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Sample records for alcohols structure-activity relationship

  1. Ecotoxicity quantitative structure-activity relationships for alcohol ethoxylate mixtures based on substance-specific toxicity predictions.

    PubMed

    Boeije, G M; Cano, M L; Marshall, S J; Belanger, S E; Van Compernolle, R; Dorn, P B; Gümbel, H; Toy, R; Wind, T

    2006-05-01

    Traditionally, ecotoxicity quantitative structure-activity relationships (QSARs) for alcohol ethoxylate (AE) surfactants have been developed by assigning the measured ecotoxicity for commercial products to the average structures (alkyl chain length and ethoxylate chain length) of these materials. Acute Daphnia magna toxicity tests for binary mixtures indicate that mixtures are more toxic than the individual AE substances corresponding with their average structures (due to the nonlinear relation of toxicity with structure). Consequently, the ecotoxicity value (expressed as effects concentration) attributed to the average structures that are used to develop the existing QSARs is expected to be too low. A new QSAR technique for complex substances, which interprets the mixture toxicity with regard to the "ethoxymers" distribution (i.e., the individual AE components) rather than the average structure, was developed. This new technique was then applied to develop new AE ecotoxicity QSARs for invertebrates, fish, and mesocosms. Despite the higher complexity, the fit and accuracy of the new QSARs are at least as good as those for the existing QSARs based on the same data set. As expected from typical ethoxymer distributions of commercial AEs, the new QSAR generally predicts less toxicity than the QSARs based on average structure.

  2. Structure activity relationships of spiramycins.

    PubMed

    Omura, S; Sano, H; Sunazuka, T

    1985-07-01

    Sixty-six derivatives of spiramycin I and neospiramycin I were synthesized and evaluated by four parameters, MIC, affinity to ribosomes (ID50), therapeutic effect in mice and retention time in HPLC. Among the derivatives, 3,3'',4''-tri-O-propionyl- and 3,4''-di-O-acetyl-3''-O-butyrylspiramycin I showed the highest therapeutic effect which was superior to acetylspiramycin. Structure activity relationships of spiramycins are discussed.

  3. Structure-activity relationship studies on neuroactive steroids in memory, alcohol and stress-related functions: a crucial benefit from endogenous level analysis.

    PubMed

    Vallée, Monique

    2014-09-01

    New research findings in the field of neuroactive steroids strongly suggest that to understand their role in physiopathology, it is essential to accurately measure their tissue levels. Through his broad chemical expertise and extensive knowledge of steroids, Dr. Robert H. Purdy pioneered structure-activity relationship studies on these compounds and developed innovative detection assays that are essential to assess their function in biological tissues. The goal of the present paper is to point out the specific contributions of Dr. Purdy and his collaborators to the current knowledge on the role of neuroactive steroids in the modulation of memory and alcohol- and stress-related effects with particular emphasis on the detection assays he developed to assess their endogenous levels. Reviewed here are the major results as well as the original and valuable methodological strategies issued by the long-term collaboration between Dr Purdy and many scientists worldwide on the investigation of the structure-activity relationship of neuroactive steroids. Altogether, the data presented herein put forward the original notion that knowledge of the chemical structure of steroids is essential for their detection and the understanding of their role in physiological and pathological conditions, including the stress response. The current challenge is to identify and quantify using appropriate methods neuroactive steroids in the context of both animal and clinical studies in order to reveal how their levels change under physiological and disease states. Dr. Purdy passed away in September 2012, but scientists all over the world will always be grateful for his pioneering work on steroid chemistry and for his great enthusiasm in research.

  4. Structure-activity relationship approaches and applications.

    PubMed

    Tong, Weida; Welsh, William J; Shi, Leming; Fang, Hong; Perkins, Roger

    2003-08-01

    New techniques and software have enabled ubiquitous use of structure-activity relationships (SARs) in the pharmaceutical industry and toxicological sciences. We review the status of SAR technology by using examples to underscore the advances as well as the unique technical challenges. Applying SAR involves two steps: Characterization of the chemicals under investigation, and application of chemometric approaches to explore data patterns or to establish the relationships between structure and activity. We describe generally but not exhaustively the SAR methodologies popular use in toxicology, including representation of chemical structure, and chemometric techniques where models are both unsupervised and supervised. The utility of SAR technology is most evident when supervised methods are used to predict toxicity of untested chemicals based only on chemical structure. Such models can predict on both an ordinal scale (e.g., active vs inactive) or a continuouis scale (e.g., median lethal dose [LD50] dose). The reader is also referred to a companion paper in this issue that discusses quantitative structure-activity relationship (QSAR) methods that have advanced markedly over the past decade.

  5. Peptide Bacteriocins--Structure Activity Relationships.

    PubMed

    Etayash, Hashem; Azmi, Sarfuddin; Dangeti, Ramana; Kaur, Kamaljit

    2015-01-01

    With the growing concerns in the scientific and health communities over increasing levels of antibiotic resistance, antimicrobial peptide bacteriocins have emerged as promising alternatives to conventional small molecule antibiotics. A substantial attention has recently focused on the utilization of bacteriocins in food preservation and health safety. Despite the fact that a large number of bacteriocins have been reported, only a few have been fully characterized and structurally elucidated. Since knowledge of the molecular structure is a key for understanding the mechanism of action and therapeutic effects of peptide, we centered our focus in this review on the structure-activity relationships of bacteriocins with a particular focus in seven bacteriocins, namely, nisin, microcin J25, microcin B17, microcin C, leucocin A, sakacin P, and pediocin PA-1. Significant structural changes responsible for the altered activity of the recent bacteriocin analogues are discussed here.

  6. Structure -activity relationships of PDE5 inhibitors.

    PubMed

    Eros, D; Szántai-Kis, Cs; Kiss, R; Kéri, Gy; Hegymegi-Barakonyi, B; Kövesdi, I; Orfi, L

    2008-01-01

    cGMP has a short-term effect on smooth muscle tone and a longer-term effect on responses to chronic drug treatment or proliferative signals. cGMP-Phosphodiesterase type 5 (PDE5) hydrolizes cGMP, and the result is smooth muscle contraction. PDE5 is a relatively novel therapeutic target of various diseases, such as erectile dysfunction and pulmonary hypertension. The most intensively examined and marketed PDE5 inhibitor was sildenafil (Viagra) but recently vardenafil (Levitra) and tadalafil (Cialis) were launched with beneficial ADME parameters and PDE5 selectivity. The increasing interest in PDE5 inhibition made it reasonable to collect the available inhibitory data from the scientific literature and set up a structure-activity relationship study. Chemical structures of 438 compounds and their cGMP-PDE5 inhibitory data (IC50) were collected from recently published articles. In this paper physiology, regulation and inhibition of PDE5 (and briefly other PDE-s) are discussed and inhibitors are tabulated by the core structures. Finally, a general QSAR model built from these data is presented. All data used in the QSAR study were summarized in a Supplement (for description please see the online version of the article).

  7. Structure-Activity Relationships of Synthetic Cathinones.

    PubMed

    Glennon, Richard A; Dukat, Małgorzata

    2017-01-01

    Until recently, there was rather little interest in the structure-activity relationships (SARs) of cathinone analogs because so few agents were available and because they represented a relatively minor drug abuse problem. Most of the early SAR was formulated on the basis of behavioral (e.g., locomotor and drug discrimination) studies using rodents. With the emergence on the clandestine market in the last few years of a large number of new cathinone analogs, termed "synthetic cathinones", and the realization that they likely act at dopamine, norepinephrine, and/or serotonin transporters as releasing agents (i.e., as substrates) or reuptake inhibitors (i.e., as transport blockers), it has now become possible to better examine their SAR and even their quantitative SAR (QSAR), in a more effective and systematic manner. An SAR picture is beginning to emerge, and key structural features, such as the nature of the terminal amine, the size of the α-substituent, stereochemistry, and the presence and position of aromatic substituents, are being found to impact action (i.e., as releasing agents or reuptake inhibitors) and transporter selectivity.

  8. Structure activity relationships of selected naphthalene derivatives

    SciTech Connect

    Schultz, T.W.; Dumont, J.N.; Sankey, F.D.; Schmoyer, R.L. Jr.

    1983-01-01

    Twenty-two derivatives of naphthalene were assayed under an acute static regime with biological activity being monitored as population growth of Tetrahymena pyriformis. Activity varied over one log unit. Substituent constant structure-activity analyses revealed the model, log BR = 0.282Ha + 0.352..pi.. + 0.692F + 0.334/sup 1/X/sub sub//sup v/ - 0.326R + 0.027, to be best and to account for 85% of the variation in log BR (BR, biological response; Ha, hydrogen acceptance; ..pi.., hydrophobic substituent constant; F, polar electronic substituent constant, /sup 1/X/sub sub//sup v/, substituent molar connectivity index; R, resonance electronic substituent constant). The Ha and ..pi.. parameters are the most important, accounting for 71% of the log BR variability. 21 references, 1 figure, 7 tables.

  9. DEVELOPMENT OF STRUCTURE ACTIVITY RELATIONSHIPS FOR ASSESSING ECOLOGICAL RISKS

    EPA Science Inventory

    In the field of environmental toxicology, structure activity relationships (SARs) have developed as scientifically-credible tools for predicting the effects of chemicals when little or no empirical data are available.

  10. DEVELOPMENT OF STRUCTURE ACTIVITY RELATIONSHIPS FOR ASSESSING ECOLOGICAL RISKS

    EPA Science Inventory

    In the field of environmental toxicology, structure activity relationships (SARs) have developed as scientifically-credible tools for predicting the effects of chemicals when little or no empirical data are available.

  11. Quantitative structure-activity relationships for fluoroelastomer/chlorofluorocarbon systems

    SciTech Connect

    Paciorek, K.J.L.; Masuda, S.R.; Nakahara, J.H. ); Snyder, C.E. Jr.; Warner, W.M. )

    1991-12-01

    This paper reports on swell, tensile, and modulus data that were determined for a fluoroelastomer after exposure to a series of chlorofluorocarbon model fluids. Quantitative structure-activity relationships (QSAR) were developed for the swell as a function of the number of carbons and chlorines and for tensile strength as a function of carbon number and chlorine positions in the chlorofluorocarbons.

  12. Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids.

    PubMed

    Cedrón, Juan C; Ravelo, Ángel G; León, Leticia G; Padrón, José M; Estévez-Braun, Ana

    2015-07-30

    The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.

  13. Research progress in structure-activity relationship of bioactive peptides.

    PubMed

    Li, Ying; Yu, Jianmei

    2015-02-01

    Bioactive peptides are specific protein fragments that have positive impact on health. They are important sources of new biomedicine, energy and high-performance materials. The beneficial effects of bioactive peptides are due to their antioxidant, antihypertensive, anticarcinogenic, antimicrobial, and immunomodulatory activities. The structure-activity relationship of bioactive peptides plays a significant role in the development of innovative and unconventional synthetic polymeric counterparts. It provides the basis of the stereospecific synthesis, transformation, and development of bioactive peptide products. This review covers the progress of studies in the structure-activity relationship of some bioactive peptides including antioxidant peptides, angiotensin-I-converting enzyme-inhibitory peptides, and anticarcinogenic peptides in the past decade.

  14. Structure-activity relationships of benzothiazole GPR35 antagonists

    PubMed Central

    Abdalhameed, Manahil M.; Zhao, Pingwei; Hurst, Dow P.; Reggio, Patricia H.; Abood, Mary E.; Croatt, Mitchell P.

