the key roles of enthalpy for vaporization of pure compounds and of entropy in liquid-vapor equilibrium of compounds in aqueous solution. A structure-property relationship (SPR) study was performed using molecular descriptors on aroma compounds to better understand their vaporization behavior. In addition to the role of polarity for vapor-liquid equilibrium of compounds in aqueous solution, the structure-property study points out the role of chain length and branching, illustrated by the correlation between the connectivity index CHI-V-1 and the difference between T and log K for vaporization of pure compounds and compounds in aqueous solution. Moreover, examination of the esters' enthalpy values allowed a probable conformation adopted by ethyl octanoate in aqueous solution to be proposed.

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

International Nuclear Information System (INIS)

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

2010-01-01

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. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

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

Energy Technology Data Exchange (ETDEWEB)

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

2010-08-15

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

Synthesis and biological activity of chimeric structures derived from the cytotoxic natural compounds dolastatin 10 and dolastatin 15.

Science.gov (United States)

Poncet, J; Busquet, M; Roux, F; Pierré, A; Atassi, G; Jouin, P

1998-04-23

The natural cytotoxic compounds dolastatins 10 and 15 exhibit great similarities in structure and in their biological activity profiles. Two compounds (1 and 2) formed by interchanging the dolaisoleuine residue of dolastatin 10 and the MeVal-Pro dipeptide of dolastatin 15 were synthesized in order to evaluate the possible equivalence of these units. These compounds can be considered as chimeras of dolastatins 10 and 15 formed by the N-terminal part of the former and the C-terminal part of the latter and vice versa. Both analogues exhibited a marked decrease in their cytotoxic activity but showed similar differential cytotoxicity with regard to the cell lines assayed compared with the parent compounds. HT-29 cell line was the least sensitive one. However, this activity was in the nanomolar level and close to that of vincristine. The differences in their effect on tubulin polymerization were less pronounced. We confirmed the already known crucial role of the Dil residue in this assay. The nonequivalence of the Dil unit and the MeVal-Pro dipeptide probably reflects modification in the relative positions of the N-dimethylamino and the phenyl moieties.

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.

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

Science.gov (United States)

Wang, Zhanggen; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen; Yang, Burton B.

2017-01-01

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. PMID:28052025

Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies.

Science.gov (United States)

Sarswat, Amit; Kumar, Rajeev; Kumar, Lalit; Lal, Nand; Sharma, Smriti; Prabhakar, Yenamandra S; Pandey, Shailendra K; Lal, Jawahar; Verma, Vikas; Jain, Ashish; Maikhuri, Jagdamba P; Dalela, Diwakar; Kirti; Gupta, Gopal; Sharma, Vishnu L

2011-01-13

A series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15-47%. Three compounds, 10, 12, and 18, had better activity profile (reduced prostate weight by 47%, 43%, and 39%, respectively) than the standard drug flutamide (24% reduction). QSAR suggested structures with more cyclic and branched moieties, increased topological separation of O and N therein, and reduced solvation connectivity index for better activity. Pharmacokinetic study with compound 10 at an oral dose of 10.0 mg/kg indicated good absorption, negligible extrahepatic elimination, and rapid distribution to the target organ (prostate) but restricted entry through the blood-brain barrier. A 10-fold decrease in PSA and 15-fold increase in ER-β gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-β mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia.

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

A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

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Cunningham AlbertR

2009-11-01

Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

Directory of Open Access Journals (Sweden)

Albert R. Cunningham

2009-01-01

Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

Scopadulciol, an inhibitor of gastric H+, K(+)-ATPase from Scoparia dulcis, and its structure-activity relationships.

Science.gov (United States)

Hayashi, T; Asano, S; Mizutani, M; Takeguchi, N; Kojima, T; Okamura, K; Morita, N

1991-01-01

A new tetracyclic diterpenoid, scopadulciol [3], together with 6-methoxybenzoxazolinone, glutinol, and acacetin, was isolated from the 70% EtOH extract of Scoparia dulcis collected in Taiwan. Its structure was elucidated to be 6 beta-benzoyl-12-methyl-13-oxo-9(12)a,9(12)b-dihomo-18-podocarpanol on the basis of spectral data. It mildly inhibited hog gastric H+, K(+)-ATPase. Examination of the inhibitory activities of derivatives of scopadulcic acid B [2], including 3, revealed that methylation of the carboxyl group and introduction of an acetyl group or oxime at C-13 or C-18 markedly enhanced the inhibitory activity, while debenzoylation reduced the activity. Among the 30 compounds tested, compound 12, a methyl ester of scopadulcic acid B [2], showed the most potent activity.

The structures of binary compounds

CERN Document Server

Hafner, J; Jensen, WB; Majewski, JA; Mathis, K; Villars, P; Vogl, P; de Boer, FR

1990-01-01

- Up-to-date compilation of the experimental data on the structures of binary compounds by Villars and colleagues. - Coloured structure maps which order the compounds into their respective structural domains and present for the first time the local co-ordination polyhedra for the 150 most frequently occurring structure types, pedagogically very helpful and useful in the search for new materials with a required crystal structure. - Crystal co-ordination formulas: a flexible notation for the interpretation of solid-state structures by chemist Bill Jensen. - Recent important advances in unders

Cationic lipids: molecular structure/ transfection activity relationships and interactions with biomembranes.

Science.gov (United States)

Koynova, Rumiana; Tenchov, Boris

2010-01-01

Abstract Synthetic cationic lipids, which form complexes (lipoplexes) with polyanionic DNA, are presently the most widely used constituents of nonviral gene carriers. A large number of cationic amphiphiles have been synthesized and tested in transfection studies. However, due to the complexity of the transfection pathway, no general schemes have emerged for correlating the cationic lipid chemistry with their transfection efficacy and the approaches for optimizing their molecular structures are still largely empirical. Here we summarize data on the relationships between transfection activity and cationic lipid molecular structure and demonstrate that the transfection activity depends in a systematic way on the lipid hydrocarbon chain structure. A number of examples, including a large series of cationic phosphatidylcholine derivatives, show that optimum transfection is displayed by lipids with chain length of approximately 14 carbon atoms and that the transfection efficiency strongly increases with increase of chain unsaturation, specifically upon replacement of saturated with monounsaturated chains.

The structure of active centers and the kinetic isotopic effect in the ionic polymerization of heterocyclic compounds

International Nuclear Information System (INIS)

Ponomarienko, W.A.; Berman, E.L.

1979-01-01

The method of kinetic isotopic effect has been applied to the elucidation of the structure of the active growth centres in the polymerization of some selected heterocyclic compounds. The cationic polymerization of ehtylene oxide, tetrahydrofuran and 1.3-dioxolane as well as the anionic and coordination polymerization of ethylene oxide have been discussed. (author)

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.

Active compounds from cyanobacteria and microalgae: properties and potential applications in biomedicine

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Alexey Llopiz

2016-05-01

Full Text Available Cyanobacteria and microalgae are source of many chemicals substances with potential applications on biopharmaceutical industry. Many structures have been characterized in these organism, such as: peptides, proteins, carbohydrates, terpenoids, polyinsatured fatty acids, flavonoids, phenolic compounds, vitamins, porfirins and other organic substances. Chemicals structures of isolated compounds are diverse and it depends of microalgae habitats. Pharmacological activities located in microalgae are bactericides, immunomodulatory, antioxidants, cytoprotective, fungicides and antivirals. These properties may possible the potential treatment of many diseases including autoimmunes disorders, tumoral, and infectious process. In this review are presented and discussed some elements associated to chemical structure and biological activities around of compounds with potential uses as biopharmaceuticals.

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

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Li-Wei Zou

2017-06-01

Full Text Available Human carboxylesterase 1 (hCE1, one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs were assayed using D-Luciferin methyl ester (DME and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA, and ursolic acid (UA were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22, led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking

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

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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.

Follow-up: Prospective compound design using the ‘SAR Matrix’ method and matrix-derived conditional probabilities of activity [v1; ref status: indexed, http://f1000r.es/56v

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Disha Gupta-Ostermann

2015-03-01

Full Text Available In a previous Method Article, we have presented the ‘Structure-Activity Relationship (SAR Matrix’ (SARM approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a “chemical space envelope” around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach.

Follow-up: Prospective compound design using the ‘SAR Matrix’ method and matrix-derived conditional probabilities of activity [v2; ref status: indexed, http://f1000r.es/59v

Directory of Open Access Journals (Sweden)

Disha Gupta-Ostermann

2015-04-01

Full Text Available In a previous Method Article, we have presented the ‘Structure-Activity Relationship (SAR Matrix’ (SARM approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a “chemical space envelope” around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach.

Structure modification and functionality of whey proteins: quantitative structure-activity relationship approach.

Science.gov (United States)

Nakai, S; Li-Chan, E

1985-10-01

According to the original idea of quantitative structure-activity relationship, electric, hydrophobic, and structural parameters should be taken into consideration for elucidating functionality. Changes in these parameters are reflected in the property of protein solubility upon modification of whey proteins by heating. Although solubility is itself a functional property, it has been utilized to explain other functionalities of proteins. However, better correlations were obtained when hydrophobic parameters of the proteins were used in conjunction with solubility. Various treatments reported in the literature were applied to whey protein concentrate in an attempt to obtain whipping and gelling properties similar to those of egg white. Mapping simplex optimization was used to search for the best results. Improvement in whipping properties by pepsin hydrolysis may have been due to higher protein solubility, and good gelling properties resulting from polyphosphate treatment may have been due to an increase in exposable hydrophobicity. However, the results of angel food cake making were still unsatisfactory.

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...

Heterocyclic Naphthalimides as New Skeleton Structure of Compounds with Increasingly Expanding Relational Medicinal Applications.

Science.gov (United States)

Gong, Huo-Hui; Addla, Dinesh; Lv, Jing-Song; Zhou, Cheng-He

2016-01-01

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.

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.

Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.

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Melissa L Sykes

Full Text Available Human African Trypanosomiasis (HAT is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs. An approach to identify starting points for new drug candidates is high throughput screening (HTS of large compound library collections. We describe the application of an Alamar Blue based, 384-well HTS assay to screen a library of 87,296 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei bloodstream form lister 427. Primary hits identified against T.b. brucei were retested and the IC(50 value compounds were estimated for T.b. brucei and a mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Cluster analysis of these compounds, taking into account chemical and structural properties required for drug-like compounds, afforded a panel of eight compounds for further biological analysis. These compounds had IC(50 values ranging from 0.22 µM to 4 µM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new chemical classes with activity against the causative species of HAT, which can be considered potential candidates for HAT early drug discovery. Structure activity relationship (SAR mining revealed components of those hit compound structures that may be important for biological activity. Four of these compounds have undergone further testing to 1 determine whether they are cidal or static in vitro at the minimum inhibitory concentration (MIC, and 2 estimate the time to kill.

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.

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

Science.gov (United States)

Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M; Koolen, Karin J M; Dechering, Koen J; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania

2018-04-25

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba 2+ current through Ca v 1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A combined Fisher and Laplacian score for feature selection in QSAR based drug design using compounds with known and unknown activities.

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Valizade Hasanloei, Mohammad Amin; Sheikhpour, Razieh; Sarram, Mehdi Agha; Sheikhpour, Elnaz; Sharifi, Hamdollah

2018-02-01

Quantitative structure-activity relationship (QSAR) is an effective computational technique for drug design that relates the chemical structures of compounds to their biological activities. Feature selection is an important step in QSAR based drug design to select the most relevant descriptors. One of the most popular feature selection methods for classification problems is Fisher score which aim is to minimize the within-class distance and maximize the between-class distance. In this study, the properties of Fisher criterion were extended for QSAR models to define the new distance metrics based on the continuous activity values of compounds with known activities. Then, a semi-supervised feature selection method was proposed based on the combination of Fisher and Laplacian criteria which exploits both compounds with known and unknown activities to select the relevant descriptors. To demonstrate the efficiency of the proposed semi-supervised feature selection method in selecting the relevant descriptors, we applied the method and other feature selection methods on three QSAR data sets such as serine/threonine-protein kinase PLK3 inhibitors, ROCK inhibitors and phenol compounds. The results demonstrated that the QSAR models built on the selected descriptors by the proposed semi-supervised method have better performance than other models. This indicates the efficiency of the proposed method in selecting the relevant descriptors using the compounds with known and unknown activities. The results of this study showed that the compounds with known and unknown activities can be helpful to improve the performance of the combined Fisher and Laplacian based feature selection methods.

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles

Directory of Open Access Journals (Sweden)

Marcos Lorca

2018-05-01

Full Text Available The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB, and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR techniques. This is the first combined comparative molecular field analysis (CoMFA and comparative molecular similarity index analysis (CoMSIA study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2ncv = 0.993 and 0.984 and values of r2test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2m, etc. and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561.

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

International Nuclear Information System (INIS)

Ressler, T.; Jentoft, R.E.; Wienold, J.; Girgsdies, F.; Neisius, T.; Timpe, O.

2003-01-01

Knowing the composition and the evolution of the bulk structure of a heterogeneous catalyst under working conditions (in situ) is a pre-requisite for understanding structure-activity relationships. X-ray absorption spectroscopy can be employed to study a catalytically active material in situ. In addition to steady-state investigations, the technique permits experiments with a time-resolution in the sub-second range to elucidate the solid-state kinetics of the reactions involved. Combined with mass spectrometry, the evolution of the short-range order structure of a heterogeneous catalyst, the average valence of the constituent metals, and the phase composition can be obtained. Here we present results obtained from time-resolved studies on the reduction of MoO 3 in propene and in propene and oxygen

Quantitative structure-cytotoxicity relationship of piperic acid amides.

Science.gov (United States)

Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Miyashiro, Takaki; Sugita, Yoshiaki; Sakagami, Hiroshi

2014-09-01

A total of 12 piperic acid amides, including piperine, were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to find new biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of the CC50 to 50% HIV infection-cytoprotective concentration (EC50). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by LowModeMD method followed by density functional theory method. All compounds showed low-to-moderate tumor selectivity, but no anti-HIV activity. N-Piperoyldopamine ( 8: ) which has a catechol moiety, showed the highest tumor selectivity, possibly due to its unique molecular shape and electrostatic interaction, especially its largest partial equalization of orbital electronegativities and vsurf descriptors. The present study suggests that molecular shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of piperic acid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Biological Activities of Phenolic Compounds of Extra Virgin Olive Oil

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Maurizio Servili

2013-12-01

Full Text Available Over the last few decades, multiple biological properties, providing antioxidant, anti-inflammatory, chemopreventive and anti-cancer benefits, as well as the characteristic pungent and bitter taste, have been attributed to Extra Virgin Olive Oil (EVOO phenols. In particular, growing efforts have been devoted to the study of the antioxidants of EVOO, due to their importance from health, biological and sensory points of view. Hydrophilic and lipophilic phenols represent the main antioxidants of EVOO, and they include a large variety of compounds. Among them, the most concentrated phenols are lignans and secoiridoids, with the latter found exclusively in the Oleaceae family, of which the drupe is the only edible fruit. In recent years, therefore, we have tackled the study of the main properties of phenols, including the relationships between their biological activity and the related chemical structure. This review, in fact, focuses on the phenolic compounds of EVOO, and, in particular, on their biological properties, sensory aspects and antioxidant capacity, with a particular emphasis on the extension of the product shelf-life.

Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines.

Science.gov (United States)

Wu, Wenyan; Sil, Diptesh; Szostak, Michal L; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Kimbrell, Matthew R; Cromer, Jens R; David, Sunil A

2009-01-15

The toxicity of gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of gram-negative sepsis. We had previously identified in rapid-throughput screens several guanylhydrazones as potent LPS binders. We were desirous of examining if the presence of the guanylhydrazone (rather than an amine) functionality would afford greater LPS sequestration potency. In evaluating a congeneric set of guanylhydrazone analogues, we find that C(16) alkyl substitution is optimal in the N-alkylguanylhydrazone series; a homospermine analogue with the terminal amine N-alkylated with a C(16) chain with the other terminus of the molecule bearing an unsubstituted guanylhydrazone moiety is marginally more active, suggesting very slight, if any, steric effects. Neither C(16) analogue is significantly more active than the N-C(16)-alkyl or N-C(16)-acyl compounds that we had characterized earlier, indicating that basicity of the phosphate-recognizing cationic group, is not a determinant of LPS sequestration activity.