    2017-01-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound. PMID:27989666

  15. Structure-activity relationships of benzothiazole GPR35 antagonists.

    PubMed

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  16. Structure-activity relationship of crustacean peptide hormones.

    PubMed

    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.

  17. Partitioning and lipophilicity in quantitative structure-activity relationships.

    PubMed Central

    Dearden, J C

    1985-01-01

    The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374

  18. Structure-activity relationship studies for multitarget antithrombotic drugs.

    PubMed

    Neves, Ana R; Correia-da-Silva, Marta; Sousa, Emília; Pinto, Madalena

    2016-12-01

    Thrombosis is a complex process involving multiple pathways. Currently, therapy relies on the combination of two or more antithrombotic drugs, showing that inhibiting more than one target provides benefits in the prevention and treatment of thrombosis. This review focuses on structure-activity relationship studies of molecules possessing multiple actions against thrombosis, namely, dual inhibitors of coagulation, dual inhibitors of coagulation and platelet aggregation, and also dual inhibitors of platelet aggregation. EP217609 has just entered clinical trials, which raise the expectations on the multitarget strategy to prevent or treat thrombosis.

  19. Structure-activity relationship of karrikin germination stimulants.

    PubMed

    Flematti, Gavin R; Scaffidi, Adrian; Goddard-Borger, Ethan D; Heath, Charles H; Nelson, David C; Commander, Lucy E; Stick, Robert V; Dixon, Kingsley W; Smith, Steven M; Ghisalberti, Emilio L

    2010-08-11

    Karrikins (2H-furo[2,3-c]pyran-2-ones) are potent smoke-derived germination promoters for a diverse range of plant species but, to date, their mode of action remains unknown. This paper reports the structure-activity relationship of numerous karrikin analogues to increase understanding of the key structural features of the molecule that are required for biological activity. The results demonstrate that modification at the C5 position is preferred over modification at the C3, C4, or C7 positions for retaining the highest bioactivity.

  20. STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY

    EPA Science Inventory

    Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity

    Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

  1. CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION

    EPA Science Inventory

    Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction

    A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...

  2. STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY

    EPA Science Inventory

    Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity

    Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

  3. Structure-activity relationship for the oxadiazole class of antibiotics.

    PubMed

    Spink, Edward; Ding, Derong; Peng, Zhihong; Boudreau, Marc A; Leemans, Erika; Lastochkin, Elena; Song, Wei; Lichtenwalter, Katerina; O'Daniel, Peter I; Testero, Sebastian A; Pi, Hualiang; Schroeder, Valerie A; Wolter, William R; Antunes, Nuno T; Suckow, Mark A; Vakulenko, Sergei; Chang, Mayland; Mobashery, Shahriar

    2015-02-12

    The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus. 5-(1H-Indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. This antibiotic is bactericidal and is orally bioavailable in mice. This class of antibiotics holds great promise in recourse against infections by MRSA.

  4. Structure activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors

    PubMed Central

    Schafer, Kelsey N.; Murale, Dhiraj P.; Kim, Kibong; Cisek, Katryna; Kuret, Jeff; Churchill, David G.

    2015-01-01

    Macrocyclic bis-carbocyanines are efficacious inhibitors of tau aggregation. To extend the structure activity relationship of this inhibitor class, N,N′-alkylene bis-thiacarbocyanines linked by three to nine carbon alkyl chains were synthesized and examined for inhibitory activity against recombinant human tau aggregation in vitro. At 10 micromolar concentration, inhibitory activity varied with linker length, with four methylene units being most efficacious. On the basis of absorbance spectroscopy measurements, linker length also affected compound folding and aggregation propensity, with a linker length of four methylene units being optimal for preserving open monomer conformation. These data suggest that inhibitory potency can be optimized through control of linker length, and that a contributory mechanism involves modulation of compound folding and aggregation. PMID:21549596

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

    NASA Astrophysics Data System (ADS)

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

    2007-04-01

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

  6. Structure-activity relationship of nuclear receptor-ligand interactions.

    PubMed

    Greschik, Holger; Moras, Dino

    2003-01-01

    Small molecules such as retinoids, steroid hormones, fatty acids, cholesterol metabolites, or xenobiotics are involved in the regulation of numerous physiological and patho-physiological processes by binding to and controlling the activity of members of the nuclear receptor (NR) superfamily of transcription factors. In addition to natural ligands, synthetic agonists or antagonists have been identified that in some cases specifically target NR isotypes, or elicit tissue-, signaling pathway-, or promoter-selective transcriptional responses. For these ligands the term "selective NR modulators" (SNRMs) has been introduced. Structure determination of apo- and holo-NR ligand-binding domains (LBDs)--some of them complexed to small coactivator or corepressor fragments--revealed the major principles of ligand-dependent NR action and determinants of (isotype-) selective ligand binding. These studies also stimulated the interpretation of tissue-specific effects of SNRMs on wild-type or mutant receptors. In contrast to the increasing knowledge on the structure-activity relationship of NRs with known SNRMs, rather basic questions remain about the regulation of orphan NRs (for which no ligands are known) or "adopted" orphan NRs (for which only recently ligands were identified). Several crystal structures of orphan NR LBDs uncovered unexpected properties, contributed to the understanding of orphan NR function, and may in the future permit the identification or design of ligands. This review will (i) focus on the current understanding of the structure-activity relationship of NR-ligand interactions, (ii) discuss recent advances in the field of "orphan" NR crystallography, and (iii) outline future challenges in NR structural biology.

  7. Quantitative Structure-Activity Relationships for Organophosphate Enzyme Inhibition (Briefing Charts)

    DTIC Science & Technology

    2011-09-22

    1 AFRL-RH-WP-TR-2012-0089 Quantitative Structure- Activity Relationships for Organophosphate Enzyme Inhibition (Briefing Charts...REPORT TYPE Interim 3. DATES COVERED (From - To) September 10 – September 12 4. TITLE AND SUBTITLE Quantitative Structure- Activity Relationships for...difficult to quickly obtain. To address this concern, quantitative structure- activity relationship (QSAR) models were developed to predict

  8. Structure activity relationships: their function in biological prediction

    SciTech Connect

    Schultz, T.W.

    1982-01-01

    Quantitative structure activity relationships provide a means of ranking or predicting biological effects based on chemical structure. For each compound used to formulate a structure activity model two kinds of quantitative information are required: (1) biological activity and (2) molecular properties. Molecular properties are of three types: (1) molecular shape, (2) physiochemical parameters, and (3) abstract quantitations of molecular structure. Currently the two best descriptors are the hydrophobic parameter, log 1-octanol/water partition coefficient (log P), and the /sup 1/X/sup v/(one-chi-v) molecular connectivity index. Biological responses can be divided into three main categories: (1) non-specific effects due to membrane perturbation, (2) non-specific effects due to interaction with functional groups of proteins, and (3) specific effects due to interaction with receptors. Twenty-six synthetic fossil fuel-related nitrogen-containing aromatic compounds were examined to determine the quantitative correlation between log P and /sup 1/X/sup v/ and population growth impairment of Tetrahymena pyriformis. Nitro-containing compounds are the most active, followed by amino-containing compounds and azaarenes. Within each analog series activity increases with alkyl substitution and ring addition. The planar model log BR = 0.5564 log P + 0.3000 /sup 1/X/sup v/ -2.0138 was determined using mono-nitrogen substituted compounds. Attempts to extrapolate this model to dinitrogen-containing molecules were, for the most part, unsuccessful because of a change in mode of action from membrane perturbation to uncoupling of oxidative phosphoralation.

  9. Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

    NASA Astrophysics Data System (ADS)

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

    2008-05-01

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

  10. The structure-activity relationship in herbicidal monosubstituted sulfonylureas.

    PubMed

    Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei

    2012-04-01

    The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesised in the authors' laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated. Copyright © 2011 Society of Chemical Industry.

  11. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.

    PubMed

    Christensen, Mette K; Erichsen, Kamille D; Olesen, Uffe H; Tjørnelund, Jette; Fristrup, Peter; Thougaard, Annemette; Nielsen, Søren Jensby; Sehested, Maxwell; Jensen, Peter B; Loza, Einars; Kalvinsh, Ivars; Garten, Antje; Kiess, Wieland; Björkling, Fredrik

    2013-11-27

    Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.

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

    EPA Pesticide Factsheets

    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

  13. Structure activity relationships to assess new chemicals under TSCA

    SciTech Connect

    Auletta, A.E.

    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.

  14. Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids.

    PubMed

    Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F

    2016-10-18

    Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews. Whereas most of the early compounds were derived from the prototypic naphthoylindole JWH-018, currently popular synthetic cannabinoids include tetramethylcyclopropyl ketones and indazole-derived cannabinoids (e.g., AB-PINACA, AB-CHMINACA). Despite their structural differences, psychoactive synthetic cannabinoids bind with high affinity to CB1 receptors in the brain and, when tested, have been shown to activate these receptors and to produce a characteristic profile of effects, including suppression of locomotor activity, antinociception, hypothermia, and catalepsy, as well as Δ(9)-tetrahydrocannabinol (THC)-like discriminative stimulus effects in mice. When they have been tested, synthetic cannabinoids are often found to be more efficacious at activation of the CB1 receptor and more potent in vivo. Further, their chemical alteration by thermolysis during use and their uncertain stability and purity may result in exposure to degradants that differ from the parent compound contained in the original product. Consequently, while their intoxicant effects may be similar to those of THC, use of synthetic cannabinoids may be accompanied by unpredicted, and sometimes harmful, effects.

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

    EPA Pesticide Factsheets

    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

  16. Quantitative structure-activity relationship studies on nitrofuranyl antitubercular agents

    PubMed Central

    Hevener, Kirk E.; Ball, David M.; Buolamwini, John K.

    2008-01-01

    A series of nitrofuranylamide and related aromatic compounds displaying potent activity against M. tuberculosis has been investigated utilizing 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) techniques. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to produce 3D-QSAR models that correlated the Minimum Inhibitory Concentration (MIC) values against M. tuberculosis with the molecular structures of the active compounds. A training set of 95 active compounds was used to develop the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 15 compounds was used for the external validation. Different alignment and ionization rules were investigated as well as the effect of global molecular descriptors including lipophilicity (cLogP, LogD), Polar Surface Area (PSA), and steric bulk (CMR), on model predictivity. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross validated r2 > .5) have been developed. Incorporation of lipophilicity descriptors into the models had negligible effects on model predictivity. The models developed will be used to predict the activity of proposed new structures and advance the development of next generation nitrofuranyl and related nitroaromatic anti-tuberculosis agents. PMID:18701298

  17. Chemistry and Structure-Activity Relationships of Psychedelics.

    PubMed

    Nichols, David E

    2017-03-26

    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-HT2A 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-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A 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.

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

    PubMed

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

    2017-02-07

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

  19. The structure-activity relationship in herbicidal monosubstituted sulfonylureas

    SciTech Connect

    Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei

    2012-05-24

    The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.