Characteristics of chemical binding to alpha 2u-globulin in vitro--evaluating structure-activity relationships

International Nuclear Information System (INIS)

Borghoff, S.J.; Miller, A.B.; Bowen, J.P.; Swenberg, J.A.

1991-01-01

alpha 2u-Globulin (alpha 2u) has been shown to accumulate in the kidneys of male rats treated with 2,2,4-trimethylpentane (TMP). 2,4,4-Trimethyl-2-pentanol (TMP-2-OH), a metabolite of TMP, is found reversibly bound to alpha 2u isolated from the kidneys of these treated rats. The objectives of the following study were to characterize the ability of [3H]TMP-2-OH to bind to alpha 2u in vitro and to determine whether other compounds that cause this protein to accumulate have the same binding characteristics. Although compounds that have been shown to cause the accumulation of alpha 2u in male rat kidneys compete in vitro with [3H]TMP-2-OH for binding to alpha 2u, they do so to varying degrees. The binding affinity (Kd) of the [3H]TMP-2-OH-alpha 2u complex was calculated to be on the order of 10(-7) M. The inhibition constant values (Ki) determined for d-limonene, 1,4-dichlorobenzene, and 2,5-dichlorophenol were all in the range 10(-4) M, whereas the Ki values for isophorone, 2,4,4- or 2,2,4-trimethyl-1-pentanol, and d-limonene oxide were determined to be in the range 10(-6) and 10(-7) M, respectively. TMP and 2,4,4- and 2,2,4-trimethylpentanoic acid did not compete for binding. This suggests that other factors, besides binding, are involved in the accumulation of alpha 2u. In this study the ability of a chemical to bind to alpha 2u was used as a measure of biological activity to assess structure-activity relationships among the chemicals tested and known to cause the accumulation of alpha 2u. The results so far suggest that binding is dependent on both hydrophobic interactions and hydrogen bonding

Electronic structure of A15 compounds

International Nuclear Information System (INIS)

Pickett, W.E.

1980-01-01

For the past twenty-five years compounds with the A15 crystal structure have dominated the class of high temperature superconductors. The crystal structure of an A15 compound A 3 B is cubic (space group O/sub h/ 3 ). However, the site symmetry (D/sub 2d/) of the A atoms is much lower than cubic, an unusual occurrence in cubic binary compounds. Variations on this theme have supplied the basis of many theoretical models of the anomalous temperature (T) dependence of normal state properties and the low temperature cubic reversible tetragonal structural transformations which accompany high values of T/sub c/ in A15 compounds. In this paper results of self-consistent pseudopotential band structure calculations are used to assess some important aspects of the unique and unusual behavior in A15 compounds: (1) the role of the B atom in determining the overall electronic structure will be shown to be important; (2) the effect of the low site symmetry of the A atom on the charge density and potential will be assessed; and (3) the bonding will be shown to be metallic-covalent with no significant A-B charge transfer

Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds.

Science.gov (United States)

Macfarlane, D E; Manzel, L

1998-02-01

Phosphorothioate oligodeoxynucleotides containing CpG (CpG-ODN) activate immune responses. We report that quinacrine, chloroquine, and structurally related compounds completely inhibit the antiapoptotic effect of CpG-ODN on WEHI 231 murine B lymphoma cells and inhibit CpG-ODN-induced secretion of IL-6 by WEHI 231. They also inhibit IL-6 synthesis and thymidine uptake by human unfractionated PBMC induced by CpG-ODN. The compounds did not inhibit LPS-induced responses. Half-maximal inhibition required 10 nM quinacrine or 100 nM chloroquine. Inhibition was noncompetitive with respect to CpG-ODN. Quinine, quinidine, and primaquine were much less powerful. Quinacrine was effective even when added after the CpG-ODN. Near-toxic concentrations of ammonia plus bafilomycin A1 (used to inhibit vesicular acidification) did not reduce the efficacy of the quinacrine, but the effects of both quinacrine and chloroquine were enhanced by inhibition of the multidrug resistance efflux pump by verapamil. Agents that bind to DNA, including propidium iodide, Hoechst dye 33258, and coralyne chloride did not inhibit CpG-ODN effect, nor did 4-bromophenacyl bromide, an inhibitor of phospholipase A2. Examination of the structure-activity relationship of seventy 4-aminoquinoline and 9-aminoacridine analogues reveals that increased activity was conferred by bulky hydrophobic substituents on positions 2 and 6 of the quinoline nucleus. No correlation was found between published antimalarial activity and ability to block CpG-ODN-induced effects. These results are discussed in the light of the ability of quinacrine and chloroquine to induce remission of rheumatoid arthritis and lupus erythematosus.

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.

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

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.

Differentiation of the molecular structure of nitro compounds as the basis for simulation of their thermal destruction processes

Energy Technology Data Exchange (ETDEWEB)

Korolev, V L; Pivina, Tatyana S; Sheremetev, Aleksei B [N.D.Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow (Russian Federation); Porollo, A A [University of Cincinnati, Cincinnati (United States); Petukhova, T V; Ivshin, Viktor P [Mari State University, Yoshkar-Ola (Russian Federation)

2009-10-31

Data on the experimental and theoretical studies of thermal decomposition of C- and N-nitro compounds of aliphatic, alicyclic, aromatic and heteroaromatic compounds, which formed the grounds for the development of ab initio approach to the prediction of the mechanisms of thermolysis of energetic compounds, are described systematically. The relationships between the structures and thermolysis mechanisms of compounds based on differentiation of the structural fragments depending on the functional surrounding of nitro groups are identified. Using the RRN (Recombination Reaction Network) strategy and original CASB (Computer Assisted Structure Building) software, full reaction mechanisms for the thermal destruction of nitro compounds at different thermal decomposition levels (including extensive ones) are simulated. The full set of possible mechanisms of thermal decomposition of 38 chemically different nitro compounds is presented

Synthesis and biological activity of sulfur compounds showing structural analogy with combretastatin A-4

Energy Technology Data Exchange (ETDEWEB)

Santos, Edson dos A. dos; Prado, Paulo C.; Carvalho, Wanderley R. de; Lima, Ricardo V. de; Beatriz, Adilson; Lima, Denis P. de, E-mail: denis.lima@ufms.br [Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, MS (Brazil). Departamento de Quimica; Hamel, Ernest [Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD (United States); Dyba, Marzena A. [Basic Science Program , SAIC-Frederick, Inc., Structural Biophysics Laboratory National Cancer Institute, Frederick, MD (United States); Albuquerque, Sergio [Universidade de Sao Paulo (USP), Ribeirao Preto, SP (Brazil). Faculdade de Ciencias Farmaceuticas

2013-09-01

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904),and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15). (author)

Relationship between structure and antiproliferative activity of 1-azaflavanones.

Science.gov (United States)

Kawaii, Satoru; Endo, Kotaro; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-07-01

The synthesis of 19 derivatives of 2-phenyl-3,4-dihydroquinolin-4(1H)-one, as aza analogs of flavanones, was carried out and these compounds were further screened for their antiproliferative activity toward HL60 promyelocytic leukemia cells. In comparison with flavanone the replacement of C-ring ether oxygen atom with a nitrogen atom potentiated activity by more than 100-fold. It was suggested that the aromaticity of the B-ring contributes greatly to the activity of 1-azaflavanones.

A New Variable Selection Method Based on Mutual Information Maximization by Replacing Collinear Variables for Nonlinear Quantitative Structure-Property Relationship Models

Energy Technology Data Exchange (ETDEWEB)

Ghasemi, Jahan B.; Zolfonoun, Ehsan [Toosi University of Technology, Tehran (Korea, Republic of)

2012-05-15

Selection of the most informative molecular descriptors from the original data set is a key step for development of quantitative structure activity/property relationship models. Recently, mutual information (MI) has gained increasing attention in feature selection problems. This paper presents an effective mutual information-based feature selection approach, named mutual information maximization by replacing collinear variables (MIMRCV), for nonlinear quantitative structure-property relationship models. The proposed variable selection method was applied to three different QSPR datasets, soil degradation half-life of 47 organophosphorus pesticides, GC-MS retention times of 85 volatile organic compounds, and water-to-micellar cetyltrimethylammonium bromide partition coefficients of 62 organic compounds.The obtained results revealed that using MIMRCV as feature selection method improves the predictive quality of the developed models compared to conventional MI based variable selection algorithms.

A New Variable Selection Method Based on Mutual Information Maximization by Replacing Collinear Variables for Nonlinear Quantitative Structure-Property Relationship Models

International Nuclear Information System (INIS)

Ghasemi, Jahan B.; Zolfonoun, Ehsan

2012-01-01

Selection of the most informative molecular descriptors from the original data set is a key step for development of quantitative structure activity/property relationship models. Recently, mutual information (MI) has gained increasing attention in feature selection problems. This paper presents an effective mutual information-based feature selection approach, named mutual information maximization by replacing collinear variables (MIMRCV), for nonlinear quantitative structure-property relationship models. The proposed variable selection method was applied to three different QSPR datasets, soil degradation half-life of 47 organophosphorus pesticides, GC-MS retention times of 85 volatile organic compounds, and water-to-micellar cetyltrimethylammonium bromide partition coefficients of 62 organic compounds.The obtained results revealed that using MIMRCV as feature selection method improves the predictive quality of the developed models compared to conventional MI based variable selection algorithms

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.

Quantitative structure-retention relationship studies using immobilized artificial membrane chromatography I: amended linear solvation energy relationships with the introduction of a molecular electronic factor.

Science.gov (United States)

Li, Jie; Sun, Jin; Cui, Shengmiao; He, Zhonggui

2006-11-03

Linear solvation energy relationships (LSERs) amended by the introduction of a molecular electronic factor were employed to establish quantitative structure-retention relationships using immobilized artificial membrane (IAM) chromatography, in particular ionizable solutes. The chromatographic indices, log k(IAM), were determined by HPLC on an IAM.PC.DD2 column for 53 structurally diverse compounds, including neutral, acidic and basic compounds. Unlike neutral compounds, the IAM chromatographic retention of ionizable compounds was affected by their molecular charge state. When the mean net charge per molecule (delta) was introduced into the amended LSER as the sixth variable, the LSER regression coefficient was significantly improved for the test set including ionizable solutes. The delta coefficients of acidic and basic compounds were quite different indicating that the molecular electronic factor had a markedly different impact on the retention of acidic and basic compounds on IAM column. Ionization of acidic compounds containing a carboxylic group tended to impair their retention on IAM, while the ionization of basic compounds did not have such a marked effect. In addition, the extra-interaction with the polar head of phospholipids might cause a certain change in the retention of basic compounds. A comparison of calculated and experimental retention indices suggested that the semi-empirical LSER amended by the addition of a molecular electronic factor was able to reproduce adequately the experimental retention factors of the structurally diverse solutes investigated.

Unraveling the structure and chemical mechanisms of highly oxygenated intermediates in oxidation of organic compounds

KAUST Repository

Wang, Zhandong

2017-11-28

Decades of research on the autooxidation of organic compounds have provided fundamental and practical insights into these processes; however, the structure of many key autooxidation intermediates and the reactions leading to their formation still remain unclear. This work provides additional experimental evidence that highly oxygenated intermediates with one or more hydroperoxy groups are prevalent in the autooxidation of various oxygenated (e.g., alcohol, aldehyde, keto compounds, ether, and ester) and nonoxygenated (e.g., normal alkane, branched alkane, and cycloalkane) organic compounds. These findings improve our understanding of autooxidation reaction mechanisms that are routinely used to predict fuel ignition and oxidative stability of liquid hydrocarbons, while also providing insights relevant to the formation mechanisms of tropospheric aerosol building blocks. The direct observation of highly oxygenated intermediates for the autooxidation of alkanes at 500–600 K builds upon prior observations made in atmospheric conditions for the autooxidation of terpenes and other unsaturated hydrocarbons; it shows that highly oxygenated intermediates are stable at conditions above room temperature. These results further reveal that highly oxygenated intermediates are not only accessible by chemical activation but also by thermal activation. Theoretical calculations on H-atom migration reactions are presented to rationalize the relationship between the organic compound’s molecular structure (n-alkane, branched alkane, and cycloalkane) and its propensity to produce highly oxygenated intermediates via extensive autooxidation of hydroperoxyalkylperoxy radicals. Finally, detailed chemical kinetic simulations demonstrate the influence of these additional reaction pathways on the ignition of practical fuels.

Unraveling the structure and chemical mechanisms of highly oxygenated intermediates in oxidation of organic compounds

KAUST Repository

Wang, Zhandong; Popolan-Vaida, Denisia M.; Chen, Bingjie; Moshammer, Kai; Mohamed, Samah; Wang, Heng; Sioud, Salim; Raji, Misjudeen; Kohse-Hö inghaus, Katharina; Hansen, Nils; Dagaut, Philippe; Leone, Stephen R.; Sarathy, Mani

2017-01-01

Decades of research on the autooxidation of organic compounds have provided fundamental and practical insights into these processes; however, the structure of many key autooxidation intermediates and the reactions leading to their formation still remain unclear. This work provides additional experimental evidence that highly oxygenated intermediates with one or more hydroperoxy groups are prevalent in the autooxidation of various oxygenated (e.g., alcohol, aldehyde, keto compounds, ether, and ester) and nonoxygenated (e.g., normal alkane, branched alkane, and cycloalkane) organic compounds. These findings improve our understanding of autooxidation reaction mechanisms that are routinely used to predict fuel ignition and oxidative stability of liquid hydrocarbons, while also providing insights relevant to the formation mechanisms of tropospheric aerosol building blocks. The direct observation of highly oxygenated intermediates for the autooxidation of alkanes at 500–600 K builds upon prior observations made in atmospheric conditions for the autooxidation of terpenes and other unsaturated hydrocarbons; it shows that highly oxygenated intermediates are stable at conditions above room temperature. These results further reveal that highly oxygenated intermediates are not only accessible by chemical activation but also by thermal activation. Theoretical calculations on H-atom migration reactions are presented to rationalize the relationship between the organic compound’s molecular structure (n-alkane, branched alkane, and cycloalkane) and its propensity to produce highly oxygenated intermediates via extensive autooxidation of hydroperoxyalkylperoxy radicals. Finally, detailed chemical kinetic simulations demonstrate the influence of these additional reaction pathways on the ignition of practical fuels.

Optimization of triazine nitriles as rhodesain inhibitors: structure-activity relationships, bioisosteric imidazopyridine nitriles, and X-ray crystal structure analysis with human cathepsin L.

Science.gov (United States)

Ehmke, Veronika; Winkler, Edwin; Banner, David W; Haap, Wolfgang; Schweizer, W Bernd; Rottmann, Matthias; Kaiser, Marcel; Freymond, Céline; Schirmeister, Tanja; Diederich, François

2013-06-01

The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2 nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsin L confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed

Synthesis and structure-activity relationship of di-(3, 8-diazabicyclo[3.2.1]octane) diquaternary ammonium salts as unique analgesics.

Science.gov (United States)

Liu, Hong; Cheng, Tie-Ming; Zhang, Hong-Mei; Li, Run-Tao

2003-11-01

Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.

Electrochemical activity of thiahelicenes: Structure effects and electrooligomerization ability

International Nuclear Information System (INIS)

Bossi, Alberto; Falciola, Luigi; Graiff, Claudia; Maiorana, Stefano; Rigamonti, Clara; Tiripicchio, Antonio; Licandro, Emanuela; Mussini, Patrizia Romana

2009-01-01

Thiahelicenes are polycondensed heteroaromatic molecules characterized by a chiral helix-like structure including multiple thiophene units, with a lowering effect on the oxidation potentials and a shrinking effect on the band gaps. As a consequence they can be regarded as electrochemically and optically active conducting materials, exhibiting interesting properties under electrical or magnetic polarization, and are under study for non-linear optics (NLO) applications. The present extensive investigation on 11 thiahelicenes with different chain length and functionalization (including the first example of a thiahelicene with perfluorinated alkyl chains) together with the precursor benzodithiophene provides a deep insight on the structure vs. electrochemical activity relationship within this attractive compound class, focusing on both electron transfer (ET) properties and oligomerization ability (hinging on free α positions on terminal thiophene groups).

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.

Novel enaminones as non-cytotoxic compounds with mild antibacterial activity: Synthesis and structure-activity correlations

Science.gov (United States)

Cindrić, Marina; Rubčić, Mirta; Hrenar, Tomica; Pisk, Jana; Cvijanović, Danijela; Lovrić, Jasna; Vrdoljak, Višnja

2018-02-01

Six non-symmetric enaminones 4-[(2-hydroxy-5-methylphenyl)amino]pent-3-en-2-one (H2L1), 4-[(2-hydroxy-4-methylphenyl)amino]pent-3-en-2-one (H2L2), 4-[(4-hydroxy-2-methylphenyl)amino)]pent-3-en-2-one (H2L3), 3-[(2-hydroxy-5-methylphenyl)amino]-1-phenylbut-2-en-1-one (H2L4), 3-[(2-hydroxy-4-methylphenyl)amino]-1-phenylbut-2-en-1-one (H2L5) and 3-[(4-hydroxy-2-methylphenyl)amino]-1-phenylbut-2-en-1-one (H2L6) have been prepared by solution based method. The enaminones were characterized by elemental and DSC analysis, NMR and IR spectroscopy. Crystal and molecular structures of H2L1, H2L2, H2L4 and H2L6 were determined via single crystal X-ray analysis. The prepared enaminones were screened against THP-1 and HepG2 cells, and Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Moraxella catarrhalis bacteria to assess their cytotoxic and antibacterial activity, respectively. All compounds proved to be non-cytotoxic and showed mild or no antibacterial activity. Quantum mechanical calculations suggest that the presence of hydroxy group in ortho position, combined with the methyl group on the same aromatic ring, has a significant impact on the biological activities.

Antifeedant effect of polygodial and drimenol derivatives against Spodoptera frugiperda and Epilachna paenulata and quantitative structure-activity analysis.

Science.gov (United States)

Montenegro, Iván J; Del Corral, Soledad; Diaz Napal, Georgina N; Carpinella, María C; Mellado, Marco; Madrid, Alejandro M; Villena, Joan; Palacios, Sara M; Cuellar, Mauricio A

2018-01-08

The antifeedant activity of 18 sesquiterpenoids of the drimane family (polygodial, drimenol and derivatives) was investigated. Polygodial, drimanic and nordrimanic derivatives were found to exert antifeedant effects against two insect species, Spodoptera frugiperda and Epilachna paenulata, which are pests of agronomic interest, indicating that they have potential as biopesticide agents. Among the 18 compounds tested, the epoxynordrimane compound (11) and isonordrimenone (4) showed the highest activity [50% effective concentration (EC 50 ) = 23.28 and 25.63 nmol cm - 2 , respectively, against S. frugiperda, and 50.50 and 59.00 nmol/cm 2 , respectively, against E. paenulata]. The results suggest that drimanic compounds have potential as new agents against S. frugiperda and E. paenulata. A quantitative structure-activity relationship (QSAR) analysis of the whole series, supported by electronic studies, suggested that drimanic compounds have structural features necessary for increasing antifeedant activity, namely a C-9 carbonyl group and an epoxide at C-8 and C-9. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and insight into the structure-activity relationships of its analogues as antiplasmodial agents.

Science.gov (United States)

Aratikatla, Eswar K; Valkute, Tushar R; Puri, Sunil K; Srivastava, Kumkum; Bhattacharya, Asish K

2017-09-29

Syncarpamide 1, a norepinephrine alkaloid isolated from the leaves of Zanthoxylum syncarpum (Rutaceae) exhibited promising antiplasmodial activities against Plasmodium falciparum with reported IC 50 values of 2.04 μM (D6 clone), 3.06 μM (W2 clone) and observed by us 3.90 μM (3D7 clone) and 2.56 μM (K1 clone). In continuation of our work on naturally occurring antimalarial compounds, synthesis of syncarpamide 1 and its enantiomer, (R)-2 using Sharpless asymmetric dihydroxylation as a key step has been accomplished. In order to study structure-activity-relationship (SAR) in detail, a library of 55 compounds (3-57), which are analogues/homologues of syncarpamide 1 were synthesized by varying the substituents on the aromatic ring, by changing the stereocentre at the C-7 and/or by varying the acid groups in the ester and/or amide side chain based on the natural product lead molecule and further assayed in vitro against 3D7 and K1 strains of P. falciparum to evaluate their antiplasmodial activities. In order to study the effect of position of functional groups on antiplasmodial activity profile, a regioisomer (S)-58 of syncarpamide 1 was synthesized however, it turned out to be inactive against both the strains. Two compounds, (S)-41 and its enantiomer, (R)-42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better antiplasmodial activity with IC 50 values of 3.16, 2.28 μM (3D7) and 1.78, 2.07 μM (K1), respectively than the natural product, syncarpamide 1. Three compounds (S)-13, (S)-17, (S)-21 exhibited antiplasmodial activities with IC 50 values of 6.39, 6.82, 6.41 μM against 3D7 strain, 4.27, 7.26, 2.71 μM against K1 strain and with CC 50 values of 147.72, 153.0, >200 μM respectively. The in vitro antiplasmodial activity data of synthesized library suggests that the electron density and possibility of resonance in both the ester and amide side chains increases the antiplasmodial activity as compared to the parent natural product 1

Structure-Activity Relationship Study of N(6)-Benzoyladenine-Type BRD4 Inhibitors and Their Effects on Cell Differentiation and TNF-α Production.

Science.gov (United States)

Amemiya, Seika; Yamaguchi, Takao; Sakai, Taki; Hashimoto, Yuichi; Noguchi-Yachide, Tomomi

2016-01-01

Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.

Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries.

Science.gov (United States)

Ma, Xiao H; Jia, Jia; Zhu, Feng; Xue, Ying; Li, Ze R; Chen, Yu Z

2009-05-01

Machine learning methods have been explored as ligand-based virtual screening tools for facilitating drug lead discovery. These methods predict compounds of specific pharmacodynamic, pharmacokinetic or toxicological properties based on their structure-derived structural and physicochemical properties. Increasing attention has been directed at these methods because of their capability in predicting compounds of diverse structures and complex structure-activity relationships without requiring the knowledge of target 3D structure. This article reviews current progresses in using machine learning methods for virtual screening of pharmacodynamically active compounds from large compound libraries, and analyzes and compares the reported performances of machine learning tools with those of structure-based and other ligand-based (such as pharmacophore and clustering) virtual screening methods. The feasibility to improve the performance of machine learning methods in screening large libraries is discussed.

Structure of inorganic phosphorus-nitrogen tetrahedral compounds

International Nuclear Information System (INIS)

Vitola, A.; Ronis, J.; Avotins, V.; Millers, T.

1997-01-01

The structure analysis of phosphorus-nitrogen compounds has shown the possibility of the P(O,N) 4 tetrahedra to form various kinds of structures. The wide spectrum of the properties determined by the diversity of structures marks the considerable promise to the future application of phosphorus-nitrogen compounds

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...

Antioxidant Activity of Phenolic Compounds from Fava Bean Sprouts.

Science.gov (United States)

Okumura, Koharu; Hosoya, Takahiro; Kawarazaki, Kai; Izawa, Norihiko; Kumazawa, Shigenori

2016-06-01

Fava beans are eaten all over the world and recently, marketing for their sprouts began in Japan. Fava bean sprouts contain more polyphenols and l-3,4-dihydroxyphenylalanine (l-DOPA) than the bean itself. Our antioxidant screening program has shown that fava bean sprouts also possess a higher antioxidant activity than other commercially available sprouts and mature beans. However, the individual constituents of fava bean sprouts are not entirely known. In the present study, we investigated the phenolic compounds of fava bean sprouts and their antioxidant activity. Air-dried fava bean sprouts were treated with 80% methanol and the extract was partitioned in water with chloroform and ethyl acetate. HPLC analysis had shown that the ethyl acetate-soluble parts contained phenolic compounds, separated by preparative HPLC to yield 5 compounds (1-5). Structural analysis using NMR and MS revealed that the compounds isolated were kaempferol glycosides. All isolated compounds had an α-rhamnose at the C-7 position with different sugars attached at the C-3 position. Compounds 1-5 had β-galactose, β-glucose, α-rhamnose, 6-acetyl-β-galactose and 6-acetyl-β-glucose, respectively, at the C-3 position. The amount of l-DOPA in fava bean sprouts was determined by the quantitative (1) H NMR technique. The l-DOPA content was 550.45 mg ± 11.34 /100 g of the raw sprouts. The antioxidant activities of compounds 2-5 and l-DOPA were evaluated using the 2,2-diphenyl-1-picrylhydrazyl scavenging assay. l-DOPA showed high antioxidant activity, but the isolated kaempferol glycosides showed weak activity. Therefore, it can be suggested that l-DOPA contributed to the antioxidant activity of fava bean sprouts. © 2016 Institute of Food Technologists®

Teaching Structure-Property Relationships: Investigating Molecular Structure and Boiling Point

Science.gov (United States)

Murphy, Peter M.

2007-01-01

A concise, well-organized table of the boiling points of 392 organic compounds has facilitated inquiry-based instruction in multiple scientific principles. Many individual or group learning activities can be derived from the tabulated data of molecular structure and boiling point based on the instructor's education objectives and the students'…

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

Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

Energy Technology Data Exchange (ETDEWEB)

Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Quimica Fundamental]. E-mail: mramos@ufpe.br; Melo, Sebastiao Jose de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Antibioticos]. E-mail: melosebastiao@yahoo.com.br; Falcao, Emerson Peter da Silva [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Centro Academico de Vitoria de Santo Antao; Catanho, Maria Teresa J. de Almeida [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Biofisica e Radiobiologia

2008-07-01

The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

International Nuclear Information System (INIS)

Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de; Melo, Sebastiao Jose de; Falcao, Emerson Peter da Silva; Catanho, Maria Teresa J. de Almeida

2008-01-01

The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

Structure-activity relationships of bumetanide derivatives

DEFF Research Database (Denmark)

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

2015-01-01

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. EXPERIMENTAL APPROACH: In this study......, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its...... 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....

Structure-antioxidant activity relationships of flavonoids isolated from the resinous exudate of Heliotropium sinuatum.

Science.gov (United States)

Modak, Brenda; Contreras, M Leonor; González-Nilo, Fernando; Torres, René

2005-01-17

Relationships between the structural characteristics of flavonoids isolated from the resinous exudate of Heliotropium sinuatum and their antioxidant activity were studied. Radical formation energies, DeltaH of dehydrogenation and spin densities were calculated using DFT methods (B3LYP/6-31G*). Results show that studied flavonoids can be divided into two sets according to their activity. It has been found that antioxidant activity depends both on substitution pattern of hydroxyl groups of the flavonoid skeleton and the presence of an unsaturation at the C2-C3 bond. A good tendency between DeltaH of dehydrogenation and antioxidant activity was established.

Synthesis and anticonvulsant activity of certain chalcone based pyrazoline compounds

Directory of Open Access Journals (Sweden)

Sudhakara Rao Gerapati

2015-09-01

Full Text Available Convulsions are involuntary, violent, spasmodic and prolonged contractions of skeletal muscles. That means a patient may have epilepsy without convulsions and vice versa. Epilepsy is a common neurological abnormality affecting about 1% of the world population. The primary objectives of these synthesized compounds are to suppress seizures and provide neuroprotection by minimizing the effects from seizure attacks. Here some of the chalcones and chalcone based various pyrazolines were evaluated for anticonvulsant activity. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H-NMR & Mass spectroscopy. A preliminary evaluation of the prepared compounds has indicated that some of them exhibit moderate to significant anticonvulsant activity compared to a diazepam standard1-3.  All compounds were tested for their anticonvulsant activity using maximal electroshock induced convulsions (MES in mice at a dose level of 4 mg/kg.b.w. The compounds  Ph1, Ph2 , Py2 ,Py3 and Py4 have shown  to  good anticonvulsant activity when doses are administered as 25mg/ kg.b.w  , reduced the phases of seizures severity and  found to be active and also  increased survival rate. Remaining compounds are less efficacious.

Synthesis, Characterization, and Antimicrobial Activities of Coordination Compounds of Aspartic Acid

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T. O. Aiyelabola

2016-01-01

Full Text Available Coordination compounds of aspartic acid were synthesized in basic and acidic media, with metal ligand M : L stoichiometric ratio 1 : 2. The complexes were characterized using infrared, electronic and magnetic susceptibility measurements, and mass spectrometry. Antimicrobial activity of the compounds was determined against three Gram-positive and three Gram-negative bacteria and one fungus. The results obtained indicated that the availability of donor atoms used for coordination was a function of the pH of the solution in which the reaction was carried out. This resulted in varying geometrical structures for the complexes. The compounds exhibited a broad spectrum of activity and in some cases better activity than the standard.

Relationship between Chemical Structure and Antimicrobial Activities of Isothiocyanates from Cruciferous Vegetables against Oral Pathogens.

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Ko, Mi-Ok; Kim, Mi-Bo; Lim, Sang-Bin

2016-12-28

We evaluated the potentials of 10 isothiocyanates (ITCs) from cruciferous vegetables and radish root hydrolysate for inhibiting the growth of oral pathogens, with an emphasis on assessing any structure-function relationship. Structural differences in ITCs impacted their antimicrobial activities against oral pathogens differently. The indolyl ITC (indol-3-carbinol) was the most potent inhibitor of the growth of oral pathogens, followed by aromatic ITCs (benzyl ITC (BITC) and phenylethyl ITC (PEITC)) and aliphatic ITCs (erucin, iberin, and sulforaphene). Sulforaphene, which is similar in structure, but has one double bond, showed higher antimicrobial activity than sulforaphane. Erucin, which has a thiol group, showed higher antimicrobial activity than sulforaphane, which has a sulfinyl group. BITC and iberin with a short chain exhibited higher antimicrobial potential than PEITC and sulforaphane with a longer chain, respectively. ITCs have strong antimicrobial activities and may be useful in the prevention and management of dental caries.

Pharmacological and Structure-Activity Relationship Evaluation of 4-aryl-1-Diphenylacetyl(thiosemicarbazides

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Monika Wujec

2014-04-01

Full Text Available This article describes the synthesis of six 4-aryl-(thiosemicarbazides (series a and b linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenylthiosemicarbazide 1b was found to be the most potent analgesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4-(4-methoxyphenylsemicarbazide 2b was observed. The computational studies strongly support the obtained results.

Anti-human rhinoviral activity of polybromocatechol compounds isolated from the rhodophyta, Neorhodomela aculeata.

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Park, Soon-Hye; Song, Jae-Hyoung; Kim, Taejung; Shin, Woon-Seob; Park, Gab Man; Lee, Seokjoon; Kim, Young-Joo; Choi, Pilju; Kim, Heejin; Kim, Hui-Seong; Kwon, Dur-Han; Choi, Hwa Jung; Ham, Jungyeob

2012-10-01

An extract of the red alga, Neorhodomela aculeata, exhibited antiviral activity against human rhinoviruses. Bioassay-guided purification was performed to yield six compounds, which were subsequently identified as lanosol (1) and five polybromocatechols (2-6) by spectroscopic methods, including 1D and 2D NMR and mass spectrometric analyses. Structurally, all of these compounds, except compound 5, contain one or two 2,3-dibromo-4,5-dihydroxyphenyl moieties. In a biological activity assay, compound 1 was found to possess antiviral activity with a 50% inhibitory concentration (IC₅₀) of 2.50 μg/mL against HRV2. Compound 3 showed anti-HRV2 activity, with an IC₅₀ of 7.11 μg/mL, and anti-HRV3 activity, with an IC₅₀ of 4.69 μg/mL, without demonstrable cytotoxicity at a concentration of 20 μg/mL. Collectively, the results suggest that compounds 1 and 3 are candidates for novel therapeutics against two different groups of human rhinovirus.

Ring-substituted 4-Hydroxy-1H-quinolin-2-ones: Preparation and Biological Activity

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Jiri Dohnal

2009-03-01

Full Text Available In the study, a series of twelve ring-substituted 4-hydroxy-1H-quinolin-2-one derivatives were prepared. The procedures for synthesis of the compounds are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity and tested for their photosynthesis-inhibiting activity using spinach (Spinacia oleracea L. chloroplasts. All the synthesized compounds were also evaluated for antifungal activity using in vitro screening with eight fungal strains. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR.

Improving quantitative structure-activity relationship models using Artificial Neural Networks trained with dropout.