  20. Structure-activity relationship in cationic lipid mediated gene transfection.

    PubMed

    Niculescu-Duvaz, Dan; Heyes, James; Springer, Caroline J

    2003-07-01

    Non-viral synthetic vectors for gene delivery represent a safer alternative to viral vectors. Their main drawback is the low transfection efficiency, especially in vivo. Among the non-viral vectors currently in use, the cationic liposomes composed of cationic lipids are the most common. This review discusses the physicochemical properties of cationic lipids, the formation, macrostructure and specific parameters of the corresponding formulated liposomes, and the effect of all these parameters on transfection efficiency. The optimisation of liposomal vectors requires both the understanding of the biological variables involved in the transfection process, and the effect of the structural elements of the cationic lipids on these biological variables. The biological barriers relevant for in vitro and in vivo transfection are identified, and solutions to overcome them based on rational design of the cationic lipids are discussed. The review focuses on the relationship between the structure of the cationic lipid and the transfection activity. The structure is analysed in a modular manner. The hydrophobic domain, the cationic head group, the backbone that acts as a scaffold for the other domains, the linkers between backbone, hydrophobic domain and cationic head group, the polyethyleneglycol chains and the targeting moiety are identified as distinct elements of the cationic lipids used in gene therapy. The main chemical functionalities used to built these domains, as well as overall molecular features such as architecture and geometry, are presented. Studies of structure-activity relationships of each cationic lipid domain, including the authors', and the trends identified by these studies, help furthering the understanding of the mechanism governing the formation and behaviour of cationic liposomes in gene delivery, and therefore the rational design of new improved cationic lipids vectors capable of achieving clinical significance.

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

    NASA Astrophysics Data System (ADS)

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

    2013-05-01

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

  2. Natural and synthetic endocannabinoids and their structure-activity relationships.

    PubMed

    Palmer, S L; Khanolkar, A D; Makriyannis, A

    2000-09-01

    significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.

  3. Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase.

    PubMed

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

    2013-02-01

    Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure-activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William's plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <-2, indicating potential outliers or activity cliffs. The results show that the HOMO-LUMO energy gap contributed most significantly to the binding affinity. A mean training R (2) of 0.80, a mean test set R (2) of 0.76 and a consensus external test set R (2) of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in

  4. Structure-Activity Relationship of Nerve-Highlighting Fluorophores

    PubMed Central

    Gibbs, Summer L.; Xie, Yang; Goodwill, Haley L.; Nasr, Khaled A.; Ashitate, Yoshitomo; Madigan, Victoria J.; Siclovan, Tiberiu M.; Zavodszky, Maria; Tan Hehir, Cristina A.; Frangioni, John V.

    2013-01-01

    Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability. PMID:24039960

  5. PubChem structure-activity relationship (SAR) clusters.

    PubMed

    Kim, Sunghwan; Han, Lianyi; Yu, Bo; Hähnke, Volker D; Bolton, Evan E; Bryant, Stephen H

    2015-01-01

    Developing structure-activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information. Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named "PubChem SAR clusters", were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity. The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.

  6. Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification.

    PubMed

    Sun, Xicheng; Qiu, Jian; Strong, Sarah A; Green, Louis S; Wasley, Jan W F; Blonder, Joan P; Colagiovanni, Dorothy B; Stout, Adam M; Mutka, Sarah C; Richards, Jane P; Rosenthal, Gary J

    2012-03-15

    The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.

  7. Structure-Activity Relationships of Agents Modifying Cholinergic Transmissions

    DTIC Science & Technology

    1983-09-01

    apparatus. .~."-t,,.•±.Lbiphenyl (4). Anhydrous ,\\LCl 3 "’..-7 ,, •.𔃾) ArtLh mixture of 10 mL of CS2 and 1.54 ; (0.01 ool) of Miphenyl. lcetyL...COo01). imeth:l Siyohen yl-4,4’-dicarboxy•late (6). Compound 5 (3 . jt •r"erin 75 L of anhydrous MeoH and 2 drops of cone HS heaied 0 inder rofA ui fhe... anhydrous tetrahydrofuran was added dropwise over 15 min at 0°C to a stirred solution of 2 mL of triethylamine and alcohol-free diazomethane (prepared

  8. Quantitative Structure-Activity Relationship Modeling of Kinase Selectivity Profiles.

    PubMed

    Kothiwale, Sandeepkumar; Borza, Corina; Pozzi, Ambra; Meiler, Jens

    2017-09-19

    The discovery of selective inhibitors of biological target proteins is the primary goal of many drug discovery campaigns. However, this goal has proven elusive, especially for inhibitors targeting the well-conserved orthosteric adenosine triphosphate (ATP) binding pocket of kinase enzymes. The human kinome is large and it is rather difficult to profile early lead compounds against around 500 targets to gain an upfront knowledge on selectivity. Further, selectivity can change drastically during derivatization of an initial lead compound. Here, we have introduced a computational model to support the profiling of compounds early in the drug discovery pipeline. On the basis of the extensive profiled activity of 70 kinase inhibitors against 379 kinases, including 81 tyrosine kinases, we developed a quantitative structure-activity relation (QSAR) model using artificial neural networks, to predict the activity of these kinase inhibitors against the panel of 379 kinases. The model's performance in predicting activity ranges from 0.6 to 0.8 depending on the kinase, from the area under the curve (AUC) of the receiver operating characteristics (ROC). The profiler is available online at http://www.meilerlab.org/index.php/servers/show?s_id=23.

  9. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC).

    PubMed

    Jung, Michael E; Ouk, Samedy; Yoo, Dongwon; Sawyers, Charles L; Chen, Charlie; Tran, Chris; Wongvipat, John

    2010-04-08

    A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

  10. Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

  11. Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

  12. PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

    EPA Science Inventory

    Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

  13. PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

    EPA Science Inventory

    Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

  14. Aedes aegypti (Diptera: Culicidae) Biting Deterrence: Structure-Activity Relationship of Saturated and Unsaturated Fatty Acids

    DTIC Science & Technology

    2012-11-01

    VECTOR CONTROL, PEST MANAGEMENT, RESISTANCE, REPELLENTS Aedes aegypti (Diptera: Culicidae) Biting Deterrence: Structure- Activity Relationship of...deterrent effects of a series of saturated and unsaturated fatty acids against Aedes aegypti (L), yellow fever mosquito (Diptera: Culicidae) using theK...corresponding C12:0 and C12:1 homologues. KEYWORDS fatty acid, biting deterrence, repellent, structure-activity relationship, Aedes aegypti Mosquitoes transmit

  15. Synthetic and structure-activity relationship of insecticidal bufadienolides.

    PubMed

    Hidayat, Ace Tatang; Zainuddin, Achmad; Dono, Danar; Hermawan, Wawan; Hayashi, Hideo; Supratman, Unang

    2014-07-01

    A new synthetic analog of bufadienolide, methyl isobryophyllinate A (1), and a known synthetic analog, methyl isobersaldegenate-1,3,5-orthoacetate (2), were obtained by methanolysis of bryophyllin A (3) and bersaldegenin-1,3,5-orthoacetate (5) in basic solution. Structure-insecticidal activity relationship studies revealed both orthoacetate and alpha-pyrone moieties seemed to be essential structural elements for exhibiting insecticidal activity, whereas oxygenated substituents in the C ring enhanced the insecticidal activity against the third instar larvae of silkworm (Bombyx mori).

  16. Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration.

    PubMed

    Wallace, K B; Kissling, G E; Melnick, R L; Blystone, C R

    2013-10-09

    Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPARα and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20μM) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity

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

    PubMed

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

    2017-03-27

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

  18. Structure activity relationship of synaptic and junctional neurotransmission

    PubMed Central

    Goyal, Raj K; Chaudhury, Arun

    2013-01-01

    Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between ‘bare’ portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasing recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable for ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the ‘closed’ synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting in milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is ‘open’ to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into ‘close’ and ‘wide’ junctions. Functionally, the ‘close’ and the ‘wide’ junctions can be distinguished by postjunctional potentials lasting ~1 second and 10s of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors. PMID:23535140

  19. Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic compounds.

    PubMed

    Hau, K M; Connell, D W; Richardson, B J

    1999-01-01

    A model was developed for describing the triggering of nasal pungency in humans, based on the partition of volatile organic compounds (VOCs) between the air phase and the biophase. Two partition parameters are used in the model: the water-air partition coefficient and the octanol-water partition coefficient. The model was validated using data from the literature, principally on alcohols, acetates and ketones. The model suggests that all test compounds, regardless of their chemical functional groups, bind to a common receptor site within the hydrophobic interior of the bilayer membrane of the trigeminal nerve endings. There is probably only a slight, non-specific interaction between the VOC molecule and the receptor molecule, whereas this type of non-specific interaction for the detection of odor is much stronger. In practical terms, the suggestion that all VOCs share a common irritation receptor site implies that nasal-pungency thresholds of individual VOCs may be additive. Quantitative structure-activity relationships (QSARs) for nasal-pungency thresholds were also developed from the model, which can be used to predict nasal-pungency thresholds of common VOCs. Although the present model does not offer additional precision over that of M.H. Abraham et al., 1996, Fundam. Appl. Toxicol. 31, 71-76, it requires fewer descriptors and offers a physiological basis to the QSAR. Another advantage of the present model is that it also provides a basis for comparison between the olfactory process and nasal pungency.

  20. Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection.

    PubMed

    Zhou, Kun; Chen, Dongdong; Li, Bin; Zhang, Bingyu; Miao, Fang; Zhou, Le

    2017-01-01

    A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure-activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4-28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure-activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly.

  1. Macrolide-Based Microtubule-Stabilizing Agents - Chemistry and Structure-Activity Relationships

    NASA Astrophysics Data System (ADS)

    Pfeiffer, B.; Kuzniewski, C. N.; Wullschleger, C.; Altmann, K.-H.

    This article provides an overview on the chemistry and structure-activity relationships of macrolide-based microtubule-stabilizing agents. The primary focus will be on the total synthesis or examples thereof, but a brief summary of the current state of knowledge on the structure-activity relationships of epothilones, laulimalide, dictyostatin, and peloruside A will also be given. This macrolide class of compounds, over the last decade, has become the subject of growing interest due to their ability to inhibit human cancer cell proliferation through a taxol-like mechanism of action.

  2. Rational approaches, design strategies, structure activity relationship and mechanistic insights for esterase inhibitors.

    PubMed

    Singh, Harbinder; Singh, Jatinder Vir; Kaur, Navdeep; Sanduja, Mohit; Singh, Gurpreet; Bedi, Preet Mohinder Singh; Sharma, Sahil

    2017-08-07

    Esterase is an enzyme that splits esters into an acid and alcohol. Varieties of esterases are present in human body to control diverse set of cellular processes and execute their specific functions. It can be seen that any increase in metabolites produced by these enzymes lead to severe pathological conditions like Alzheimer disease, hypercholesterolemia etc. Numerous esterase inhibitors have been developed and reported by the researchers around the globe, but not systematically summarized yet. Therefore, this assemblage focuses on various reported esterase inhibitors during recent past with detailed account of the design strategies employed for the synthesis of novel drug entities. The article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of inhibitors as esterase inhibition. The interactions with the amino acid residues responsible for esterase inhibitory potential of molecules have also been discussed. This compilation will be of great interest for the researchers working in the area of esterase inhibitors. Rivastigmine derivatives (44-53), tacrine-piperazine hybrid (136), coumarin-benzofuran derivative (169), coumarin-benzylpiperidine hybrid (181) and phenylcinnamide derivative (220) found to be exerting cholinesterase inhibition with IC50 below the range of 1 nM. Whereas, flavone (258) has displayed anticholesterol esterase potential below 1 nM. Benzil like derivative, (273) has also been designed and reported to possess remarkable inhibitory potential (IC50 < 1 nM) against carboxylesterase. These representative results place them in forefront as potential future drug candidates to further develop potent and specific esterase inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Skin sensitization: reaction mechanistic applicability domains for structure-activity relationships.

    PubMed

    Aptula, Aynur O; Patlewicz, Grace; Roberts, David W

    2005-09-01

    The prediction of skin sensitization potential with minimum animal testing is currently of great importance in light of forthcoming legislation. A number of structure-activity relationships for skin sensitization have been published over the years, but their applicability has often been limited to structural classes. The concept of an applicability domain for a quantitative structure-activity relationship [(Q)SAR] is increasingly being viewed as key for the predictive application of (Q)SARs. This is particularly the case for skin sensitization if more widely applicable SARs are to be developed. In this paper, we analyze a recently published chemical data set for skin sensitization, apply reaction mechanistic criteria to domain classification, and evaluate the structure-activity trends observed within each of these mechanistic domains.

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

    PubMed

    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.

  5. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR CHEMICAL REDUCTIONS OF ORGANIC CONTAMINANTS

    EPA Science Inventory

    Sufficient kinetic data on abiotic reduction reactions involving organic contaminants are now available that quantitative structure-activity relationships (QSARs) for these reactions can be developed. Over 50 QSARs have been reported, most in just the last few years, and they ar...

  6. Quantitative structure-activity relationships and docking studies of calcitonin gene-related peptide antagonists.

    PubMed

    Kyani, Anahita; Mehrabian, Mohadeseh; Jenssen, Håvard

    2012-02-01

    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 resulted in an extremely robust and highly predictive model with calibration, leave-one-out and leave-20-out validation R(2) of 0.9194, 0.9103, and 0.9214, respectively. We performed docking of the most potent calcitonin gene-related peptide antagonists with the calcitonin gene-related peptide receptor and demonstrated that peptide antagonists act by blocking access to the peptide-binding cleft. We also demonstrated the direct contact of residues 28-37 of the calcitonin gene-related peptide antagonists with the receptor. These results are in agreement with the conclusions drawn from the quantitative structure-activity relationship model, indicating that both electrostatic and steric factors should be taken into account when designing novel calcitonin gene-related peptide antagonists.

  7. DETERMINING THE STRUCTURE-ACTIVITY RELATIONSHIPS OF AMINOBIPHENYL AND BENZIDINE ANALOGS

    EPA Science Inventory

    Determining the structure-activity relationships of aminobiphenyl and benzidine analogues

    Benzidine is a confirmed human carcinogen causing bladder and other types of cancer in humans and animals. Many of the benzidine and related aminobiphenyl compounds are mutagenic in t...

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

    PubMed Central

    Zhang, Jun; Li, Chunxia; Yu, Guangli; Guan, Huashi

    2014-01-01

    Glycoglycerolipids occur widely in natural products, especially in the marine species. Glycoglycerolipids have been shown to possess a variety of bioactivities. This paper will review the different methodologies and strategies for the synthesis of biological glycoglycerolipids and their analogs for bioactivity assay. In addition, the bioactivities and structure-activity relationship of the glycoglycerolipids are also briefly outlined. PMID:24945415

  9. DETERMINING THE STRUCTURE-ACTIVITY RELATIONSHIPS OF AMINOBIPHENYL AND BENZIDINE ANALOGS

    EPA Science Inventory

    Determining the structure-activity relationships of aminobiphenyl and benzidine analogues

    Benzidine is a confirmed human carcinogen causing bladder and other types of cancer in humans and animals. Many of the benzidine and related aminobiphenyl compounds are mutagenic in t...

  10. Neuritogenic activity of gangliosides from echinoderms and their structure-activity relationship.

    PubMed

    Kaneko, Masafumi; Yamada, Koji; Miyamoto, Tomofumi; Inagaki, Masanori; Higuchi, Ryuichi

    2007-03-01

    The effects of the gangliosides isolated from echinoderms on the neuritogenesis of a rat pheochromocytoma cell line (PC-12 cells) in the presence of nerve growth factor were investigated. The results show that they displayed neuritogenic activity. Based on the observed results, a structure-activity relationship has been established.

  11. Relationship Functioning Among Adult Children of Alcoholics*

    PubMed Central

    Kearns-Bodkin, Jill N.; Leonard, Kenneth E.

    2008-01-01

    Objective: The purpose of the current research was to examine the impact of both maternal and paternal alcoholism on the relationship functioning of husbands and wives over the early years of marriage. Method: Couples (N = 634) were assessed at the time of marriage, and again at their first, second, and fourth anniversaries. Husbands and wives completed separate, self-administered questionnaires at home. Results: Results of separate repeated measures analyses of covariance revealed that, for both husbands and wives, the appraisal of their marital relationship was associated with alcoholism in the opposite gender parent. That is, for husbands, alcoholism in the mother was associated with lower marital satisfaction across the 4 years of marriage. For wives, alcoholism in the father was related to lower marital intimacy. Husbands' physical aggression was influenced by mother's and father's alcoholism; high levels of physical aggression were present among men with alcoholic mothers and nonalcoholic fathers. Interestingly, wives' experience of husband's aggression was also highest among women with alcoholic mothers and nonalcoholic fathers. Wives also reported engaging in high levels of physical aggression when they had an alcoholic mother and a nonalcoholic father, but this effect was restricted to the early part of the marriage. Finally, parental alcoholism was associated with both husbands' and wives' attachment representations. Conclusions: The present findings suggest that children raised in alcoholic families may carry the problematic effects of their early family environment into their adult romantic relationships. PMID:18925353

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

    PubMed Central

    Zou, Li-Wei; Dou, Tong-Yi; Wang, Ping; Lei, Wei; Weng, Zi-Miao; Hou, Jie; Wang, Dan-Dan; Fan, Yi-Ming; Zhang, Wei-Dong; Ge, Guang-Bo; Yang, Ling

    2017-01-01

    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 simulations

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

    PubMed

    Zou, Li-Wei; Dou, Tong-Yi; Wang, Ping; Lei, Wei; Weng, Zi-Miao; Hou, Jie; Wang, Dan-Dan; Fan, Yi-Ming; Zhang, Wei-Dong; Ge, Guang-Bo; Yang, Ling

    2017-01-01

    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 simulations

  14. Structure-guided unravelling: Phenolic hydroxyls contribute to reduction of acrylamide using multiplex quantitative structure-activity relationship modelling.

    PubMed

    Zhang, Yu; Huang, Mengmeng; Wang, Qiao; Cheng, Jun

    2016-05-15

    We reported a structure-activity relationship study on unravelling phenolic hydroxyls instead of alcoholic hydroxyls contribute to the reduction of acrylamide formation by flavonoids. The dose-dependent study shows a close correlation between the number of phenolic hydroxyls of flavonoids and their reduction effects. In view of positions of hydroxyls, the 3',4'(ortho)-dihydroxyls in B cycle, 3-hydroxyl or hydroxyls of 3-gallate in C cycle, and 5,7(meta)-dihydroxyls in A cycle of flavonoid structures play an important role in the reduction of acrylamide. Flavone C-glycosides are more effective at reducing the formation of acrylamide than flavone O-glycosides when sharing the same aglycone. The current multiplex quantitative structure-activity relationship (QSAR) equations effectively predict the inhibitory rates of acrylamide using selected chemometric parameters (R(2): 0.835-0.938). This pioneer study opens a broad understanding on the chemoprevention of acrylamide contaminants on a structural basis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. ALCOHOLISM AND PSORIASIS-AN IMMUNOLOGICAL RELATIONSHIP

    PubMed Central

    Srinivasan, T.N.; Suresh, T.R.; Devar, J.V.; Jayaram, Vasantha

    1991-01-01

    SUMMARY Studies on association of psychiatric diseases and immunopathology has been an area of recent research activities. Alcohol has been implicated in some immune mediated disorders. Observation of occurrence of psoriasis, an immune mediated skin disorder in alcoholic patients has not been reported anywhere in literature. We report here 4 cases of alcoholism related psoriasis and discuss the possible immunological relationship between these two disorders. The need for study of effect of alcoholism on cell-medicated immunity associated conditions like auto-immune disorders and malignancy is presented. PMID:21897472

  16. Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement.

    PubMed

    Sun, Xicheng; Qiu, Jian; Strong, Sarah A; Green, Louis S; Wasley, Jan W F; Colagiovanni, Dorothy B; Mutka, Sarah C; Blonder, Joan P; Stout, Adam M; Richards, Jane P; Chun, Lawrence; Rosenthal, Gary J

    2011-06-15

    S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.

  17. Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor

    PubMed Central

    Khandelwal, Anuj; Hall, Jessica

    2014-01-01

    Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity. PMID:23834230

  18. Antitumor activity and structure-activity relationship of diterpenoids with a dehydroabietyl skeleton.

    PubMed

    Rao, Xiaoping; Huang, Xiuzhi; He, Ling; Song, Jie; Song, Zhanqian; Shang, Shibin

    2012-12-01

    A series of novel diterpenoids including imines, amides and ureas with a dehydroabietyl skeleton were screened to hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), glioma (C-6) and breast carcinoma (MCF-7) tumor cells by MTT method. Their antitumor activity and structure activity relationship were analyzed. Several of the title compounds such as I-2, I-10, I-6 and I-5, possess noticeable antitumor activity against SMMC-7721, A-549, C-6 and MCF-7 tumor cells, with lowest IC(50) values of 6.65, 0.75, 0.81 and 10.65μM, respectively. Based on the structure-activity relationship investigation, the three kinds of diterpenoids with a dehydroabietyl skeleton show high activity to SMMC-7721 cells. Imines derivatives exhibit broad spectrum and highly efficient activities to the selected four kinds of tumor cells.

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

    PubMed Central

    Zhang, Hui; Zhang, Lu; Peng, Li-juan; Dong, Xiao-wu; Wu, Di; Wu, Vivian Chi-Hua; Feng, Feng-qin

    2012-01-01

    Fatty acids and derivatives (FADs) are resources for natural antimicrobials. In order to screen for additional potent antimicrobial agents, the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay. Monoglycerides of fatty acids were the most potent class of fatty acids, among which monotridecanoin possessed the most potent antimicrobial activity. The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR: R 2=0.942, Q 2 LOO=0.910; CoMFA: R 2=0.979, Q 2=0.588, respectively). Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structure-activity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents. PMID:22302421

  20. Cycloartane triterpenes from Beesia calthaefolia and their anticomplement structure-activity relationship study.

    PubMed

    Mu, Li-Hua; Zhao, Jin-Yuan; Zhang, Jing; Liu, Ping

    2016-11-01

    Fifteen cycloartane triterpenes were isolated from Beesia calthaefolia and among them one was new cycloartane triterpenoid. The structure of new compound was determined by the application of spectroscopic analyses and chemical methods. The fifteen compounds were evaluated for their anticomplement activity by classic pathway. The structure-activity relationship analysis indicated that the configurations of 12-OH is preferable to be α than β, and 18-OH can decrease while 15-OH can increase the anticomplement activity, but saponin with both 15-OH and 18-OH lost most of its activity. The glycosyl moiety of most isolated cycloartane triterpenes is xylosyl. When xylosyl was substituted by glucosyl or galactosyl, their anticomplement activities were decreased or increased, respectively. Further structure-activity relationship (SAR) studies must be carried out to achieve general conclusions regarding the effect of further functionalizations on the anticomplement saponins.

  1. Structure-activity relationship of citrus polymethoxylated flavones and their inhibitory effects on Aspergillus niger.