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Mendenhall, Jeffrey; Meiler, Jens

2016-02-01

Dropout is an Artificial Neural Network (ANN) training technique that has been shown to improve ANN performance across canonical machine learning (ML) datasets. Quantitative Structure Activity Relationship (QSAR) datasets used to relate chemical structure to biological activity in Ligand-Based Computer-Aided Drug Discovery pose unique challenges for ML techniques, such as heavily biased dataset composition, and relatively large number of descriptors relative to the number of actives. To test the hypothesis that dropout also improves QSAR ANNs, we conduct a benchmark on nine large QSAR datasets. Use of dropout improved both enrichment false positive rate and log-scaled area under the receiver-operating characteristic curve (logAUC) by 22-46 % over conventional ANN implementations. Optimal dropout rates are found to be a function of the signal-to-noise ratio of the descriptor set, and relatively independent of the dataset. Dropout ANNs with 2D and 3D autocorrelation descriptors outperform conventional ANNs as well as optimized fingerprint similarity search methods.

4-Phenylphenalenones as a template for new photodynamic compounds against Mycosphaerella fijiensis.

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Hidalgo, William; Cano, Marisol; Arbelaez, Manuela; Zarrazola, Edwin; Gil, Jesús; Schneider, Bernd; Otálvaro, Felipe

2016-04-01

Evaluation of 4-phenylphenalenones and structural analogues against the fungal pathogen Mycosphaerella fijiensis (causal agent of black sigatoka disease in bananas) under light-controlled conditions uncovered some key structural features for the design of photodynamic compounds. Structure-activity relationship analysis revealed the importance of a chromophoric aryl-ketone and a steroidomimetic structural motif in the activity of the assayed compounds. The results pointed to 1,2-dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2-b]furan-3-one, which displayed an activity in the range of propiconazole but with photodynamic behaviour. The present work demonstrates that 1,2-dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2-b]heterocyclic-3-one derivatives can be used as potential lead compounds for the development of fungicides, relying on a dual mode of action. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

New heterocyclic compounds: Synthesis and antitrypanosomal properties.

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Pomel, S; Dubar, F; Forge, D; Loiseau, P M; Biot, C

2015-08-15

Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 μM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 μM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 μmol/kg by intraperitoneal route. Although no clear-cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series. Copyright © 2015 Elsevier Ltd. All rights reserved.

Activity Prediction of Schiff Base Compounds using Improved QSAR Models of Cinnamaldehyde Analogues and Derivatives

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Hui Wang

2015-10-01

Full Text Available In past work, QSAR (quantitative structure-activity relationship models of cinnamaldehyde analogues and derivatives (CADs have been used to predict the activities of new chemicals based on their mass concentrations, but these approaches are not without shortcomings. Therefore, molar concentrations were used instead of mass concentrations to determine antifungal activity. New QSAR models of CADs against Aspergillus niger and Penicillium citrinum were established, and the molecular design of new CADs was performed. The antifungal properties of the designed CADs were tested, and the experimental Log AR values were in agreement with the predicted Log AR values. The results indicate that the improved QSAR models are more reliable and can be effectively used for CADs molecular design and prediction of the activity of CADs. These findings provide new insight into the development and utilization of cinnamaldehyde compounds.

Mutagenic activities of a chlorination by-product of butamifos, its structural isomer, and their related compounds.

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Kamoshita, Masahiro; Kosaka, Koji; Endo, Osamu; Asami, Mari; Aizawa, Takako

2010-01-01

The mutagenic activities of 5-methyl-2-nitrophenol (5M2NP), a chlorination by-product of butamifos, its structural isomer 2-methyl-5-nitrophenol (2M5NP), and related compounds were evaluated by the Ames assay. The mutagenic activities of 5M2NP and 2M5NP were negative or not particularly high. However, those of their chlorinated derivatives were increased in Salmonella typhimurium strain TA100 and the overproducer strains YG1026, and YG1029 in the absence and/or presence of a rat liver metabolic activation system (S9 mix), particularly for YG1029. The mutagenic activities of 6-chloro-2-methyl-5-nitrophenol (6C2M5NP) in YG1029 in the absence and presence of S9 mix were 70000 and 110000 revertants mg(-1), respectively. When nitro functions of 6C2M5NP and 4-chloro-5-methyl-2-nitrophenol (4C5M2NP) were reduced to amino functions, their mutagenic activities were markedly decreased. The mutagenic activities of 5M2NP and 4C5M2NP were lower than those of 2M5NP and 6C2M5NP, respectively. Thus, it was shown that substituent position is a key factor for the mutagenic activities of methylnitrophenols (MNPs) and related compounds. The mutagenic activities of the extracts of 2M5NP in chlorination increased early during the reaction time and then decreased. The main chlorination by-product contributing to the mutagenic activities of the extracts of 2M5NP in chlorination was 6C2M5NP. The results of chlorination of 2M5NP suggested that MNPs were present as their dichlorinated derivatives or further chlorination by-products in drinking water. Copyright 2009 Elsevier Ltd. All rights reserved.

Natural compounds with herbicidal activity

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Mariano Fracchiolla

2007-12-01

Full Text Available Research about phytotoxic activity of natural compounds could lead both to find new herbicidal active ingredients and to plan environmental friendly weed control strategies. Particularly, living organisms could be a source of compounds that are impossible, for their complexity, to synthesize artificially. More over, they could have alternative sites of action respect to the known chemical herbicides and, due to their origin, they should be more environmental safe. Many living organism, such as bacteria, fungi, insects, lichens and plants, are able to produce bioactive compounds. They generally are secondary metabolites or simply waste molecules. In this paper we make a review about these compounds, highlighting potential and constraints.

Natural compounds with herbicidal activity

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Pasquale Montemurro

2011-02-01

Full Text Available Research about phytotoxic activity of natural compounds could lead both to find new herbicidal active ingredients and to plan environmental friendly weed control strategies. Particularly, living organisms could be a source of compounds that are impossible, for their complexity, to synthesize artificially. More over, they could have alternative sites of action respect to the known chemical herbicides and, due to their origin, they should be more environmental safe. Many living organism, such as bacteria, fungi, insects, lichens and plants, are able to produce bioactive compounds. They generally are secondary metabolites or simply waste molecules. In this paper we make a review about these compounds, highlighting potential and constraints.

Urea derivatives on the move: cytokinin-like activity and adventitious rooting enhancement depend on chemical structure.

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Ricci, A; Bertoletti, C

2009-05-01

Urea derivatives are synthetic compounds, some of which have proved to be positive regulators of cell division and differentiation. N-phenyl-N'-(2-chloro-4-pyridyl)urea (forchlorofenuron, CPPU) and N-phenyl-N'-(1,2,3-thiadiazol-5-yl)urea (thidiazuron, TDZ), well known urea cytokinin representatives, are extensively used in in vitro plant morphogenesis studies, as they show cytokinin-like activity often exceeding that of adenine compounds. In recent years, renewed interest in structure-activity relationship studies allowed identification of new urea cytokinins and other urea derivatives that specifically enhance adventitious root formation. In this review, we report the research history of urea derivatives, new insights into their biological activity, and recent progress on their mode of action.

Cucurbitane Glycosides Derived from Mogroside IIE: Structure-Taste Relationships, Antioxidant Activity, and Acute Toxicity

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Lei Wang

2014-08-01

Full Text Available Mogroside IIE is a bitter triterpenoid saponin which is the main component of unripe Luo Han Guo fruit and a precursor of the commercially available sweetener mogroside V. In this study, we developed an enzymatic glycosyl transfer method, by which bitter mogroside IIE could be converted into a sweet triterpenoid saponin mixture. The reactant concentration, temperature, pH and buffer system were studied. New saponins with the α-glucose group were isolated from the resulting mixtures, and the structures of three components of the extract were determined. The structure-taste relationships of these derivatives were also studied together with those of the natural mogrosides. The number and stereoconfiguration of glucose groups present in the mogroside molecules were found to be the main factor to determine the sweet or bitter taste of a compound. The antioxidant and food safety properties were initially evaluated by their radical scavenging ability and via 7 day mice survival tests, respectively. The results showed that the sweet triterpenoid saponin mixture has the same favorable physiological and safety characteristics as the natural mogrosides.

Evolutionary Structure Prediction of Stoichiometric Compounds

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Zhu, Qiang; Oganov, Artem

2014-03-01

In general, for a given ionic compound AmBn\\ at ambient pressure condition, its stoichiometry reflects the valence state ratio between per chemical specie (i.e., the charges for each anion and cation). However, compounds under high pressure exhibit significantly behavior, compared to those analogs at ambient condition. Here we developed a method to solve the crystal structure prediction problem based on the evolutionary algorithms, which can predict both the stable compounds and their crystal structures at arbitrary P,T-conditions, given just the set of chemical elements. By applying this method to a wide range of binary ionic systems (Na-Cl, Mg-O, Xe-O, Cs-F, etc), we discovered a lot of compounds with brand new stoichimetries which can become thermodynamically stable. Further electronic structure analysis on these novel compounds indicates that several factors can contribute to this extraordinary phenomenon: (1) polyatomic anions; (2) free electron localization; (3) emergence of new valence states; (4) metallization. In particular, part of the results have been confirmed by experiment, which warrants that this approach can play a crucial role in new materials design under extreme pressure conditions. This work is funded by DARPA (Grants No. W31P4Q1210008 and W31P4Q1310005), NSF (EAR-1114313 and DMR-1231586).

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

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

2014-10-01

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

3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

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Dhar, T G Murali; Shen, Zhongqi; Gu, Henry H; Chen, Ping; Norris, Derek; Watterson, Scott H; Ballentine, Shelley K; Fleener, Catherine A; Rouleau, Katherine A; Barrish, Joel C; Townsend, Robert; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2003-10-20

A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.

Influence of lipophilicity in O-acyl and O-alkyl derivatives of juglone and lawsone: a structure-activity relationship study in the search for natural herbicide models.

Science.gov (United States)

Durán, Alexandra G; Chinchilla, Nuria; Molinillo, José Mg; Macías, Francisco A

2018-03-01

Naphthoquinones are known for their broad range of biological activities. Given the increasing demands of consumers in relation to food quality and growing concerns about the impact of synthetic herbicides, it is necessary to search for new agrochemicals. Natural products and allelopathy provide new alternatives for the development of pesticides with lower toxicity and greater environmental compatibility. A structure-activity relationship to evaluate the effect of bioavailability was performed. A total of 44 O-acyl and O-alkyl derivatives of juglone and lawsone with different linear chain lengths were prepared. These compounds were tested on etiolated wheat coleoptiles, standard target species (STS) and four weeds, Echinochloa crus-galli L., Lolium rigidum Gaud., Lolium perenne L. and Avena fatua L. The results showed a strong influence of lipophilicity and, in most cases, the data fitted a logP-dependent quadratic mathematical model. The effects produced were mostly stunting and necrosis caused by growth inhibition. The potential structure and activity behaviour is described. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Structure Elucidation of A New Coumarin Type Compound, Alternamin, Isolated from the Plant (Murraya Alternans (Kurz) Swingle) Having The Antidote Activity on Snake Venoms

International Nuclear Information System (INIS)

Hla Myo Min; Mya Aye

2004-06-01

The structure of a new coumarin type compound isolated from the entitled species was elucidated by the full spectral analysis consisting of FTIR, 1H NMR, DQF COSY, 13C NMR, DEPT, EIMS (HR-EIMS), HMQC and HMBC. The antidote activities of the fresh juice and the ethanolic extract of the plant, and the isolated compound alternamin were also determined

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

Polyphenolic compounds with antioxidant potential and neuro-protective effect from Cimicifuga dahurica (Turcz.) Maxim.

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Qin, Rulan; Zhao, Ying; Zhao, Yudan; Zhou, Wanrong; Lv, Chongning; Lu, Jincai

2016-12-01

Three new phenolic compounds (1-3), along with five known compounds (4-8) were isolated from the rhizome of Cimicifuga dahurica (Turcz.) Maxim. Their structures were elucidated by spectroscopic methods including 1D-NMR, 2D-NMR and HR-MS techniques. DPPH method and protective effect on PC12 cells against H 2 O 2 -induced oxidative damage model were carried to evaluate the antioxidant capability of these compounds. Compound 5 showed significant antioxidant activity with IC 50 values 9.33μM in DPPH assay and compound 2 displayed marked neuro-protective effect with 87.65% cell viability at the concentration of 10μM. Additionally, the possible structure-activity relationships of these phenolic compounds were tentatively discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Effective anti-leishmanial activity of minimalist squaramide-based compounds.

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Marín, Clotilde; Ximenis, Marta; Ramirez-Macías, Inmaculada; Rotger, Carmen; Urbanova, Kristina; Olmo, Francisco; Martín-Escolano, Rubén; Rosales, María José; Cañas, Rocio; Gutierrez-Sánchez, Ramón; Costa, Antonio; Sánchez-Moreno, Manuel

2016-11-01

In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by 1 H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17 > 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent. Copyright © 2016. Published by Elsevier Inc.

STRUCTURE – ANTIOXIDANT ACTIVITIES RELATIONSHIP ANALYSIS OF ISOEUGENOL, EUGENOL, VANILIN AND THEIR DERIVATIVES

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Nur Aini

2010-06-01

Full Text Available Structure Activity Relationship (SAR technique between the theoretical parameters and antioxidant activities of isoeugenol, eugenol, vanillin and their derivatives as Mannich reaction products, have been analyzed. Antioxidant activities were examined by oxidation reaction of oleic acid at 60 °C with b-carotene methods, whereas theoretical parameters of the activities were determined by calculating Bonding Dissociation Enthalpy (BDE and net charge of oxygen atom(-OH using AM1 semi empiric methods. The result from both test showed in the following orders: BHT > Mannich product of isoeugenol > isoeugenol > Mannich product of eugenol > eugenol > Mannich product of vanillin > vanillin. The antioxidant activities increase with small the BDE value and high the net charge. Electron donating groups will increase the antioxidants activity with lowering the BDE value and increasing the net charge, while electron-withdrawing groups will decrease antioxidants activity.   Keywords: SAR, antioxidants, Bonding Dissociation Entalphy, eugenol.

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.

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

OpenAIRE

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

2012-01-01

An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifi...

Structural investigation of a new antimicrobial thiazolidine compound

Energy Technology Data Exchange (ETDEWEB)

Cozar, I. B.; Pîrnău, A. [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, RO-400293 Cluj-Napoca (Romania); Vedeanu, N.; Nastasă, C. [Iuliu Hatieganu University of Medicine and Pharmacy, Faculty of Pharmacy, RO-400023 Cluj-Napoca (Romania)

2013-11-13

Thiazoles and their derivatives have attracted the interest over the last decades because of their varied biological activities: antibacterial, antiviral, antifungal, inflammation or in the treatment of allergies. A new synthesized compound 3-[2-(4-Methyl-2-phenyl-thiazol-5-yl)-2-oxo-ethyl]-thazolidine-2,4-dione was investigated by FT-IR, FT-Raman, {sup 1}H, {sup 13}C NMR spectroscopies and also by DFT calculations at B3LYP/6-31G(d) level of theory. The very good correlation found between the experimental and theoretical data shows that the optimized molecular structure is very close to reality. Also the NMR spectra show a monomeric behaviour of this compound in solutions.

Evaluation of some organic compounds on bloodstream forms of Trypanosoma cruzi

Directory of Open Access Journals (Sweden)

João S. Silva

1992-09-01

Full Text Available Accidental transmission of Chagas' disease to man by blood transfusion is a serious problem in Latin-America. This paper describes the testing of several synthetic, semi-synthetic, and natural compounds for their activity against blood trypomastigotes in vitro at 4-C. The compounds embody several types of chemical structures: benzoquinone, naphthoquinone, anthracenequinone, phenanthrenequinone, imidazole, piperazine, quinoline, xanthene, and simple benzenic and naphthalenic derivates. Some of them are for the first time tested against Trypanosoma cruzi. The toxic effect these compounds on this parasite was done by two quite distinct sets of experiments. In one set, the compounds were added to infected blood as ethanolic solution. In this situation the most active one was a furan-1, 2-naphthoquinone, in the same range as gentian violet, a new fact to be considered in the assessment of structure-activity relationships in this class of compounds. In other set, we tentatively evaluated the biological activity of water insoluble compounds by adding them in a pure form without solvent into infected blood. In this way some appear to be very active and it was postulated that the effectiveness of such compounds must result from interactions between them and specific blood components.