    PubMed

    Liu, Li; Xu, Xiaoyun; Cheng, Dan; Yao, Xiaolin; Pan, Siyi

    2012-05-02

    Citrus peels are rich in polymethoxylated flavones (PMFs) and are potential sources of natural preservatives. Six PMFs extracts, isolated and purified from the peels of three mandarins (Citrus reticulata) and three sweet oranges (Citrus sinensis), were identified and quantitated. Their inhibitory effects on Aspergillus niger were evaluated using a microbroth dilution assay. The Red tangerine variety exhibited the greatest antifungal activity (MIC = 0.2 mg/mL), while Jincheng showed the lowest activity (MIC = 1.8 mg/mL). An analysis of principal components was applied to the results in order to elucidate the structure-activity relationships of the citrus PMFs. The structure-activity relationship analysis revealed that, for good inhibitory effect, the 5-OH, 3-OCH₃, and 8-OCH₃ functionalities were essential, while the presence of 3-OH and 3'-OCH₃ greatly reduced inhibition. The findings of this study provide important information for the exploitation and utilization of citrus PMFs as natural biopreservatives.

  2. Sphaeropsidones, phytotoxic dimedone methyl ethers produced by Diplodia cupressi: a structure-activity relationship study.

    PubMed

    Evidente, Antonio; Maddau, Lucia; Scanu, Bruno; Andolfi, Anna; Masi, Marco; Motta, Andrea; Tuzi, Angela

    2011-04-25

    Sphaeropsidone and episphaeropsidone are two phytotoxic dimedone methyl ethers produced by Diplodia cupressi, the causal agent of a canker disease of cypress in the Mediterranean area. In this study, eight derivatives obtained by chemical modifications and two natural analogues were assayed for phytotoxic and antifungal activities, and a structure-activity relationship was examined. Each compound was tested on nonhost plants and on five fungal pathogenic species belonging to the genus Phytophthora. The results provide insights into structure-activity relationships within these compounds. It was found that the hydroxy group at C-5, the absolute C-5 configuration, the epoxy group, and the C-2 carbonyl group appear to be structural features important in conferring biological activity. The conversion of sphaeropsidone into the corresponding 1,4-dione derivative led to a compound showing greater antifungal activity than its precursor. This finding could be useful in devising new natural fungicides for practical application in agriculture.

  3. Structure-activity relationships of novel neuritogenic steroid glycosides from the Okinawan starfish Linckia laevigata.

    PubMed

    Han, Chunguang; Qi, Jianhua; Ojika, Makoto

    2006-07-01

    Six new steroid glycosides, linckosides F-K, and a related metabolite were isolated from the Okinawan blue starfish Linckia laevigata as mimics or enhancers of nerve growth factor (NGF). Their structures and stereochemistry were elucidated by spectroscopic methods and chemical derivatization. Structure-activity relationships suggest that both a carbon branch modified by a pentose at the side chain and 2'-O-methylxylopyranose at C-3 of the aglycon are important for neuritogenic activity.

  4. Anticancer Activity of Estradiol Derivatives: A Quantitative Structure--Activity Relationship Approach

    NASA Astrophysics Data System (ADS)

    Muranaka, Ken

    2001-10-01

    Commercial packages to implement modern QSAR (quantitative structure-activity relationship) techniques are highly priced; however, the essence of QSAR can be taught without them. Microsoft Excel was used to analyze published data on anticancer activities of estradiol analogs by a QSAR approach. The resulting QSAR equations highly correlate the structural features and physicochemical properties of the analogs with the observed biological activities by multiple linear regression.

  5. Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro.

    PubMed Central

    Franzblau, S G; O'Sullivan, J F

    1988-01-01

    Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663). PMID:3056241

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

    SciTech Connect

    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.

  7. Promises and pitfalls of quantitative structure-activity relationship approaches for predicting metabolism and toxicity.

    PubMed

    Zvinavashe, Elton; Murk, Albertinka J; Rietjens, Ivonne M C M

    2008-12-01

    The description of quantitative structure-activity relationship (QSAR) models has been a topic for scientific research for more than 40 years and a topic within the regulatory framework for more than 20 years. At present, efforts on QSAR development are increasing because of their promise for supporting reduction, refinement, and/or replacement of animal toxicity experiments. However, their acceptance in risk assessment seems to require a more standardized and scientific underpinning of QSAR technology to avoid possible pitfalls. For this reason, guidelines for QSAR model development recently proposed by the Organization for Economic Cooperation and Development (OECD) [Organization for Economic Cooperation and Development (OECD) (2007) Guidance document on the validation of (quantitative) structure-activity relationships [(Q)SAR] models. OECD Environment Health and Safety Publications: Series on Testing and Assessment No. 69, Paris] are expected to help increase the acceptability of QSAR models for regulatory purposes. The guidelines recommend that QSAR models should be associated with (i) a defined end point, (ii) an unambiguous algorithm, (iii) a defined domain of applicability, (iv) appropriate measures of goodness-of-fit, robustness, and predictivity, and (v) a mechanistic interpretation, if possible [Organization for Economic Cooperation and Development (OECD) (2007) Guidance document on the validation of (quantitative) structure-activity relationships [(Q)SAR] models. The present perspective provides an overview of these guidelines for QSAR model development and their rationale, as well as the promises and pitfalls of using QSAR approaches and these guidelines for predicting metabolism and toxicity of new and existing chemicals.

  8. Exploring the structure-activity relationships of ABCC2 modulators using a screening approach.

    PubMed

    Wissel, Gloria; Kudryavtsev, Pavel; Ghemtio, Leo; Tammela, Päivi; Wipf, Peter; Yliperttula, Marjo; Finel, Moshe; Urtti, Arto; Kidron, Heidi; Xhaard, Henri

    2015-07-01

    ABCC2 is a transporter with key influence on liver and kidney pharmacokinetics. In order to explore the structure-activity relationships of compounds that modulate ABCC2, and by doing so gain insights into drug-drug interactions, we screened a library of 432 compounds for modulators of radiolabeled β-estradiol 17-(β-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7'-dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80μM, dose-response curves were used to investigate in detail 86 compounds, identifying 16 low μM inhibitors and providing data about the structure-activity relationships in four series containing 19, 24, 10, and eight analogues. Measurements with the CDCF probe were consistently more robust than for the EG probe. Only one compound was clearly probe-selective with a 50-fold difference in the IC50s obtained by the two assays. We built 24 classification models using the SVM and fused-XY Kohonen methods, revealing molecular descriptors related to number of rings, solubility and lipophilicity as important to distinguish inhibitors from inactive compounds. This study is to the best of our knowledge the first to provide details about structure-activity relationships in ABCC2 modulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Communicating alcohol narratives: creating a healthier relationship with alcohol.

    PubMed

    Anderson, Peter; Amaral-Sabadini, Michaela Bitarello do; Baumberg, Ben; Jarl, Johan; Stuckler, David

    2011-08-01

    Alcohol, like mental health, is a neglected topic in public health discussions. However, it should be defined as a priority public health area because the evidence available to support this is very persuasive. Although only half the world's population drinks alcohol, it is the world's third leading cause of ill health and premature death, after low birth weight and unsafe sex, and the world's greatest cause of ill health and premature death among individuals between 25 and 59 years of age. This article aims to outline current global experiences with alcohol policies and suggests how to communicate better evidence-based policy responses to alcohol-related harm using narratives. The text summarizes 6 actions to provide incentives that would favor a healthier relationship with alcohol in contemporary society. Actions include price and availability changes, marketing regulations, changes in the format of drinking places and on the product itself, and actions designed to nudge people at the time of their purchasing decisions. Communicating alcohol narratives to policymakers more successfully will likely require a discourse emphasizing the reduction of heavy drinking occasions and the protection of others from someone else's problematic drinking.

  10. Quantitative structure-activity relationships for the in vitro antimycobacterial activity of pyrazinoic acid esters.

    PubMed

    Bergmann, K E; Cynamon, M H; Welch, J T

    1996-08-16

    Substituted pyrazinoic acid esters have previously been reported to have in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as Mycobacterium tuberculosis. Modification of both the pyrazine nucleus and the ester functionality was successful in expanding the antimycobacterial activity associated with pyrazinamide to include M. avium and M. kansasii, organisms usually not susceptible to pyrazinamide. In an attempt to understand the relationship between the activity of the esters with the needed biostability, a quantitative structure-activity relationship has been developed. This derived relationship is consistent with the observation that tert-butyl 5-chloropyrazinoate (13) and 2'-(2'-methyldecyl) 5-chloropyrazinoate (25), compounds which are both 100-fold more active than pyrazinamide against M. tuberculosis and possess a serum stability 900-1000 times greater than the lead compounds in the series.

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

    PubMed

    Zou, Tang-Bin; He, Tai-Ping; Li, Hua-Bin; Tang, Huan-Wen; Xia, En-Qin

    2016-01-12

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

  12. HomoSAR: bridging comparative protein modeling with quantitative structural activity relationship to design new peptides.

    PubMed

    Borkar, Mahesh R; Pissurlenkar, Raghuvir R S; Coutinho, Evans C

    2013-11-15

    Peptides play significant roles in the biological world. To optimize activity for a specific therapeutic target, peptide library synthesis is inevitable; which is a time consuming and expensive. Computational approaches provide a promising way to simply elucidate the structural basis in the design of new peptides. Earlier, we proposed a novel methodology termed HomoSAR to gain insight into the structure activity relationships underlying peptides. Based on an integrated approach, HomoSAR uses the principles of homology modeling in conjunction with the quantitative structural activity relationship formalism to predict and design new peptide sequences with the optimum activity. In the present study, we establish that the HomoSAR methodology can be universally applied to all classes of peptides irrespective of sequence length by studying HomoSAR on three peptide datasets viz., angiotensin-converting enzyme inhibitory peptides, CAMEL-s antibiotic peptides, and hAmphiphysin-1 SH3 domain binding peptides, using a set of descriptors related to the hydrophobic, steric, and electronic properties of the 20 natural amino acids. Models generated for all three datasets have statistically significant correlation coefficients (r(2)) and predictive r2 (r(pred)2) and cross validated coefficient ( q(LOO)2). The daintiness of this technique lies in its simplicity and ability to extract all the information contained in the peptides to elucidate the underlying structure activity relationships. The difficulties of correlating both sequence diversity and variation in length of the peptides with their biological activity can be addressed. The study has been able to identify the preferred or detrimental nature of amino acids at specific positions in the peptide sequences. Copyright © 2013 Wiley Periodicals, Inc.

  13. Electron-density descriptors as predictors in quantitative structure--activity/property relationships and drug design.

    PubMed

    Matta, Chérif F; Arabi, Alya A

    2011-06-01

    The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

  14. A computational quantitative structure-activity relationship study of carbamate anticonvulsants using quantum pharmacological methods.

    PubMed

    Knight, J L; Weaver, D F

    1998-10-01

    A pattern recognition quantitative structure-activity relationship (QSAR) study has been performed to determine the molecular features of carbamate anticonvulsants which influence biological activity. Although carbamates, such as felbamate, have been used to treat epilepsy, their mechanisms of efficacy and toxicity are not completely understood. Quantum and classical mechanics calculations have been exploited to describe 46 carbamate drugs. Employing a principal component analysis and multiple linear regression calculations, five crucial structural descriptors were identified which directly relate to the bioactivity of the carbamate family. With the resulting mathematical model, the biological activity of carbamate analogues can be predicted with 85-90% accuracy.

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

    PubMed

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

    2009-08-01

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

  16. Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships.

    PubMed

    Singh, Ranee; Reed, Anthony N; Chu, Peifei; Scully, Conor C G; Yau, Mei-Kwan; Suen, Jacky Y; Durek, Thomas; Reid, Robert C; Fairlie, David P

    2015-12-01

    Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed.