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

In vitro assessment of the growth and plasma membrane H+ -ATPase inhibitory activity of ebselen and structurally related selenium- and sulfur-containing compounds in Candida albicans.

Science.gov (United States)

Orie, Natalie N; Warren, Andrew R; Basaric, Jovana; Lau-Cam, Cesar; Piętka-Ottlik, Magdalena; Młochowski, Jacek; Billack, Blase

2017-06-01

Ebselen (EB, compound 1) is an investigational organoselenium compound that reduces fungal growth, in part, through inhibition of the fungal plasma membrane H + -ATPase (Pma1p). In the present study, the growth inhibitory activity of EB and of five structural analogs was assessed in a fluconazole (FLU)-resistant strain of Candida albicans (S2). While none of the compounds were more effective than EB at inhibiting fungal growth (IC 50  ∼ 18 μM), two compounds, compounds 5 and 6, were similar in potency. Medium acidification assays performed with S2 yeast cells revealed that compounds 4 and 6, but not compounds 2, 3, or 5, exerted an inhibitory activity comparable to EB (IC 50  ∼ 14 μM). Using a partially purified Pma1p preparation obtained from S2 yeast cells, EB and all the analogs demonstrated a similar inhibitory activity. Taken together, these results indicate that EB analogs are worth exploring further for use as growth inhibitors of FLU-resistant fungi. © 2017 Wiley Periodicals, Inc.

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

Science.gov (United States)

Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

2015-01-01

The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Anti-Human Rhinoviral Activity of Polybromocatechol Compounds Isolated from the Rhodophyta, Neorhodomela aculeata

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Hui-Seong Kim

2012-10-01

Full Text Available An extract of the red alga, Neorhodomela aculeata, exhibited antiviral activity against human rhinoviruses. Bioassay-guided purification was performed to yield six compounds, which were subsequently identified as lanosol (1 and five polybromocatechols (2–6 by spectroscopic methods, including 1D and 2D NMR and mass spectrometric analyses. Structurally, all of these compounds, except compound 5, contain one or two 2,3-dibromo-4,5-dihydroxyphenyl moieties. In a biological activity assay, compound 1 was found to possess antiviral activity with a 50% inhibitory concentration (IC50 of 2.50 μg/mL against HRV2. Compound 3 showed anti-HRV2 activity, with an IC50 of 7.11 μg/mL, and anti-HRV3 activity, with an IC50 of 4.69 μg/mL, without demonstrable cytotoxicity at a concentration of 20 μg/mL. Collectively, the results suggest that compounds 1 and 3 are candidates for novel therapeutics against two different groups of human rhinovirus.

Structural studies of novel coordination compounds run in the Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences

International Nuclear Information System (INIS)

Antipin, M.Yu.; Starikova, Z.A.; Yanovskij, A.I.; Dolgushin, F.M.; Lysenko, K.A.; Khrustalev, V.N.; Vorontsov, I.I.; Korlyukov, A.A.; Andreev, G.B.; Neretin, I.S.

2001-01-01

The results of the investigation into structural chemistry of coordination compounds taking place in the X-ray Laboratory of the Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences are given. The review gives an idea on the tendencies to structural researches of complexes of varying categories of coordination compounds, among which are lithium, strontium, cadmium compounds, rare earth compounds, transuranium compounds, transition element compounds, carboranes, fullerenes. An attempt was made to prove the structure and reveal the novel structural and crystallochemical regularities in the studied series of relative compounds. The outlooks for the following progress of studies on this field are determined [ru

Correlation between the structure and biological activity studies of supramolecular coordination azodye compounds

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M.I. Abou-Dobara

2017-02-01

Full Text Available A series of novel bidentate azodye quinoline ligands were synthesized with various p-aromatic amines like p-(OCH3, CH3, H, Cl and NO2. Novel azodye (HLn and complexes [Cu(II/Ni(II] of these ligands have been characterized on the basis of elemental analysis, molar conductance and magnetic measurements, infrared and electronic spectral studies. Suitable structures have been proposed for these complexes. The synthesized ligands and their metal complexes were screened for their antimicrobial activity against four local bacterial species, two Gram positive bacteria (Bacillus cereus and Staphylococcus aureus and two Gram negative bacteria (Escherichia coli and Klebsiella pneumoniae as well as against four local fungal species; namely Aspergillus niger, Alternaria alternata, Penicillium italicum and Fusarium oxysporium. The tested compounds have good antibacterial activity against B. cereus, E. coli and K. pneumoniae. Very low effect was detected against S. aureus and F. oxysporium. We found that the results of antifungal activity of HLn revealed that the complexes are more toxic than ligands against fungi due to the transition metal involved in the coordination. Also Cu2+ complexes are more active than Ni2+ complexes against B. cereus, E. coli and K. pneumoniae. The size of the clear zone was in the following order p-(OCH3 < CH3 < H < Cl < NO2 as expected from Hammett’s constants σR.

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

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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.

Activity-Guided Isolation of Antioxidant Compounds from Andrographis stenophylla Leaf

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Neelaveni Thangavel

2010-01-01

Full Text Available The antioxidant potency of various extracts of Andrographis stenophylla leaf was evaluated in vitro using ferric thiocyanate method. Reductive ability and free radical scavenging activity of the extracts were also investigated. Amounts of phenolic compounds in each of the extracts were determined using Folin-Ciocalteau reagent and compared to observe the correlation between antioxidant activities and total phenolic content. Methanol extract exhibited maximum antioxidant activity and was found to contain 2% of total phenolic compounds. Methanol extract was subjected to column chromatographic separation over silica gel G using ethyl acetate: formic acid: acetic acid: water. Fractions thus obtained were screened for their antioxidant activity. Among the eleven fractions screened, fraction C was more active than the standard butylated hydroxyanisole. Fraction C on further fractionation with n-butanol: acetic acid: water afforded two flavanoids namely acacetine and isosakuranetine. Fraction A was also shown to possess good antioxidant activity which was developed using TLC and indicated the presence of a terpenoid, Andrographolide. The structures of the isolated compounds were confirmed by UV, IR, MS, 1H and 13C NMR spectral data. This is the first report wherein Andrographolide, Acacetine and Isosakuranetine are isolated from Andrographis stenophylla leaf.

Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-Chromen-2-One Core: Structure-Based and Ligand-Based Derived Three-Dimensional Quantitative Structure-Activity Relationships Predictive Models.

Science.gov (United States)

Mladenović, Milan; Patsilinakos, Alexandros; Pirolli, Adele; Sabatino, Manuela; Ragno, Rino

2017-04-24

Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure-activity relationships (QSAR) models derived from available cocrystallized inhibitor-MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a

Structure and properties of intermetallic ternary rare earth compounds

International Nuclear Information System (INIS)

Casper, Frederick

2008-01-01

The so called material science is an always growing field in modern research. For the development of new materials not only the experimental characterization but also theoretical calculation of the electronic structure plays an important role. A class of compounds that has attracted a great deal of attention in recent years is known as REME compounds. These compounds are often referred to with RE designating rare earth, actinide or an element from group 1-4, M representing a late transition metal from groups 8-12, and E belonging to groups 13-15. There are more than 2000 compounds with 1:1:1 stoichiometry belonging to this class of compounds and they offer a broad variety of different structure types. Although many REME compounds are know to exist, mainly only structure and magnetism has been determined for these compounds. In particular, in the field of electronic and transport properties relatively few efforts have been made. The main focus in this study is on compounds crystallizing in MgAgAs and LiGaGe structure. Both structures can only be found among 18 valence electron compounds. The f electrons are localized and therefor not count as valence electrons. A special focus here was also on the magnetoresistance effects and spintronic properties found among the REME compounds. An examination of the following compounds was made: GdAuE (E=In,Cd,Mg), GdPdSb, GdNiSb, REAuSn (RE=Gd,Er,Tm) and RENiBi (RE=Pr,Sm,Gd-Tm,Lu). The experimental results were compared with theoretic band structure calculations. The first half metallic ferromagnet with LiGaGe structure (GdPdSb) was found. All semiconducting REME compounds with MgAgAs structure show giant magnetoresistance (GMR) at low temperatures. The GMR is related to a metal-insulator transition, and the value of the GMR depends on the value of the spin-orbit coupling. Inhomogeneous DyNiBi samples show a small positive MR at low temperature that depends on the amount of metallic impurities. At higher fields the samples show a

Structure and properties of intermetallic ternary rare earth compounds

Energy Technology Data Exchange (ETDEWEB)

Casper, Frederick

2008-12-17

The so called material science is an always growing field in modern research. For the development of new materials not only the experimental characterization but also theoretical calculation of the electronic structure plays an important role. A class of compounds that has attracted a great deal of attention in recent years is known as REME compounds. These compounds are often referred to with RE designating rare earth, actinide or an element from group 1-4, M representing a late transition metal from groups 8-12, and E belonging to groups 13-15. There are more than 2000 compounds with 1:1:1 stoichiometry belonging to this class of compounds and they offer a broad variety of different structure types. Although many REME compounds are know to exist, mainly only structure and magnetism has been determined for these compounds. In particular, in the field of electronic and transport properties relatively few efforts have been made. The main focus in this study is on compounds crystallizing in MgAgAs and LiGaGe structure. Both structures can only be found among 18 valence electron compounds. The f electrons are localized and therefor not count as valence electrons. A special focus here was also on the magnetoresistance effects and spintronic properties found among the REME compounds. An examination of the following compounds was made: GdAuE (E=In,Cd,Mg), GdPdSb, GdNiSb, REAuSn (RE=Gd,Er,Tm) and RENiBi (RE=Pr,Sm,Gd-Tm,Lu). The experimental results were compared with theoretic band structure calculations. The first half metallic ferromagnet with LiGaGe structure (GdPdSb) was found. All semiconducting REME compounds with MgAgAs structure show giant magnetoresistance (GMR) at low temperatures. The GMR is related to a metal-insulator transition, and the value of the GMR depends on the value of the spin-orbit coupling. Inhomogeneous DyNiBi samples show a small positive MR at low temperature that depends on the amount of metallic impurities. At higher fields the samples show a

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

Science.gov (United States)

Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites.

Science.gov (United States)

Sugawara, Mitsuru; Mochizuki, Takahiro; Takekuma, Yoh; Miyazaki, Katsumi

2005-08-15

It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogenous compounds, and toxins. However, little is known about the structure-affinity relationship. The aim of this study was to elucidate the structure-affinity relationship using a series of structurally related compounds that interact with hOAT1. Inhibitory effects of xanthine- and uric acid-related compounds on the transport of p-aminohippuric acid were examined using CHO-K1 cells stably expressing hOAT1. The order of potency for the inhibitory effects of xanthine-related compounds on PAH uptake was 1-methyl derivative>7-methyl derivative>3-methyl derivative falling dotsxanthine>1,3,7-trimethyl derivative (caffeine). The order of potency of the inhibition was 1,3,7-trimethyluric acid>1,3-dimethyluric acid>1,7-dimethyluric acid>1-methyluric acid>uric acid. A significant correlation between inhibitory potency and lipophilicity of the tested uric acid-related compounds was observed. The main determinant of the affinity of xanthine-related compounds is the position of the methyl group. On the other hand, lipophilicity is the main determinant of the affinity of uric acid-related compounds.

Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Science.gov (United States)

Harada, Shusaku; Hiromori, Youhei; Nakamura, Shota; Kawahara, Kazuki; Fukakusa, Shunsuke; Maruno, Takahiro; Noda, Masanori; Uchiyama, Susumu; Fukui, Kiichi; Nishikawa, Jun-Ichi; Nagase, Hisamitsu; Kobayashi, Yuji; Yoshida, Takuya; Ohkubo, Tadayasu; Nakanishi, Tsuyoshi

2015-02-01

Organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) act as endocrine disruptors through the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. We recently found that TPT is a particularly strong agonist of PPARγ. To elucidate the mechanism underlying organotin-dependent PPARγ activation, we here analyzed the interactions of PPARγ ligand-binding domain (LBD) with TPT and TBT by using X-ray crystallography and mass spectroscopy in conjunction with cell-based activity assays. Crystal structures of PPARγ-LBD/TBT and PPARγ-LBD/TPT complexes were determined at 1.95 Å and 1.89 Å, respectively. Specific binding of organotins is achieved through non-covalent ionic interactions between the sulfur atom of Cys285 and the tin atom. Comparisons of the determined structures suggest that the strong activity of TPT arises through interactions with helix 12 of LBD primarily via π-π interactions. Our findings elucidate the structural basis of PPARγ activation by TPT.

Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.

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Sabine Kuettel

2011-05-01

Full Text Available BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP utilizing adenosine triphosphate (ATP as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK: the structure of TbrAK in complex with the bisubstrate inhibitor P(1,P(5-di(adenosine-5'-pentaphosphate (AP5A at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl-2H-pyrazol-3-yl]morpholine (compound 1 at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.

Applications of genetic algorithms on the structure-activity relationship analysis of some cinnamamides.

Science.gov (United States)

Hou, T J; Wang, J M; Liao, N; Xu, X J

1999-01-01

Quantitative structure-activity relationships (QSARs) for 35 cinnamamides were studied. By using a genetic algorithm (GA), a group of multiple regression models with high fitness scores was generated. From the statistical analyses of the descriptors used in the evolution procedure, the principal features affecting the anticonvulsant activity were found. The significant descriptors include the partition coefficient, the molar refraction, the Hammet sigma constant of the substituents on the benzene ring, and the formation energy of the molecules. It could be found that the steric complementarity and the hydrophobic interaction between the inhibitors and the receptor were very important to the biological activity, while the contribution of the electronic effect was not so obvious. Moreover, by construction of the spline models for these four principal descriptors, the effective range for each descriptor was identified.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

Science.gov (United States)

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

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.

Organotin compounds cause structure-dependent induction of progesterone in human choriocarcinoma Jar cells.

Science.gov (United States)

Hiromori, Youhei; Yui, Hiroki; Nishikawa, Jun-ichi; Nagase, Hisamitsu; Nakanishi, Tsuyoshi

2016-01-01

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are typical environmental contaminants and suspected endocrine-disrupting chemicals because they cause masculinization in female mollusks. In addition, previous studies have suggested that the endocrine disruption by organotin compounds leads to activation of peroxisome proliferator-activated receptor (PPAR)γ and retinoid X receptor (RXR). However, whether organotin compounds cause crucial toxicities in human development and reproduction is unclear. We here investigated the structure-dependent effect of 12 tin compounds on mRNA transcription of 3β-hydroxysteroid dehydrogenase type I (3β-HSD I) and progesterone production in human choriocarcinoma Jar cells. TBT, TPT, dibutyltin, monophenyltin, tripropyltin, and tricyclohexyltin enhanced progesterone production in a dose-dependent fashion. Although tetraalkyltin compounds such as tetrabutyltin increased progesterone production, the concentrations necessary for activation were 30-100 times greater than those for trialkyltins. All tested active organotins increased 3β-HSD I mRNA transcription. We further investigated the correlation between the agonistic activity of organotin compounds on PPARγ and their ability to promote progesterone production. Except for DBTCl2, the active organotins significantly induced the transactivation function of PPARγ. In addition, PPARγ knockdown significantly suppressed the induction of mRNA transcription of 3β-HSD I by all active organotins except DBTCl2. These results suggest that some organotin compounds promote progesterone biosynthesis in vitro by inducing 3β-HSD I mRNA transcription via the PPARγ signaling pathway. The placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might cause local changes in progesterone concentration in pregnant women. Copyright © 2014 Elsevier Ltd. All rights reserved.

Relationships between the structure of wheat gluten and ACE inhibitory activity of hydrolysate: stepwise multiple linear regression analysis.

Science.gov (United States)

Zhang, Yanyan; Ma, Haile; Wang, Bei; Qu, Wenjuan; Wali, Asif; Zhou, Cunshan

2016-08-01

Ultrasound pretreatment of wheat gluten (WG) before enzymolysis can improve the angiotensin converting enzyme (ACE) inhibitory activity of the hydrolysates by alerting the structure of substrate proteins. Establishment of a relationship between the structure of WG and ACE inhibitory activity of the hydrolysates to judge the end point of the ultrasonic pretreatment is vital. The results of stepwise multiple linear regression (MLR) showed that the contents of free sulfhydryl, α-helix, disulfide bond, surface hydrophobicity and random coil were significantly correlated to ACE Inhibitory activity of the hydrolysate, with the standard partial regression coefficients were 3.729, -0.676, -0.252, 0.022 and 0.156, respectively. The R(2) of this model was 0.970. External validation showed that the stepwise MLR model could well predict the ACE inhibitory activity of hydrolysate based on the content of free sulfhydryl, α-helix, disulfide bond, surface hydrophobicity and random coil of WG before hydrolysis. A stepwise multiple linear regression model describing the quantitative relationships between the structure of WG and the ACE Inhibitory activity of the hydrolysates was established. This model can be used to predict the endpoint of the ultrasonic pretreatment. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Structure-activity relationship studies on the mosquito toxicity and biting deterrency of callicarpenal derivatives.

Science.gov (United States)

Cantrell, Charles L; Klun, Jerome A; Pridgeon, Julia; Becnel, James; Green, Solomon; Fronczek, Frank R

2009-04-01

Callicarpenal (=13,14,15,16-tetranorclerod-3-en-12-al=[(1S,2R,4aR,8aR)-1,2,3,4,4a,7,8,8a-octahydro-1,2,4a,5-tetramethylnaphthalen-1-yl]acetaldehyde; 1) has previously demonstrated significant mosquito bite-deterring activity against Aedes aegypti and Anopheles stephensi in addition to repellent activity against host-seeking nymphs of the blacklegged tick, Ixodes scapularis. In the present study, structural modifications were performed on callicarpenal (1) in an effort to understand the functional groups necessary for maintaining and/or increasing its activity and to possibly lead to more effective insect control agents. All modifications in this study targeted the C(12) aldehyde or the C(3) alkene functionalities or combinations thereof. Mosquito biting deterrency appeared to be influenced most by C(3) alkene modification as evidenced by catalytic hydrogenation that resulted in a compound having significantly less effectiveness than 1 at a test amount of 25 nmol/cm2. Oxidation and/or reduction of the C(12) aldehyde did not diminish mosquito biting deterrency, but, at the same time, none of the modifications were more effective than 1 in deterring mosquito biting. Toxicities of synthesized compounds towards Ae. aegypti ranged from an LD50 value of 2.36 to 40.11 microg per mosquito. Similarly, LD95 values ranged from a low of 5.59 to a high of 104.9 microg.

Microwave assistant synthesis, crystal structure and biological activity of a 1,2,4-triazole compound

International Nuclear Information System (INIS)

Ke, W.; Sun, N.B.

2013-01-01

The title compound (C/sub 17/H/sub 14/F/sub 2/N/sub 4/SO) were synthesized and recrystallized from CH/sub 3/CN. The compound was characterized by 1h-nmr, ftir, ms, hrms and x-ray diffraction. the compound crystallized in the monoclinic space group c2/c with a = 27.532(6), b 8.9596(18), c 14.609(3) alpha = 90, beta = 112.59(3), lambda =90 degree, gamma = 3327.1(12) alpha 3, z = 8 and r = 0.0327 for 2596 observed reflections with 1 > 2 (i). x-ray analysis reveals that not only intermolecular N-H-N interactions, but also C-H Pie stacking interactions exist in the adjacent molecules. The biological activities results showed that it exhibited significant herbicidal activity towards brassica napus. (author)

Synthesis, crystal structure and biological activity of novel diester cyclophanes

International Nuclear Information System (INIS)

Zhang, Pengfei; Yang, Bingqin; Fang, Xianwen; Cheng, Zhao; Yang, Meipan

2012-01-01

A series of novel diester cyclophanes was synthesized by esterification of 1,2-benzenedicarbonyl chloride with eight different diols under high dilution conditions. The structures of the compounds were verified by elemental analysis, 1 H nuclear magnetic resonance (NMR), IR spectroscopy and high resolution mass spectrometry (HRMS). The crystal structures of two compounds were characterized by single crystal X-ray diffractometry (XRD). All the new cyclophanes were evaluated for biological activities and the results showed that some of these compounds have low antibacterial or antifungal activities (author)

Relationships between structure and activity of carbon as a multifunctional support for electrocatalysts.

Science.gov (United States)

Stevanović, Sanja I; Panić, Vladimir V; Dekanski, Aleksandar B; Tripković, Amalija V; Jovanović, Vladislava M

2012-07-14

We report on new insights into the relationships between structure and activity of glassy carbon (GC), as a model material for electrocatalyst support, during its anodization in acid solution. Our investigation strongly confirms the role of CFGs in promotion of Pt activity by the "spill-over" effect related to CO(ads) for methanol electrooxidation (MEO) on a carbon-supported Pt catalyst. Combined analysis of voltammetric and impedance behaviour as well as changes in GC surface morphology induced by intensification of anodizing conditions reveal an intrinsic influence of the carbon functionalization and the structure of a graphene oxide (GO) layer on the electrical and electrocatalytic properties of activated GC. Although GO continuously grows during anodization, it structurally changes from being a graphite inter-layer within graphite ribbons toward a continuous GO surface layer that deteriorates the native structure of GC. As a consequence of the increased distance between GO-spaced graphite layers, the GC conductivity decreases until the case of profound GO exfoliation under drastic anodizing conditions. This exposes the native, yet abundantly functionalized, GC texture. While GC capacitance continuously increases with intensification of anodizing conditions, the surface nano-roughness and GO resistance reach the highest values at modest anodizing conditions, and then decrease upon drastic anodization due to the onset of GO exfoliation. We found for the first time that the activity of a GC-supported Pt catalyst in MEO, as one of the promising half-reactions in polymer electrolyte fuel cells, strictly follows the changes in GC nano-roughness and GO-induced GC resistance. The highest GC/Pt MEO activity is reached when optimal distance between graphite layers and optimal degree of GC functionalization bring the highest amount of CFGs into intimate contact with the Pt surface. This confirms the promoting role of CFGs in MEO catalysis.

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

Directory of Open Access Journals (Sweden)

Richard D. Beger

2012-03-01

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

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

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

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Stephanie Forschner-Dancause

2016-07-01

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

Structure-activity relations of 2-(methylthio)benzimidazole by FTIR, FT-Raman, NMR, DFT and conceptual DFT methods.

Science.gov (United States)

Arjunan, V; Raj, Arushma; Ravindran, P; Mohan, S

2014-01-24

The vibrational fundamental modes of 2-(methylthio)benzimidazole (2MTBI) have been analysed by combining FTIR, FT-Raman and quantum chemical calculations. The structural parameters of the compound are determined from the optimised geometry by B3LYP with 6-31G(∗∗), 6-311++G(∗∗) and cc-pVTZ basis sets and giving energies, harmonic vibrational frequencies, depolarisation ratios, IR intensities and Raman activities. (1)H and (13)C NMR spectra have been analysed and (1)H and (13)C nuclear magnetic resonance chemical shifts are calculated using the gauge independent atomic orbital (GIAO) method. The structure-activity relationship of the compound is also investigated by conceptual DFT methods. The chemical reactivity and site selectivity of the molecule has been determined with the help of global and local reactivity descriptors. Copyright © 2013 Elsevier B.V. All rights reserved.

Designing a Quantitative Structure-Activity Relationship for the ...

Science.gov (United States)

Toxicokinetic models serve a vital role in risk assessment by bridging the gap between chemical exposure and potentially toxic endpoints. While intrinsic metabolic clearance rates have a strong impact on toxicokinetics, limited data is available for environmentally relevant chemicals including nearly 8000 chemicals tested for in vitro bioactivity in the Tox21 program. To address this gap, a quantitative structure-activity relationship (QSAR) for intrinsic metabolic clearance rate was developed to offer reliable in silico predictions for a diverse array of chemicals. Models were constructed with curated in vitro assay data for both pharmaceutical-like chemicals (ChEMBL database) and environmentally relevant chemicals (ToxCast screening) from human liver microsomes (2176 from ChEMBL) and human hepatocytes (757 from ChEMBL and 332 from ToxCast). Due to variability in the experimental data, a binned approach was utilized to classify metabolic rates. Machine learning algorithms, such as random forest and k-nearest neighbor, were coupled with open source molecular descriptors and fingerprints to provide reasonable estimates of intrinsic metabolic clearance rates. Applicability domains defined the optimal chemical space for predictions, which covered environmental chemicals well. A reduced set of informative descriptors (including relative charge and lipophilicity) and a mixed training set of pharmaceuticals and environmentally relevant chemicals provided the best intr

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.

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.

Synthesis, crystal structure and biological activity of novel diester cyclophanes

Energy Technology Data Exchange (ETDEWEB)

Zhang, Pengfei; Yang, Bingqin; Fang, Xianwen; Cheng, Zhao; Yang, Meipan, E-mail: yangbq@nwu.edu.cn [Department of Chemistry, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, Northwest University, Shaanxi (China)

2012-10-15

A series of novel diester cyclophanes was synthesized by esterification of 1,2-benzenedicarbonyl chloride with eight different diols under high dilution conditions. The structures of the compounds were verified by elemental analysis, {sup 1}H nuclear magnetic resonance (NMR), IR spectroscopy and high resolution mass spectrometry (HRMS). The crystal structures of two compounds were characterized by single crystal X-ray diffractometry (XRD). All the new cyclophanes were evaluated for biological activities and the results showed that some of these compounds have low antibacterial or antifungal activities (author)

Structure-cytotoxicity relationships for dietary flavonoids

DEFF Research Database (Denmark)

Breinholt, V.; Dragsted, L.O.

1998-01-01

The cytotoxicity of a large series of dietary flavonoids was tested in a non-tumorigenic mouse and two human cancer cell lines, using the neutral red dye exclusion assay. All compounds tested exhibited a concentration-dependent cytotoxic action in the employed cell lines. The relative cytotoxicity...... of the flavonoids, however, Tvas found to vary greatly among the different cell Lines. With a few exceptions, the investigated flavonoids were more cytotoxic to the human cancer cell lines, than the mouse cell line. The differences in cytotoxicity were accounted for in part by differences in cellular uptake...... and metabolic capacity among the different cell types. In 3T3 cells fairly consistent structure-cytotoxicity relationships were found. The most cytotoxic structures tested in 3T3 cells were flavonoids with adjacent 3',4' hydroxy groups on the B-ring, such as luteolin, quercetin, myricetin, fisetin, eriodictyol...

Synthesis, cytotoxicity and haemolytic activity of Pulsatilla saponin A, D derivatives.

Science.gov (United States)

Chen, Zhong; Duan, Huaqing; Wang, Minglei; Han, Li; Liu, Yanli; Zhu, Yongming; Yang, Shilin

2015-06-15

The strong haemolytic activity of Pulsatilla saponin A (PSA), D (PSD) hampered their clinical development of antitumor agents. In order to solve this problem, C-28 position modification derivatives of PSA/PSD were synthesized. The cytotoxicity and haemolytic activity of these compounds were evaluated. Structure-activity relationship and structure-toxicity relationship had been observed. The mice acute toxicity of compound 11 was reduced greatly than that of PSA. This study indicates that compound 11 may represent an interesting class of potent antitumor agents from triterpenoid saponins avoiding the haemolysis problem. The present study has important significance for the development of antitumor saponins. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Quantitative structure-retention relationships of flavonoids unraveled by immobilized artificial membrane chromatography.

Science.gov (United States)

Santoro, Adriana Leandra; Carrilho, Emanuel; Lanças, Fernando Mauro; Montanari, Carlos Alberto

2016-06-10

The pharmacokinetic properties of flavonoids with differing degrees of lipophilicity were investigated using immobilized artificial membranes (IAMs) as the stationary phase in high performance liquid chromatography (HPLC). For each flavonoid compound, we investigated whether the type of column used affected the correlation between the retention factors and the calculated octanol/water partition (log Poct). Three-dimensional (3D) molecular descriptors were calculated from the molecular structure of each compound using i) VolSurf software, ii) the GRID method (computational procedure for determining energetically favorable binding sites in molecules of known structure using a probe for calculating the 3D molecular interaction fields, between the probe and the molecule), and iii) the relationship between partition and molecular structure, analyzed in terms of physicochemical descriptors. The VolSurf built-in Caco-2 model was used to estimate compound permeability. The extent to which the datasets obtained from different columns differ both from each other and from both the calculated log Poct and the predicted permeability in Caco-2 cells was examined by principal component analysis (PCA). The immobilized membrane partition coefficients (kIAM) were analyzed using molecular descriptors in partial least square regression (PLS) and a quantitative structure-retention relationship was generated for the chromatographic retention in the cholesterol column. The cholesterol column provided the best correlation with the permeability predicted by the Caco-2 cell model and a good fit model with great prediction power was obtained for its retention data (R(2)=0.96 and Q(2)=0.85 with four latent variables). Copyright © 2015 Elsevier B.V. All rights reserved.

Structural analysis and antimicrobial activity of 2[1H]-pyrimidinethione/selenone derivatives

Science.gov (United States)

Żesławska, Ewa; Korona-Głowniak, Izabela; Szczesio, Małgorzata; Olczak, Andrzej; Żylewska, Alicja; Tejchman, Waldemar; Malm, Anna

2017-08-01

Four new crystal structures of sulfur and selenium analogues of 2[1H]-pyrimidinone derivatives were determined with the use of X-ray diffraction method. The molecular geometry and intermolecular interactions of the investigated molecules were analyzed in order to find the structural features and geometrical parameters, which can be responsible for antimicrobial activities. The influence of chalcogen substituents (sulfur and selenium) on the crystal packing was also studied. The main differences in the molecular structures exist in mutual arrangement of two aromatic rings. The intermolecular interactions in all investigated compounds are similar. Furthermore, the in vitro antibacterial and antifungal activities for these compounds were evaluated. Preliminary investigations have identified two highly potent antibacterial compounds containing selenium atom, which display selectivity towards staphylococci and micrococci. This selectivity was not observed for a control compound used as a drug, namely vancomycin. These compounds possess also good antifungal activity. This is the first report of biological activities of 2[1H]-pyrimidineselenone derivatives.

Antioxidant and Anti-Osteoporotic Activities of Aromatic Compounds and Sterols from Hericium erinaceum.

Science.gov (United States)

Li, Wei; Lee, Sang Hyun; Jang, Hae Dong; Ma, Jin Yeul; Kim, Young Ho

2017-01-11

Hericium erinaceum , commonly called lion's mane mushroom, is a traditional edible mushroom widely used in culinary applications and herbal medicines in East Asian countries. In this study, a new sterol, cerevisterol 6-cinnamate ( 6 ), was isolated from the fruiting bodies of H. erinaceum together with five aromatic compounds 1 - 5 and five sterols 7 - 11 . The chemical structures of these compounds were elucidated using chemical and physical methods and comparison of HRESIMS, ¹D-NMR (¹H, 13 C, and DEPT) and 2D-NMR (COSY, HMQC, HMBC, and NOESY) spectra with previously reported data. The antioxidant and anti-osteoporotic activities of extracts and the isolated compounds 1 - 11 were investigated. All compounds exhibited peroxyl radical-scavenging capacity but only compounds 1 , 3 , and 4 showed potent reducing capacity. Moreover, compounds 1 , 2 , 4 , and 5 showed moderate effects on cellular antioxidant activity and inhibited the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastic differentiation. These results suggested that H. erinaceum could be utilized in the development of natural antioxidant and anti-osteoporotic nutraceuticals and functional foods.

Quantitative structure-activity relationships for toxicity and genotoxicity of halogenated aliphatic compounds: wing spot test of Drosophila melanogaster.