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

    PubMed

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

    2016-01-14

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

  18. A Receptor-Grounded Approach to Teaching Nonsteroidal Antiinflammatory Drug Chemistry and Structure-Activity Relationships

    PubMed Central

    2009-01-01

    Objective To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Design Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Assessment Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Conclusion Student performance on NSAID-focused quizzes and examinations documented the success of this approach. PMID:20221336

  19. Identification and structure-activity relationship study of carvacrol derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.

    PubMed

    Alokam, Reshma; Jeankumar, Variam Ullas; Sridevi, Jonnalagadda Padma; Matikonda, Siddharth Sai; Peddi, Santosh; Alvala, Mallika; Yogeeswari, Perumal; Sriram, Dharmarajan

    2014-08-01

    In the present study, we identified carvacrol, a major phenolic component of oregano oil as a novel small molecule inhibitor of Mycobacterium tuberculosis (MTB) chorismate mutase (CM) enzyme with IC50 of 1.06 ± 0.4 µM. Virtual screening of the BITS-Pilani in-house database using the crystal structure of the MTB CM bound transition state intermediate (PDB: 2FP2) as framework identified carvacrol as a potential lead. Further various carvacrol derivatives were evaluated in vitro for their ability to inhibit MTB CM enzyme, whole cell MTB and cytotoxicity as steps toward the derivation of structure-activity relationships (SAR) and lead optimization.

  20. Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships

    PubMed Central

    Liu, Jiawang; Sridhar, Jayalakshmi; Foroozesh, Maryam

    2014-01-01

    With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990’s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes. However, the details of structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis. PMID:24287985

  1. Structure-activity relationships of tetramethylpiperidine-substituted phenazines against Mycobacterium leprae in vitro.

    PubMed Central

    Franzblau, S G; White, K E; O'Sullivan, J F

    1989-01-01

    In a previous study of structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro, compounds containing a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen were most active. Therefore, the effect of substitution at the para positions of the phenyl and anilino groups in tetramethylpiperidine-substituted phenazines was assessed. As determined by radiorespirometry, activity in ascending order was observed in compounds substituted with hydrogens or fluorines, ethoxy groups, methyl groups, chlorines, and bromines and correlated with partition coefficients in octanol-water. PMID:2692516

  2. Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

    PubMed

    Nitta, Aiko; Iura, Yosuke; Tomioka, Hiroki; Sato, Ippei; Morihira, Koichiro; Kubota, Hirokazu; Morokata, Tatsuaki; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-ichi; Imaoka, Takayuki; Takahashi, Toshiya

    2012-08-01

    The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

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

    PubMed

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

    2016-01-01

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

  4. Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH

    PubMed Central

    Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa; Zhang, Minjia; Liu, Xiaoping; Ray, Soumya S.; MacPherson, Iain S.; Striepen, Boris; Hedstrom, Lizbeth; Cuny, Gregory D.

    2012-01-01

    Cryptosporidium parasites are important waterborne pathogens of both humans and animals. The C. parvum and C. hominis genomes indicate that the only route to guanine nucleotides is via inosine 5'-monophosphate dehydrogenase (IMPDH). Thus the inhibition of the parasite IMPDH presents a potential strategy for treating Cryptosporidium infections. A selective benzimidazole-based inhibitor of C. parvum IMPDH (CpIMPDH) was previously identified in a high throughput screen. Here we report a structure-activity relationship study of benzimidazole-based compounds that resulted in potent and selective inhibitors of CpIMPDH. Several compounds display potent antiparasitic activity in vitro. PMID:22310229

  5. Synthesis, Acaricidal Activity, and Structure-Activity Relationships of Pyrazolyl Acrylonitrile Derivatives.

    PubMed

    Yu, Haibo; Cheng, Yan; Xu, Man; Song, Yuquan; Luo, Yanmei; Li, Bin

    2016-12-28

    A series of novel pyrazolyl acrylonitrile derivatives was designed, targeting Tetranychus cinnabarinus, and synthesized. Their structures were identified by combination of (1)H NMR, (13)C NMR, and MS spectra. The structures of compounds 18 and 19 were further confirmed by X-ray diffraction. Extensive greenhouse bioassays indicated that compound 19 exhibits excellent acaricidal activity against all developmental stages of T. cinnabarinus, which is better than the commercialized compounds cyenopyrafen and spirodiclofen. It was shown that the acute toxicity of compounds 19 to mammals is quite low. The structure-activity relationships are also discussed.

  6. Induction of choline acetyltransferase activity in cholinergic neurons by stolonidiol: structure-activity relationship.

    PubMed

    Yabe, T; Yamada, H; Shimomura, M; Miyaoka, H; Yamada, Y

    2000-04-01

    The effect of stolonidiol (1), a bioactive marine diterpenoid from the Japanese soft coral Clavularia sp., on choline acetyltransferase (ChAT) activity was examined using cultured cholinergic neurons. Stolonidiol (1) showed potent ChAT inducible activity in primary cultured basal forebrain cells and clonal septal SN49 cells, suggesting that it may act as a potent neurotrophic factor-like agent on the cholinergic nervous system. Further expansion of the structure-activity relationship to include stolonidiol (1) and its derivatives demonstrated that the exo-methylene group and the epoxide group are essential for ChAT-inducing activity. Stolonidiol (1) showed the highest activity among the test samples.

  7. Structure-activity relationships and action mechanisms of collagen-like antimicrobial peptides.

    PubMed

    Masuda, Ryo; Dazai, Yui; Mima, Takehiko; Koide, Takaki

    2017-01-01

    An antimicrobial triple-helical peptide, R3, was previously obtained from a collagen-like combinatorial peptide library. In this research, based on structure-activity relationship studies of R3, a more potent peptide, RR4, with increased positive net charge and charge density relative to R3, was developed. RR4 exhibited antimicrobial activity against both Gram-negative and Gram-positive bacterial strains, including multidrug-resistant strains. Its action could be attributed to entry into cells and interactions with intercellular molecules such as DNA/RNA that inhibited cell division rather than increasing bacterial membrane permeability. Furthermore, RR4 exhibited remarkable stability in serum and low cytotoxicity.

  8. Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1

    PubMed Central

    Lu, Lianghao; Wei, Liping; Pai, Eric; Yao, Yuan; Song, Yongcheng

    2017-01-01

    Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1. Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity. PMID:28158205

  9. Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.

    PubMed

    Goyanka, Ritu; Das, Sharmistha; Samuels, Herbert H; Cardozo, Timothy

    2010-11-01

    Nuclear receptors (NRs) comprise the second largest protein family targeted by currently available drugs, acting via specific ligand interactions within the ligand binding domain (LBD). Recently, farnesyl pyrophosphate (FPP) was shown to be a unique promiscuous NR ligand, activating a subset of NR family members and inhibiting wound healing in skin. The current study aimed at visualizing the unique basis of FPP interaction with multiple receptors in order to identify general structure-activity relationships that operate across the NR family. Docking of FPP to the 3D structures of the LBDs of a diverse set of NRs consistently revealed an electrostatic FPP pyrophosphate contact with an NR arginine conserved in the NR family, a hydrophobic farnesyl contact with NR helix-12 and a ligand binding pocket volume between 300 and 430 Å(3) as the minimal requirements for FPP activation of any NR. Lack of any of these structural features appears to render a given NR resistant to FPP activation. We used these structure-activity relationships to rationally design and successfully engineer several mutant human estrogen receptors that retain responsiveness to estradiol but no longer respond to FPP.

  10. A categorical structure-activity relationship analysis of GPR119 ligands.

    PubMed

    Kumar, Pritesh; Carrasquer, Carl A; Carter, Arren; Song, Zhao-Hui; Cunningham, Albert R

    2014-01-01

    The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed. Using a leave-one-out validation routine, the best GPR119 model had an overall concordance of 99%, a sensitivity of 99%, and a specificity of 100%. Our findings from the in-depth fragment analysis of several known GPR119 agonists were consistent with previously reported GPR119 structure-activity relationship (SAR) analyses. Overall, while our results indicate that we have developed a highly predictive cat-SAR model that can be potentially used to rapidly screen for prospective GPR119 ligands, the applicability domain must be taken into consideration. Moreover, our study demonstrates for the first time that the cat-SAR expert system can be used to model G protein-coupled receptor ligands, many of which are important therapeutic agents.

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

    PubMed

    Tuenter, Emmy; Segers, Karen; Kang, Kyo Bin; Viaene, Johan; Sung, Sang Hyun; Cos, Paul; Maes, Louis; Heyden, Yvan Vander; Pieters, Luc

    2017-02-02

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

  12. Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors.

    PubMed

    Pauli, Ivani; Ferreira, Leonardo G; de Souza, Mariana L; Oliva, Glaucius; Ferreira, Rafaela S; Dessoy, Marco A; Slafer, Brian W; Dias, Luiz C; Andricopulo, Adriano D

    2017-05-01

    Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions. Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r (2)pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site. These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency.

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

    PubMed Central

    Kostova, I.; Raleva, S.; Genova, P.; Argirova, R.

    2006-01-01

    HIV/AIDS pandemics is a serious threat to health and development of mankind, and searching for effective anti-HIV agents remains actual. Considerable progress has been made in recent years in the field of drug development against HIV. A lot of structurally different coumarins were found to display potent anti-HIV activity. The current review demonstrates the variety of synthetic coumarins having unique mechanism of action referring to the different stages of HIV replication. Recent studies based on the account of various synthetic coumarins seem to indicate that some of them serve as potent non-nucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed.The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against resistant mutants. The investigation on chemical anti-HIV agents gives hope and optimism about it. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives. PMID:17497014

  14. Agropyrenol, a phytotoxic fungal metabolite, and its derivatives: a structure-activity relationship study.

    PubMed

    Cimmino, Alessio; Zonno, Maria Chiara; Andolfi, Anna; Troise, Ciro; Motta, Andrea; Vurro, Maurizio; Evidente, Antonio

    2013-02-27

    Agropyrenol is a phytotoxic substituted salicylic aldehyde produced in liquid culture by Ascochyta agropyrina var. nana , a potential mycoherbicide proposed for the control of the perennial weed Elytrigia repens. In this study, six derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on non-host weedy and agrarian plants, fungi, Gram-positive and Gram-negative bacteria, and brine shrimp larvae. The results provide insights into the structure-activity relationships of agropyrenol. Both the double bond and the diol system of the 3,4-dihydroxypentenyl side chain as well as the aldehyde group at C-1 of the phenolic ring of agropyrenol proved to be important for the phytotoxicity. The lesser polar 3',4'-O,O'-isopropylidene of agropyrenol also showed significant zootoxic and slight antimicrobial activities. This finding could be useful in devising new natural herbicides for practical application in agriculture.

  15. Three data mining techniques to improve lazy structure-activity relationships for noncongeneric compounds.

    PubMed

    Sommer, Selina; Kramer, Stefan

    2007-01-01

    We present three simple, yet effective data mining techniques for lazy structure-activity relationships (SARs) of noncongeneric compounds. In lazy SARs, classifications are particularly tailored for each test compound. Therefore, it is possible to make the most of the structure of a test compound. In our case, we derive its substructures and use them to determine similar structures. To obtain a well-balanced and representative set of structural descriptors, we enrich this set by strongly activating or deactivating fragments from the training set and subsequently remove redundant fragments. Finally, we perform k-Nearest Neighbor classification for several values of k and take a vote among the resulting predictions. These techniques (enrichment, removing redundancy, and voting) are integrated into the system iSAR (instance-based structure-activity relationships) and tested individually to show the relative contribution to the system's performance. Experiments on three data sets indicate that this simple and lightweight approach performs at least on the same level as other, more complex approaches.