Science.gov (United States)

Chroust, Karel; Pavlová, Martina; Prokop, Zbynek; Mendel, Jan; Bozková, Katerina; Kubát, Zdenek; Zajícková, Veronika; Damborský, Jiri

2007-02-01

Halogenated aliphatic compounds were evaluated for toxic and genotoxic effects in the somatic mutation and recombination test employing Drosophila melanogaster. The tested chemicals included chlorinated, brominated and iodinated; mono-, di- and tri-substituted; saturated and unsaturated alkanes: 1,2-dibromoethane, 1-bromo-2-chloroethane, 1-iodopropane, 2,3-dichloropropene, 3-bromo-1-propene, epibromohydrin, 2-iodobutane, 3-chloro-2-methylpropene, 1,2,3-trichloropropane, 1,2-dichloroethane, 1,2-dichlorobutane, 1-chloro-2-methylpropane, 1,3-dichloropropane, 1,2-dichloropropane, 2-chloroethymethylether, 1-bromo-2-methylpropane and 1-chloropentane. N-methyl-N-nitrosourea served as the positive and distilled water as the negative control. The set of chemicals for the toxicological testing was selected by the use of statistical experiment design. Group of unsaturated aliphatic hydrocarbons were generally more toxic than saturated analogues. The genotoxic effect was observed with 14 compounds in the wing spot test, while 3 substances did not show any genotoxicity by using the wing spot test at 50% lethal concentration. The highest number of wing spots was observed in genotoxicity assay with 1-bromo-2-chloroethane, 1,2-dichloroethane, 1,2-dibromoethane and 1-iodopropane. Nucleophilic superdelocalizability calculated by quantum mechanics appears to be a good parameter for prediction of both toxicity and genotoxicity effects of halogenated aliphatic compounds.

Phytotherapic compounds: the consumer-pharmacist relationship.

Science.gov (United States)

Bacchini, Marco; Cuzzolin, Laura; Camerlengo, Thomas; Velo, Giampaolo; Benoni, Giuseppina

2008-01-01

Pharmacists play an important role in providing information about natural products and in preventing risks related to these substances, particularly with respect to interactions with conventional drugs. For these reasons, a survey was specifically designed to investigate the quality of self-care counselling by pharmacists on phytotherapy. Twenty-three pharmacy stores took part in the project. Face-to-face interviews, using a pre-structured questionnaire, were undertaken by trained pharmacists to consumers buying a herbal product. The questionnaire included socio-demographic data and 17 items designed to elicit information regarding the reason of consumption, product knowledge, relationship/communication with healthcare providers, level of satisfaction, concurrent drug use and adverse reactions. The collection of interviews started in November 2006 until April 2007. From the analysis of 1420 questionnaires, it is evident that herbal use is increasing in Italy: 12% of our interviewees were buying a herbal product for the first time. The present survey highlights the favourable perception of efficacy of phytotherapic compounds by the pharmacy's consumers, who consider this healthcare modality to be an important and effective way to promote health/wellness and disease management as well as being safer overall than conventional drugs. Moreover, findings from this study demonstrate that pharmacists are more likely to answer correctly about the uses of herbal medicines than about drug interactions, adverse drug effects and cautions about these products.

Antifungal activity of the ethanolic extracts of Punica granatum L. and evaluation of the morphological and structural modifications of its compounds upon the cells of Candida spp.

Science.gov (United States)

Anibal, Paula Cristina; Peixoto, Iza Teixeira Alves; Foglio, Mary Ann; Höfling, José Francisco

2013-01-01

Ethanolic crude extracts prepared from the arils and seeds, pericarp, peels and from the whole fruit of Punica granatum, known as pomegranate, had their antifungal activity tested against Candida spp. The ethanolic crude extracts were analyzed by Mass Spectrometry and yielded many compounds such as punicalagin and galladydilacton. The extracts from the pericarp and peel showed activity against Candida spp., with MICs of 125 μg/mL. The effect of pericarp and peel extracts upon the morphological and structure of C. albicans and C. krusei were examined by scanning and transmission electron microscopy, with the visualization of an irregular membrane and hyphae, formation of vacuoles and thickening of the cell wall. The data obtained revealed potential antimicrobial activity against yeasts cells of the Candida genus, and the bioactive compounds could be responsible for changes in cell morphology and structure. The data obtained open new perspectives for future research in continuation to this study, where information such as determination of the site of action of the compounds could contribute to an alternative therapy against these organisms.

Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents

Directory of Open Access Journals (Sweden)

Pramod K. Sahu

2017-07-01

Full Text Available A series of acyclic selenopurine nucleosides 3a–f and 4a–g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a exhibited the most potent anti-herpes simplex virus (HSV-1 (EC50 = 1.47 µM and HSV-2 (EC50 = 6.34 µM activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e–g exhibited significant anti-human cytomegalovirus (HCMV activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d.

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

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

OpenAIRE

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

2012-01-01

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

Cytotoxic constituents of propolis from Myanmar and their structure-activity relationship.

Science.gov (United States)

Li, Feng; Awale, Suresh; Tezuka, Yasuhiro; Kadota, Shigetoshi

2009-12-01

Thirteen cycloartane-type tritepenes (1-13) and four prenylated flavanones (14-17) isolated from propolis collected in Myanmar, were evaluated for their cytotoxic activity against a panel of six different cancer cell lines; three murine cancer cell lines (colon 26-L5 carcinoma, B16-BL6 melanoma, and Lewis lung carcinoma) and three human cancer cell lines (lung A549 adenocarcinoma, cervix HeLa adenocarcinoma and HT-1080 fibrosarcoma). Among them, a cycloartane-type triterpene, 3alpha,27-dihydroxycycloart-24E-en-26-oic acid (3), showed the most potent cytotoxicity against B16-BL6 cells with an IC(50) value of 5.91 microM, comparable to those of positive controls, doxorubicin (IC(50), 5.66 microM) and 5-fluorouracil (IC(50), 4.88 microM). In addition, (2S)-5,7-dihydroxy-4'-methoxy-8,3'-diprenylflavanone (14) exhibited strong cytotoxicity against all the tested cancer cell lines with the IC(50) values ranging from 14.0 to 26.4 microM. Based on the observed results, the structure-activity relationships are discussed.

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal

Science.gov (United States)

Ries, Michele L.; Jabbar, Britta M.; Schmitz, Taylor W.; Trivedi, Mehul A.; Gleason, Carey E.; Carlsson, Cynthia M.; Rowley, Howard A.; Asthana, Sanjay; Johnson, Sterling C.

2009-01-01

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer’s disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants’ activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly-significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD. PMID:17445294

A structure-activity relationship study on a natural germination inhibitor, 2-methoxy-4-vinylphenol (MVP), in wheat seeds to evaluate its mode of action.

Science.gov (United States)

Darabi, Hossein Reza; Mohandessi, Shabnam; Balavar, Yadollah; Aghapoor, Kioumars

2007-01-01

The first aim of the present study was to evaluate which structural elements of the 2-methoxy-4-vinylphenol (MVP) molecule (1) are responsible for its observed activity as germination inhibitor in wheat seeds. To find its mode of action, a series of compounds with varying functional moieties and substitution patterns were prepared and evaluated for their inhibitory activity. This systematic competitive inhibition study characterized two criteria for the effective increase of the inhibiting ability: (i) ortho substitution to each of the hydroxy and methoxy groups; (ii) alkene moiety on the ring. Understanding how the structure of natural compounds relates to their inhibition function is fundamentally important and may help to facilitate their application as novel inhibitors to restrain preharvest sprouting (PHS) in wheat fields. In this regard, in MVP and its natural analogues 8 and 9 as the most active inhibitors, the ortho substitution of hydroxy and methoxy groups plays a key role in their activity and, as well, the alkene moiety influences the activity significantly.

QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities.

Science.gov (United States)

Lima, Marilia N N; Melo-Filho, Cleber C; Cassiano, Gustavo C; Neves, Bruno J; Alves, Vinicius M; Braga, Rodolpho C; Cravo, Pedro V L; Muratov, Eugene N; Calit, Juliana; Bargieri, Daniel Y; Costa, Fabio T M; Andrade, Carolina H

2018-01-01

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium , affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum ( Pf dUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei . We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as Pf dUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual Pf dUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.

Two new phenolic compounds and antitumor activities of asparinin A from Asparagus officinalis.

Science.gov (United States)

Li, Xue-Mei; Cai, Jin-Long; Wang, Le; Wang, Wen-Xiang; Ai, Hong-Lian; Mao, Zi-Chao

2017-02-01

Two new phenolic acid compounds, asparoffin C (1) and asparoffin D (2), together with four known compounds, asparenyol (3), gobicusin B (4), 1-methoxy-2-hydroxy-4-[5-(4-hydroxyphenoxy)-3-penten-1-ynyl] phenol (5), and asparinin A (6), have been isolated from the stems of Asparagus officinalis. The structures were established by extensive spectroscopic methods (MS and 1D and 2D NMR). Compound 6 has obvious antitumor activities both in vitro and in vivo.

On-rate based optimization of structure-kinetic relationship--surfing the kinetic map.

Science.gov (United States)

Schoop, Andreas; Dey, Fabian

2015-10-01

In the lead discovery process residence time has become an important parameter for the identification and characterization of the most efficacious compounds in vivo. To enable the success of compound optimization by medicinal chemistry toward a desired residence time the understanding of structure-kinetic relationship (SKR) is essential. This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis of Some Novel Thiadiazole Derivative Compounds and Screening Their Antidepressant-Like Activities

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Nafiz Öncü Can

2018-03-01

Full Text Available Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR, 1H Nuclear Magnetic Resonance Spectroscopy (1H-NMR, 13C Nuclear Magnetic Resonance Spectroscopy (13C-NMR and Electronspray Ionisation Mass Spectroscopy (ESI-MS spectroscopic methods. Antidepressant-like activities were evaluated by the tail-suspension (TST and modified forced swimming (MFST methods. Besides, possible influence of the test compounds on motor activities of the animals were examined by activity cage tests. In the TST, administration of the compounds 2c, 2d, 2e, 2f, 2g and 2h significantly decreased the immobility time of mice regarding the control values. Further, in the MFST, the same compounds reduced the total number of immobility behaviors while increasing swimming performance. However, no change was observed in the total number of climbing behaviors. These data suggested that compounds 2c, 2d, 2e, 2f, 2g and 2h possess notable antidepressant-like activities. Reference drug fluoxetine (10 mg/kg was also exhibited its antidepressant activity, as expected. No significant difference was seen between the locomotor activity values of the test groups signifying that observed antidepressant-like activities are specific. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME properties for the obtained compounds were performed and obtained data supported the antidepressant-like potential of these novel thiadiazole derivatives.

Atom-type-based AI topological descriptors: application in structure-boiling point correlations of oxo organic compounds.

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Ren, Biye

2003-01-01

Structure-boiling point relationships are studied for a series of oxo organic compounds by means of multiple linear regression (MLR) analysis. Excellent MLR models based on the recently introduced Xu index and the atom-type-based AI indices are obtained for the two subsets containing respectively 77 ethers and 107 carbonyl compounds and a combined set of 184 oxo compounds. The best models are tested using the leave-one-out cross-validation and an external test set, respectively. The MLR model produces a correlation coefficient of r = 0.9977 and a standard error of s = 3.99 degrees C for the training set of 184 compounds, and r(cv) = 0.9974 and s(cv) = 4.16 degrees C for the cross-validation set, and r(pred) = 0.9949 and s(pred) = 4.38 degrees C for the prediction set of 21 compounds. For the two subsets containing respectively 77 ethers and 107 carbonyl compounds, the quality of the models is further improved. The standard errors are reduced to 3.30 and 3.02 degrees C, respectively. Furthermore, the results obtained from this study indicate that the boiling points of the studied oxo compound dominantly depend on molecular size and also depend on individual atom types, especially oxygen heteroatoms in molecules due to strong polar interactions between molecules. These excellent structure-boiling point models not only provide profound insights into the role of structural features in a molecule but also illustrate the usefulness of these indices in QSPR/QSAR modeling of complex compounds.

A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.

Science.gov (United States)

Harrell, William A; Vieira, Rebecca C; Ensel, Susan M; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H; Webb, Robert P; Smith, Leonard A

2017-02-01

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC 50 values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay. Published by Elsevier Ltd.

Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators.

Science.gov (United States)

Li, Ridong; Ning, Xianling; Zhou, Shuo; Lin, Zhiqiang; Wu, Xingyu; Chen, Hong; Bai, Xinyu; Wang, Xin; Ge, Zemei; Li, Runtao; Yin, Yuxin

2018-01-01

Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC 50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Structure-activity relationship of Trp-containing analogs of the antimicrobial peptide gomesin.

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Domingues, Tatiana M; Buri, Marcus V; Daffre, Sirlei; Campana, Patricia T; Riske, Karin A; Miranda, Antonio

2014-06-01

Gomesin (Gm) has a broad antimicrobial activity making it of great interest for development of drugs. In this study, we analyzed three Gm analogs, [Trp(1) ]-Gm, [Trp(7) ]-Gm, and [Trp(9) ]-Gm, in an attempt to gain insight into the contributions of different regions of the peptide sequence to its activity. The incorporation of the tryptophan residue in different positions has no effect on the antimicrobial and hemolytic activities of the Gm analogs in relation to Gm. Spectroscopic studies (circular dichroism, fluorescence and absorbance) of Gm and its analogs were performed in the presence of SDS, below and above its critical micelle concentration (CMC) (~8 mM), in order to monitor structural changes induced by the interaction with this anionic surfactant (0-15 mM). Interestingly, we found that the analogs interact more strongly with SDS at low concentrations (0.3-6.0 mM) than close to or above its CMC. This suggests that SDS monomers are able to cover the whole peptide, forming large detergent-peptide aggregates. On the other hand, the peptides interact differently with SDS micelles, inserting partially into the micelle core. Among the peptides, Trp in position 1 becomes more motionally-restricted in the presence of SDS, probably because this residue is located at the N-terminal region, which presents higher conformational freedom to interact stronger with SDS molecules. Trp residues in positions 7 and 9, close to and in the region of the turn of the molecule, respectively, induced a more constrained structure and the compounds cannot insert deeper into the micelle core or be completely buried by SDS monomers. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

Antioxidant and Anti-Osteoporotic Activities of Aromatic Compounds and Sterols from Hericium erinaceum

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Wei Li

2017-01-01

Full Text Available Hericium erinaceum, commonly called lion’s mane mushroom, is a traditional edible mushroom widely used in culinary applications and herbal medicines in East Asian countries. In this study, a new sterol, cerevisterol 6-cinnamate (6, was isolated from the fruiting bodies of H. erinaceum together with five aromatic compounds 1–5 and five sterols 7–11. The chemical structures of these compounds were elucidated using chemical and physical methods and comparison of HRESIMS, 1D-NMR (1H, 13C, and DEPT and 2D-NMR (COSY, HMQC, HMBC, and NOESY spectra with previously reported data. The antioxidant and anti-osteoporotic activities of extracts and the isolated compounds 1–11 were investigated. All compounds exhibited peroxyl radical-scavenging capacity but only compounds 1, 3, and 4 showed potent reducing capacity. Moreover, compounds 1, 2, 4, and 5 showed moderate effects on cellular antioxidant activity and inhibited the receptor activator of nuclear factor κB ligand (RANKL-induced osteoclastic differentiation. These results suggested that H. erinaceum could be utilized in the development of natural antioxidant and anti-osteoporotic nutraceuticals and functional foods.

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

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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.

Identification of new 2,5-diketopiperazine derivatives as simultaneous effective inhibitors of αβ-tubulin and BCRP proteins: Molecular docking, Structure-Activity Relationships and virtual consensus docking studies

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Fani, Najmeh; Sattarinezhad, Elham; Bordbar, Abdol-Khalegh

2017-06-01

In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure-activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity.

Characterization of structure and activity of garlic peroxidase (POX(1B)).

Science.gov (United States)

El Ichi, Sarra; Miodek, Anna; Sauriat-Dorizon, Hélène; Mahy, Jean-Pierre; Henry, Céline; Marzouki, Mohamed Nejib; Korri-Youssoufi, Hafsa

2011-01-01

Structural characterization and study of the activity of new POX(1B) protein from garlic which has a high peroxidase activity and can be used as a biosensor for the detection of hydrogen peroxide and phenolic compounds were performed and compared with the findings for other heme peroxidases. The structure-function relationship was investigated by analysis of the spectroscopic properties and correlated to the structure determined by a new generation of high-performance hybrid mass spectrometers. The reactivity of the enzyme was analyzed by studies of the redox activity toward various ligands and the reactivity with various substrates. We demonstrated that, in the case of garlic peroxidase, the heme group is pentacoordinated, and has an histidine as a proximal ligand. POX(1B) exhibited a high affinity for hydrogen peroxide as well as various reducing cosubstrates. In addition, high enzyme specificity was demonstrated. The k(cat) and K(M) values were 411 and 400 mM(-1) s(-1) for 3,3',5,5'-tetramethylbenzidine and 2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), respectively. Furthermore, the reduction of nitro compounds in the presence of POX(1B) was demonstrated by iron(II) nitrosoalkane complex assay. In addition, POX(1B) showed a great potential for application for drug metabolism since its ability to react with 1-nitrohexane in the presence of sodium dithionite was demonstrated by the appearance of a characteristic Soret band at 411 nm. The high catalytic efficiency obtained in the case of the new garlic peroxidase (POX(1B)) is suitable for the monitoring of different analytes and biocatalysis.

Anti-inflammatory activities of compounds from twigs of Morus alba.

Science.gov (United States)

Tran, Huynh Nguyen Khanh; Nguyen, Van Thu; Kim, Jeong Ah; Rho, Seong Soo; Woo, Mi Hee; Choi, Jae Sui; Lee, Jeong-Hyung; Min, Byung Sun

2017-07-01

Five new compounds, 10-oxomornigrol F (1), (7″R)-(-)-6-(7″-hydroxy-3″,8″-dimethyl-2″,8″-octadien-1″-yl)apigenin (2), ramumorin A (3), ramumorin B (4), and (4S,7S,8R)-trihydroxyoctadeca-5Z-enoic acid (5), together with 31 known compounds (6-36), were isolated from the twigs of Morus alba (Moraceae). The chemical structures of these compounds were established using spectroscopic analyses, 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and Mosher's methods. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. Compounds 1, 2, 13, 17, 19, 25-28, and 32 showed inhibitory effects with IC 50 values ranging from 2.2 to 5.3μg/mL. Compounds 1, 2, 17, 25, and 32 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. In addition, pretreating the cells with compound 1, 17, and 32 significantly suppressed LPS-induced expression of cyclooxygenase-2 (COX-2) protein. Copyright © 2017. Published by Elsevier B.V.

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

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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...

Structure-activity of valencenoid derivatives and their repellence to the Formosan subterranean termite.

Science.gov (United States)

Zhu, Betty C R; Henderson, Gregg; Sauer, Anne M; Yu, Ying; Crowe, William; Laine, Roger A

2003-12-01

Eight valencenoid derivatives were evaluated for their repelling activity against Formosan subterranean termites, Coptotermes formosanus Shiraki. Among them, 1,10-dihydronootkatone was the strongest repellent, and valencene was the weakest. Results of the structure-repellency relationships indicated (1) reduction of the ketone group to the alcohol on position 2 of nootkatone curtailed the activity; (2) because of the low activity of valencene relative to nootkatone that the ketone group was essential for repellent activity; (3) reduction of the 1,10 double bond (1,10-dihydronootkatone and tetrahydronootkatone) produced compounds more repellent than nootkatone; (4) the isopropenyl group probably does not participate in binding as evidenced by no significant difference in the repellent activity among nootkatone (double bond between position 11 and 12), isonootkatone (double bond between position 7 and 11), and 11,12-dihydronootkatone.

Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants

NARCIS (Netherlands)

Harju, M.; Hamers, T.; Kamstra, J.H.; Sonneveld, E.; Boon, J.P.

2007-01-01

In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs),

Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analogues of organophosphorus compounds. (Reannouncement with new availability information)

Energy Technology Data Exchange (ETDEWEB)

Maxwell, D.M.; Brecht, K.M.

1992-02-01

A comparison of the bimolecular rate constants (ki) for inhibition of electric eel acetylcholinesterase (AChE) by the oxono (i.e., P=O) and thiono (i.e., P=S) analogues of parathion, methylparathion, leptophos, fonofos, sarin, and soman revealed that the oxono/thiono ratios of ki values varied from 14 for soman to 1240 for parathion. Analysis of the relative importance of the dissociation equilibrium constant and the phosphorylation rate constant in producing this variation in ki values indicated that the oxono analogues had phosphorylation rate constant values that varied in a narrow range from 8- to 14-fold greater than their thiono counterparts, while the oxono/thiono ratios for dissociation constants varied widely from 1 for soman to 82 for fonofos. The lower affinities of thiono analogues for AChE probably resulted from differences in the hydrophobic binding of oxono and thiono analogues to the active site of AChE, inasmuch as the hydrophobicities (i.e., octanol/water partition coefficients) of thiono organophosphorus compounds were much greater than the hydrophobicities of their oxono analogues. Quantitative structure-activity analysis indicated that the hydrophobic effects of oxono and thiono moieties correlated with log ki for AChE inhibition to a greater extent (r2 = 0.79) than their electronic effects (r2 equal to or less than 0.48). These observations suggest that the differences in hydrophobicity of oxono and thiono analogues of organophosphorus compounds may be as important as their electronic differences in determining their effectiveness as AChE inhibitors. Acetylcholinesterase, soman (GD), structure-activity analysis inhibition, oxono analogues, thiono analogues.

Quantitative structure-toxicity relationship study of some natural and synthetic coumarins using retention parameters

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Rabtti El Hadi M.A.

2012-01-01

Full Text Available Four lipophilicity descriptors (RM0, b, C0, PC1 for twelve coumarine derivatives were determined by reversed-phase thin-layer chromatography in order to analyze which descriptor best describes the lipophilicity of coumarines investigated. Moreover, possible chemical toxicity of coumarins, expressed as the probability of a compound to cause organ-specific health effects, was calculated using ACD/Tox Suite program. The quantitative relationships between toxicity and molecular descriptors, including experimentally determined lipophilicity descriptors obtained in current study, were investigated using partial least square regression. The best models were obtained for kidney and liver health effects. Quantitative structure-toxicity relationship models revealed the importance of electric polarization descriptors, size descriptors and lipophilicity descriptors. Obtained models were used for the selection of the structural features of the compounds that are significantly affecting their absorption, distribution, metabolism, excretion, and toxicity. [Acknowledgements. This work has been supported by the Ministry of Education and Science of Serbia, Grant 172017.

A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP AND MOLECULAR DOCKING STUDY ON A SERIES OF PYRIMIDINES ACTING AS ANTI-HEPATITIS C VIRUS AGENTS

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Sakshi Gupta

2013-12-01

Full Text Available A QSAR and molecular modeling study was performed on a series of pyrimidines acting as hepatitis C virus inhibitors. In this case, anti-HCV potency of the compounds was found to be significantly correlated with the hydrophobic property of the molecule, Kier’s first-order valence molecular connectivity index for a particular substituent, total structure connectivity index of the molecule, and an indicator parameter used for the presence of benzothiazole ring. The validity of the correlation was judged by leave-one-out jackknife procedure and predicting the activity of some test compounds. Using the correlation obtained, some new compounds of high potency have been predicted in the series. A docking study using Molegro Virtual Docker was performed on these predicted compounds to decipher their interactions with the receptor. It was observed that all the predicted compounds had better interaction energy and docking score than the ligand complexed with the protein.

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

Science.gov (United States)

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

2017-04-13

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

Structure-activity relationship study of steroidal 1,2,4,5-tetraoxane animalarials using computational procedures

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APURBA K. BHATTACHARJEE

2005-03-01

Full Text Available A three-dimensional QSAR pharmacophore model for antimalarial activity of steroidal 1,2,4,5-tetraoxanes was developed from a set of 17 substituted antimalarial derivatives out of 27 analogues that exhibited remarkable in vitro activity (below 100 ng/mL against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid and one hydrophobic (aliphatic feature, was found to map well onto the potent analogues and many other well-known antimalarial trioxane drugs including artemisinin, arteether, artesunic acid, and tetraoxanes. The presence of at least one hydrogen bond acceptor in the trioxane or the tetraoxane moiety appears to be necessary for potent activity of this class of compounds. Docking calculations of some of these compounds with heme are consistent with the above observation as the proximity of the heme iron to the oxygen atom of the trioxane or the tetraoxane moiety favors potent activity of the compounds. Electron transfer from the oxygen of trioxane or the tetraoxane appears to be crucial for mechanism of action of the compounds. This information together with the pharmacophore should enable search for new peroxide containing antimalarial candidates from databases and custom designed synthesis of more efficacious and safer analogues.

Structural relationships in high temperature superconductors

International Nuclear Information System (INIS)

Schuller, I.K.; Segre, C.U.; Hinks, D.G.; Jorgensen, J.D.; Soderholm, L.; Beno, M.; Zhang, K.

1987-09-01

The recent discovery of two types of metallic copper oxide compounds which are superconducting to above 90 0 K has renewed interest in the search for new high temperature superconducting materials. It is significant that both classes of compounds, La/sub 2-x/Sr/sub x/CuO/sub 4-y/ and YBa 2 Cu 3 O/sub 7-δ/ are intimately related to the extensively studied perovskite family. Both compounds contain highly oxidized, covalently bonded Cu-O sublattices, however, they differ in geometry. In this paper we discuss the relationship of these features to the superconducting properties. 30 refs., 6 figs

Antifungal agents. 10. New derivatives of 1-[(aryl)[4-aryl-1H-pyrrol-3-yl]methyl]-1H-imidazole, synthesis, anti-candida activity, and quantitative structure-analysis relationship studies.

Science.gov (United States)

Tafi, Andrea; Costi, Roberta; Botta, Maurizio; Di Santo, Roberto; Corelli, Federico; Massa, Silvio; Ciacci, Andrea; Manetti, Fabrizio; Artico, Marino

2002-06-20

The synthesis, anti-Candida activity, and quantitative structure-activity relationship (QSAR) studies of a series of 2,4-dichlorobenzylimidazole derivatives having a phenylpyrrole moiety (related to the antibiotic pyrrolnitrin) in the alpha-position are reported. A number of substituents on the phenyl ring, ranging from hydrophobic (tert-butyl, phenyl, or 1-pyrrolyl moiety) to basic (NH(2)), polar (CF(3), CN, SCH(3), NO(2)), or hydrogen bond donors and acceptor (OH) groups, were chosen to better understand the interaction of these compounds with cytochrome P450 14-alpha-lanosterol demethylase (P450(14DM)). Finally, the triazole counterpart of one of the imidazole compounds was synthesized and tested to investigate influence of the heterocyclic ring on biological activity. The in vitro antifungal activities of the newly synthesized azoles 10p-v,x-c' were tested against Candida albicans and Candida spp. at pH 7.2 and pH 5.6. A CoMFA model, previously derived for a series of antifungal agents belonging to chemically diverse families related to bifonazole, was applied to the new products. Because the results produced by this approach were not encouraging, Catalyst software was chosen to perform a new 3D-QSAR study. Catalyst was preferred this time because of the possibility of considering each compound as a collection of energetically reasonable conformations and of considering alternative stereoisomers. The pharmacophore model developed by Catalyst, named HYPO1, showed good performances in predicting the biological activity data, although it did not exhibit an unequivocal preference for one enantiomeric series of inhibitors relative to the other. One aromatic nitrogen with a lone pair in the ring plane (mapped by all of the considered compounds) and three aromatic ring features were recognized to have pharmacophoric relevance, whereas neither hydrogen bond acceptor nor hydrophobic features were found. These findings confirmed that the key interaction of azole

Synthesis, characterization, crystal structure and theoretical study of a compound with benzodiazole ring: antimicrobial activity and DNA binding.

Science.gov (United States)

Latha, P; Kodisundaram, P; Sundararajan, M L; Jeyakumar, T

2014-08-14

2-(Thiophen-2-yl)-1-((thiophen-2-yl)methyl)-1H-1,3-benzodiazole (HL) is synthesized and characterized by elemental analysis, UV-Vis, FT-IR, (1)H, (13)C NMR, mass spectra, scanning electron microscope (SEM) and single crystal X-ray diffraction. The crystal structure is stabilized by intermolecular CH⋯N and CH⋯π interactions. The molecular structure is also optimized at the B3LYP/6-31G level using density functional theory (DFT). The structural parameters from the theory are nearer to those of crystal, the calculated total energy of coordination is -1522.814a.u. The energy of HOMO-LUMO and the energy gap are -0.20718, -0.04314, 0.16404a.u, respectively. All data obtained from the spectral studies support the structural properties of the compound HL. The benzimidazole ring is essentially planar. The in vitro biological screening effects of the synthesized compound is tested against four bacterial and four fungal strains by well diffusion method. Antioxidant property and DNA binding behaviour of the compound has been investigated using spectrophotometric method. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Synthesis and structure-activity relationships of constrained heterocyclic analogues of combretastatin A4.

Science.gov (United States)

Arthuis, Martin; Pontikis, Renée; Chabot, Guy G; Seguin, Johanne; Quentin, Lionel; Bourg, Stéphane; Morin-Allory, Luc; Florent, Jean-Claude

2011-09-05

A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Antimicrobial activity of some potential active compounds against ...

African Journals Online (AJOL)

Antimicrobial activities of six potential active compounds (acetic acid, chitosan, catechin, gallic acid, lysozyme, and nisin) at the concentration of 500 g/ml against the growth of Escherichia coli, Staphylococcus aureus, Listeria innocua, and Saccharomyces cerevisiae were determined. Lysozyme showed the highest ...

Tyrosinase inhibitor activity of coumarin-resveratrol hybrids.

Science.gov (United States)

Fais, Antonella; Corda, Marcella; Era, Benedetta; Fadda, M Benedetta; Matos, Maria Joao; Quezada, Elias; Santana, Lourdes; Picciau, Carmen; Podda, Gianni; Delogu, Giovanna

2009-07-13

In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC(50) values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3',4',5'-trihydroxyphenyl)-6,8-dihydroxycoumarin (8)is the most potentcompound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.

Statistical molecular design of balanced compound libraries for QSAR modeling.

Science.gov (United States)

Linusson, A; Elofsson, M; Andersson, I E; Dahlgren, M K

2010-01-01

A fundamental step in preclinical drug development is the computation of quantitative structure-activity relationship (QSAR) models, i.e. models that link chemical features of compounds with activities towards a target macromolecule associated with the initiation or progression of a disease. QSAR models are computed by combining information on the physicochemical and structural features of a library of congeneric compounds, typically assembled from two or more building blocks, and biological data from one or more in vitro assays. Since the models provide information on features affecting the compounds' biological activity they can be used as guides for further optimization. However, in order for a QSAR model to be relevant to the targeted disease, and drug development in general, the compound library used must contain molecules with balanced variation of the features spanning the chemical space believed to be important for interaction with the biological target. In addition, the assays used must be robust and deliver high quality data that are directly related to the function of the biological target and the associated disease state. In this review, we discuss and exemplify the concept of statistical molecular design (SMD) in the selection of building blocks and final synthetic targets (i.e. compounds to synthesize) to generate information-rich, balanced libraries for biological testing and computation of QSAR models.

Relationship between peroxisome proliferator-activated receptor alpha activity and cellular concentration of 14 perfluoroalkyl substances in HepG2 cells.

Science.gov (United States)

Rosenmai, Anna Kjerstine; Ahrens, Lutz; le Godec, Théo; Lundqvist, Johan; Oskarsson, Agneta

2018-02-01

Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARα activity. We investigated the relationship between PPARα activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and PPARα activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04-4.1%) with absolute cellular concentrations in the range 4-2500 ng mg -1 protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARα activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARα activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARα activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARα activities >2.5-fold compared to controls. The concentration-response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound-specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARα activity and cellular concentration of a broad range of PFASs. Copyright © 2017 John Wiley & Sons, Ltd.

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

Science.gov (United States)

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

The contact activation proteins: a structure/function overview

NARCIS (Netherlands)

Meijers, J. C.; McMullen, B. A.; Bouma, B. N.

1992-01-01

In recent years, extensive knowledge has been obtained on the structure/function relationships of blood coagulation proteins. In this overview, we present recent developments on the structure/function relationships of the contact activation proteins: factor XII, high molecular weight kininogen,

Non-classical structures of organic compounds: unusual stereochemistry and hypercoordination

International Nuclear Information System (INIS)

Minkin, Vladimir I; Minyaev, Ruslan M; Hoffmann, Roald

2002-01-01

Non-classical structures of organic compounds are defined as molecules containing non-tetrahedral tetracoordinate and/or hypercoordinate carbon atoms. The evolution of the views on this subject is considered and the accumulated theoretical and experimental data on the structures and dynamic transformations of non-classical organic compounds are systematised. It is shown that computational analysis using the methods and the software potential of modern quantum chemistry has now acquired high predictive capacity and is the most important source of data on the structures of non-classical compounds. The bibliography includes 227 references.