  16. Quantitative structure activity relationship analysis of canonical inhibitors of serine proteases

    NASA Astrophysics Data System (ADS)

    Dell'Orco, Daniele; De Benedetti, Pier Giuseppe

    2008-06-01

    Correlation analysis was carried out between binding affinity data values from the literature and physicochemical molecular descriptors of two series of single point mutated canonical inhibitors of serine proteases, namely bovine pancreatic trypsin inhibitor (BPTI) and turkey ovomucoid third domain (OMTKY3), toward seven enzymes. Simple quantitative structure-activity relationship (QSAR) models based on either single or double linear regressions (SLR or DLR) were obtained, which highlight the role of hydrophobic and bulk/polarizability features of mutated amino acids of the inhibitors in modulating both affinity and specificity. The utility of the QSAR paradigm applied to the analysis of mutagenesis data was underlined, resulting in a simple tool to quantitatively help deciphering structure-function/activity relationships (SFAR) of different protein systems.

  17. ESTIMATION OF MICROBIAL REDUCTIVE TRANSFORMATION RATES FOR CHLORINATED BENZENES AND PHENOLS USING A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP APPROACH

    EPA Science Inventory

    A set of literature data was used to derive several quantitative structure-activity relationships (QSARs) to predict the rate constants for the microbial reductive dehalogenation of chlorinated aromatics. Dechlorination rate constants for 25 chloroaromatics were corrected for th...

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

    EPA Science Inventory

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

  19. THE USE OF STRUCTURE-ACTIVITY RELATIONSHIPS IN INTEGRATING THE CHEMISTRY AND TOXICOLOGY OF ENDOCRINE DISRUPTING CHEMICALS

    EPA Science Inventory

    Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...

  20. ESTIMATION OF MICROBIAL REDUCTIVE TRANSFORMATION RATES FOR CHLORINATED BENZENES AND PHENOLS USING A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP APPROACH

    EPA Science Inventory

    A set of literature data was used to derive several quantitative structure-activity relationships (QSARs) to predict the rate constants for the microbial reductive dehalogenation of chlorinated aromatics. Dechlorination rate constants for 25 chloroaromatics were corrected for th...

  1. THE USE OF STRUCTURE-ACTIVITY RELATIONSHIPS IN INTEGRATING THE CHEMISTRY AND TOXICOLOGY OF ENDOCRINE DISRUPTING CHEMICALS

    EPA Science Inventory

    Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...

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

    EPA Science Inventory

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

  3. Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1

    PubMed Central

    Passic, Shendra R.; Ferguson, Mary Lee; Catalone, Bradley J.; Kish-Catalone, Tina; Kholodovych, Vladyslav; Zhu, Wei; Welsh, William; Rando, Robert; Howett, Mary K.; Wigdahl, Brian; Labib, Mohamed; Krebs, Fred C.

    2013-01-01

    Previous investigations showing that polydisperse biguanide (PDBG) molecules have activity against human immunodeficiency virus type 1 (HIV-1) also suggested a relationship between PDBG biologic activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define structure-activity relationships, PDBG molecules with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and in vivo toxicity. Results of the in vitro experiments demonstrated that increases in linker length (and, therefore, increases in compound lipophilicity) were generally associated with increases in cytotoxicity and antiviral activity against HIV-1. However, a relationship between linker length asymmetry and in vitro therapeutic index (TI) suggested structural specificity in the mechanism of action against HIV-1. Polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) was found to have the highest in vitro TI (CC50/IC50) among the compounds examined. Recent improvements in PEHMB synthesis and purification have yielded preparations of PEHMB with in vitro TI values of 266 and 7000 against HIV-1 strains BaL and IIIB, respectively. The minimal toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during in vitro experiments. These structure-activity investigations increase our understanding of PDBG molecules as agents with activity against HIV-1 and provide the foundation for further preclinical studies of PEHMB and other biguanide-based compounds as antiviral and microbicidal agents. PMID:21106331

  4. Development of structure-activity relationship rules for predicting carcinogenic potential of chemicals.

    PubMed

    Woo, Y T; Lai, D Y; Argus, M F; Arcos, J C

    1995-09-01

    Since the inception of Section 5 (Premanufacturing/Premarketing Notification, PMN) of the Toxic Substances Control Act (TSCA), structure-activity relationship (SAR) analysis has been effectively used by U.S. Environmental Protection Agency's (EPA) Structure Activity Team (SAT) in the assessment of potential carcinogenic hazard of new chemicals for which test data are not available. To capture, systematize and codify the Agency's predictive expertise in order to make it more widely available to assessors outside the TSCA program, a cooperative project was initiated to develop a knowledge rule-based expert system to mimic the thinking and reasoning of the SAT. In this communication, we describe the overall structure of this expert system, discuss the scientific bases and principles of SAR analysis of chemical carcinogens used in the development of SAR knowledge rules, and delineate the major factors/rules useful for assessing the carcinogenic potential of fibers, polymers, metals/metalloids and several major classes of organic chemicals. An integrative approach using available short-term predictive tests and non-cancer toxicological data to supplement SAR analysis has also been described.

  5. Comparison of quantitative structure-activity relationship model performances on carboquinone derivatives.

    PubMed

    Bolboacă, Sorana-Daniela; Jäntschi, Lorentz

    2009-10-14

    Quantitative structure-activity relationship (qSAR) models are used to understand how the structure and activity of chemical compounds relate. In the present study, 37 carboquinone derivatives were evaluated and two different qSAR models were developed using members of the Molecular Descriptors Family (MDF) and the Molecular Descriptors Family on Vertices (MDFV). The usual parameters of regression models and the following estimators were defined and calculated in order to analyze the validity and to compare the models: Akaike's information criteria (three parameters), Schwarz (or Bayesian) information criterion, Amemiya prediction criterion, Hannan-Quinn criterion, Kubinyi function, Steiger's Z test, and Akaike's weights. The MDF and MDFV models proved to have the same estimation ability of the goodness-of-fit according to Steiger's Z test. The MDFV model proved to be the best model for the considered carboquinone derivatives according to the defined information and prediction criteria, Kubinyi function, and Akaike's weights.

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

    PubMed

    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.

  7. Structure activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase

    PubMed Central

    Kim, In-Hae; Park, Yong-Gyu; Hammock, Bruce D.; Nishi, Kosuke

    2012-01-01

    Structure activity relationships of cycloalkylamide compounds as inhibitors of human sEH were investigated. When the left side of amide function was modified by a variety of cycloalkanes, at least a C6 like cyclohexane was necessary to yield reasonable inhibition potency on the target enzyme. In compounds with a smaller cycloalkane or with a polar group on the left side of amide function, no inhibition was observed. On the other hand, increased hydrophobicity dramatically improved inhibition potency. Especially, a tetrahydronaphthalene (20) effectively increased the potency. When a series of alkyl or aryl derivatives of cycloalkylamide were investigated to continuously optimize the right side of the amide pharmacophore, a benzyl moiety functionalized with a polar group produced highly potent inhibition. Non-substituted benzyl, alkyl, aryl, or biaryl structure present in the right side of cycloalkylamide function induced a big decrease in inhibition potency. Also, a resulting potent cycloalkylamide (32) showed reasonable physical properties. PMID:21338111

  8. Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers.

    PubMed

    Kenwood, Brandon M; Calderone, Joseph A; Taddeo, Evan P; Hoehn, Kyle L; Santos, Webster L

    2015-11-01

    Chemical mitochondrial uncouplers are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. These uncouplers have potential for the treatment of diseases such as obesity, Parkinson's disease, and aging. We have previously identified a novel mitochondrial protonophore, named BAM15, which stimulates mitochondrial respiration across a broad dosing range compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Herein, we report our investigations on the structure-activity relationship profile of BAM15. Our studies demonstrate the importance of the furazan, pyrazine, and aniline rings as well as pKa in maintaining its effective protonophore activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Cyclooxygenase active bioflavonoids from Balaton tart cherry and their structure activity relationships.

    PubMed

    Wang, H; Nair, M G; Strasburg, G M; Booren, A M; Gray, I; Dewitt, D L

    2000-03-01

    Several flavonoids and isoflavonoids isolated from Balaton tart cherry were assayed for prostaglandin H endoperoxide synthase (PGHS-1) enzyme or cyclooxygenase isoform-1 (COX-1) activity. Genistein showed the highest COX-1 inhibitory activity among the isoflavonoids studied, with an IC50 value of 80 microM. Kaempferol gave the highest COX-1 inhibitory activity among the flavonoids tested, with an IC50 value of 180 microM. The structure-activity relationships of flavonoids and isoflavonoids revealed that hydroxyl groups at C4', C5 and C7 in isoflavonoids were essential for appreciable COX-1 inhibitory activity. Also, the C2-C3 double bond in flavonoids is important for COX-1 inhibitory activity. However, a hydroxyl group at the position decreased COX-1 inhibitory activity by flavonoids.

  10. Synthesis and structure-activity relationship of novel cinnamamide derivatives as antidepressant agents.

    PubMed

    Han, Min; Ma, Xiaohui; Jin, Yuanpeng; Zhou, Wangyi; Cao, Jing; Wang, Yahu; Zhou, Shuiping; Wang, Guocheng; Zhu, Yonghong

    2014-11-15

    Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure-activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.

  11. Structure-activity relationships of tulipalines, tuliposides, and related compounds as inhibitors of MurA.

    PubMed

    Mendgen, Thomas; Scholz, Therese; Klein, Christian D

    2010-10-01

    The enzyme MurA performs an essential step in peptidoglycan biosynthesis and is therefore a target for the discovery of novel antibacterial compounds. We report here the inhibition of MurA by natural products from tulips (tulipalines and tuliposides), and the structure-activity relationships of various derivatives. The inhibition of MurA can be related to antibacterial activity, and MurA is probably one of the relevant molecular targets of the tulipaline derivatives. MurA inhibition by this class of compounds depends on the presence of the substrate UNAG, which indicates non-covalent suicide inhibition as observed previously for cnicin. With respect to selectivity, however, the reactivity against arbitrary sulfhydryl groups, such as in glutathione, could not yet be sufficiently separated from MurA inhibition in the present dataset.

  12. Novel spiropyrazolone antitumor scaffold with potent activity: Design, synthesis and structure-activity relationship.

    PubMed

    Wu, Shanchao; Li, Yu; Xu, Guixia; Chen, Shuqiang; Zhang, Yongqiang; Liu, Na; Dong, Guoqiang; Miao, Chaoyu; Su, Hua; Zhang, Wannian; Sheng, Chunquan

    2016-06-10

    Phenotypic screening of high quality compound library is an effective strategy to discover novel bioactive molecules. Previously, we developed the divergent organocatalytic cascade approach to efficiently construct a focused library with scaffold diversity and successfully identified a novel spiropyrazolone antitumor scaffold. Herein, a series of spiropyrazolone derivatives were designed, synthesized and assayed. Most of them showed good in vitro antitumor activity with a broad spectrum. Preliminary structure-activity relationship for the substitutions and the stereo configuration were obtained. Compound 5k showed good antitumor activity and could effectively induce cancer cell apoptosis, which represents a good starting point for the development of novel antitumor agents. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Structure-Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry.

    PubMed

    Jung, Michael E; Chamberlain, Brian T; Ho, Chi-Lee C; Gillespie, Eugene J; Bradley, Kenneth A

    2014-04-10

    EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure-activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3-5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis.

  14. Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds.

    PubMed

    Burgess, Steven J; Kelly, Jane X; Shomloo, Shawheen; Wittlin, Sergio; Brun, Reto; Liebmann, Katherine; Peyton, David H

    2010-09-09

    We have previously shown that a "reversed chloroquine (RCQ)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum ( Burgess , S. J. ; Selzer , A. ; Kelly , J. X. ; Smilkstein , M. J. ; Riscoe , M. K. ; Peyton , D. H. J. Med. Chem. 2006 , 49 , 5623 . Andrews , S. ; Burgess , S. J. ; Skaalrud , D. ; Kelly , J. X. ; Peyton , D. H. J. Med. Chem. 2010 , 53 , 916 ). Here, we present an investigation into the structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of chloroquine.

  15. Exploration of the structure-activity relationship of 1,2,4-oxadiazole antibiotics.

    PubMed

    Ding, Derong; Boudreau, Marc A; Leemans, Erika; Spink, Edward; Yamaguchi, Takao; Testero, Sebastian A; O'Daniel, Peter I; Lastochkin, Elena; Chang, Mayland; Mobashery, Shahriar

    2015-11-01

    We have recently disclosed the discovery of the class of 1,2,4-oxadiazole antibiotics, which emerged from in silico docking and scoring efforts. This class of antibacterials exhibits Gram-positive activity, particularly against Staphylococcus aureus. We define the structure-activity relationship (SAR) of this class of antibiotics with the synthesis and evaluation of a series of 59 derivatives with variations in the C ring or C and D rings. A total of 17 compounds showed activity against S. aureus. Four derivatives were evaluated against a panel of 16 Gram-positive strains, inclusive of several methicillin-resistant S. aureus strains. These compounds are broadly active against Gram-positive bacteria.

  16. Isoxazole analogues bind the System xc− Transporter: Structure-activity Relationship and Pharmacophore Model

    PubMed Central

    Patel, Sarjubhai A.; Rajale, Trideep; O’Brien, Erin; Burkhart, David J.; Nelson, Jared K.; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I.; Gerdes, John M.; Bridges, Richard J.; Natale, Nicholas R.

    2009-01-01

    Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc−. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc−, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y′=3,5-(CF3)2, which both inhibited glutamate up-take by the System xc− transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

  17. New chromene scaffolds for adenosine A(2A) receptors: synthesis, pharmacology and structure-activity relationships.

    PubMed

    Areias, Filipe; Costa, Marta; Castro, Marián; Brea, José; Gregori-Puigjané, Elisabet; Proença, M Fernanda; Mestres, Jordi; Loza, María I

    2012-08-01

    In silico screening of a collection of 1584 academic compounds identified a small molecule hit for the human adenosine A(2A) receptor (pK(i) = 6.2) containing a novel chromene scaffold (3a). To explore the structure-activity relationships of this new chemical series for adenosine receptors, a focused library of 43 2H-chromene-3-carboxamide derivatives was synthesized and tested in radioligand binding assays at human adenosine A(1), A(2A), A(2B) and A(3) receptors. The series was found to be enriched with bioactive compounds for adenosine receptors, with 14 molecules showing submicromolar affinity (pK(i) ≥ 6.0) for at least one adenosine receptor subtype. These results provide evidence that the chromene scaffold, a core structure present in natural products from a wide variety of plants, vegetables, and fruits, constitutes a valuable source for novel therapeutic agents. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  18. Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.

    PubMed

    Mologni, Luca; Rostagno, Roberta; Brussolo, Stefania; Knowles, Phillip P; Kjaer, Svend; Murray-Rust, Judith; Rosso, Enrico; Zambon, Alfonso; Scapozza, Leonardo; McDonald, Neil Q; Lucchini, Vittorio; Gambacorti-Passerini, Carlo

    2010-02-15

    The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers. Copyright 2010 Elsevier Ltd. All rights reserved.

  19. [Researches on the in silico prediction of structure-activity relationship in the regulatory science sectors].

    PubMed

    Hirose, Akihiko

    2010-01-01

    Requirements of in silico toxicity prediction system are increasing in the chemical risk assessment fields, as well as in toxicity prediction at the early stage of the new drug development process. Recent amended chemical registration rules require internationally the risk assessment of huge amounts of existing chemicals. The (quantitative) structure-activity relationship ((Q)SAR) models are considered to be most effective tools for the acceleration of toxicity evaluation. In Europe or the United State, several research projects for the development of the (Q)SAR models are ongoing. Following this introduction, four researches on development of in silico prediction systems for (Q)SAR in the NIHS are reviewed. These activities must internationally contribute to the integrated chemical risk assessment approaches and/or could assist in the new drug development work.

  20. Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review.

    PubMed

    Yadav, Geeta; Ganguly, Swastika

    2015-06-05

    Benzimidazoles are the fused heterocyclic ring systems which form an integral part of vitamin B12 and have been luring many researchers all over the world to assess their potential therapeutic significance. They are known for their crucial role in numerous diseases via various mechanisms. Substitution of benzimidazole nucleus is a crucial step in the drug discovery process. Therefore, it is necessary to gather the latest information along with the earlier information to understand the present status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of SAR study using structural substitution pattern around the benzimidazole nucleus and aims to review the reported work related to the chemistry and pharmacological activities of benzimidazole derivatives during recent years. The present manuscript to the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure-activity relationships of benzimidazole reported to date.

  1. Design, synthesis, and structure-activity relationship studies of novel pleuromutilin derivatives having a piperazine ring.

    PubMed

    Luo, Jian; Yang, Qiu-E; Yang, Yuan-Yuan; Tang, You-Zhi; Liu, Ya-Hong

    2016-11-01

    A series of novel pleuromutilin derivatives possessing piperazine moieties were synthesized under mild conditions. The in vitro antibacterial activities of these derivatives against Staphylococcus aureus and Escherichia coli were tested by the agar dilution method. Structure-activity relationship studies resulted in compounds 11b, 13b, and 14a with the most potent in vitro antibacterial activity among the series (minimal inhibitory concentration = 0.0625-0.125 μg/mL). The binding of compounds 11b, 13b, and 14a to the E. coli ribosome was investigated by molecular modeling, and it was found that there is a reasonable correlation between the binding free energy and the antibacterial activity. © 2016 John Wiley & Sons A/S.

  2. Advances on Semisynthesis, Total Synthesis, and Structure-Activity Relationships of Honokiol and Magnolol Derivatives.

    PubMed

    Yang, Chun; Zhi, Xiaoyan; Xu, Hui

    2016-01-01

    Honokiol and magnolol (an isomer of honokiol) are small-molecule polyphenols isolated from the barks of Magnolia officinalis, which have been widely used in traditional Chinese and Japanese medicines. In the last decade, a variety of biological properties of honokiol and magnolol (e.g., anti-oxidativity, antitumor activity, anti-depressant activity, anti-inflammatory activity, neuroprotective activity, anti-diabetic activity, antiviral activity, and antimicrobial activity) have been reported. Meanwhile, certain mechanisms of action of some biological activities were also investigated. Moreover, many analogs of honokiol and magnolol were prepared by structural modification or total synthesis, and some exhibited very potent pharmacological activities with improved water solubility. Therefore, the present review will provide a systematic coverage on recent developments of honokiol and magnolol derivatives in regard to semisynthesis, total synthesis, and structure-activity relationships from 2000 up to now.

  3. A multi-dimensional Structure-Activity Relationship of a protein in its aggregated states

    PubMed Central

    Wang, Lei; Schubert, David; Sawaya, Michael R.; Eisenberg, David; Riek, Roland

    2010-01-01

    Protein aggregates are both associated with disease and function. Because a variety of factors induce protein aggregation, a given protein can aggregate into different states. Here, we compare the structures and activities of five distinct protein aggregates of a single protein. Despite the diverse chemical, physical and biological treatments used to induce aggregation, all aggregate types contain the cross-β-sheet motif. However, they are structurally distinct, having different segments of the protein sequence involved in secondary structure formation. Because of these structural differences each aggregate has a unique set of properties. These include affinity to ATP, Thioflavin T, DNA, and membrane mimics, and interference with cell viability. The key to their multiple properties may be that the repetitive nature of the cross-β-sheet motif guarantees for many potent activities through cooperativity. The observed multidimensional structure-activity relationship of protein aggregates may be important for amyloid diseases but may also be advantageous in nanotechnology. PMID:20397175

  4. Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies.

    PubMed

    Dharmaratne, H R W; Sakagami, Yoshikazu; Piyasena, K G P; Thevanesam, Vasanthi

    2013-01-01

    Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. γ-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 µg mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of γ-mangostin and α-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7-tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity.

  5. The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface.

    PubMed

    Camerino, Michelle A; Zhong, Nan; Dong, Aiping; Dickson, Bradley M; James, Lindsey I; Baughman, Brandi M; Norris, Jacqueline L; Kireev, Dmitri B; Janzen, William P; Arrowsmith, Cheryl H; Frye, Stephen V

    2013-11-01

    We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding.

  6. The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface

    PubMed Central

    Camerino, Michelle A.; Zhong, Nan; Dong, Aiping; Dickson, Bradley M.; James, Lindsey I.; Baughman, Brandi M.; Norris, Jacqueline L.; Kireev, Dmitri B.; Janzen, William P.; Arrowsmith, Cheryl H.

    2013-01-01

    We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding. PMID:24466405

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

    NASA Astrophysics Data System (ADS)

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

    2017-07-01

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

  8. A descriptor of amino acids: SVRG and its application to peptide quantitative structure-activity relationship.

    PubMed

    Tong, J; Che, T; Li, Y; Wang, P; Xu, X; Chen, Y

    2011-01-01

    In this work, a descriptor, SVRG (principal component scores vector of radial distribution function descriptors and geometrical descriptors), was derived from principal component analysis (PCA) of a matrix of two structural variables of coded amino acids, including radial distribution function index (RDF) and geometrical index. SVRG scales were then applied in three panels of peptide quantitative structure-activity relationships (QSARs) which were modelled by partial least squares regression (PLS). The obtained models with the correlation coefficient (R²(cum)), cross-validation correlation coefficient (Q²(LOO)) were 0.910 and 0.863 for 48 bitter-tasting dipeptides; 0.968 and 0.931 for 21 oxytocin analogues; and 0.992 and 0.954 for 20 thromboplastin inhibitors. Satisfactory results showed that SVRG contained much chemical information relating to bioactivities. The approach may be a useful structural expression methodology for studies on peptide QSAR.

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

    PubMed

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

    2012-03-01

    Eleven eremophilanolides, 1-3 and 6-13, and two eremophilanes, 24 and 25, were isolated from Senecio candidans and S. magellanicus from the Magallanes Region (Chile). Compounds 2, 3, 9, and 10 have not been previously reported as natural products. Their structures were established by NMR spectroscopic analysis and chemical transformations. The X-ray analysis of compounds 11, 13, and 17 were also performed. Different semisynthetic analogs from eremophilanolide 11 were generated to carry out a structure-activity relationship study. Their possible plant defensive role was tested against herbivorous insects (Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae) and plants (Lactuca sativa). Additionally, their effects on insect (Sf9) and mammalian (CHO) cell lines were tested. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

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

    PubMed

    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.

  11. Partial least squares modeling and genetic algorithm optimization in quantitative structure-activity relationships.

    PubMed

    Hasegawa, K; Funatsu, K

    2000-01-01

    Quantitative structure-activity relationship (QSAR) studies based on chemometric techniques are reviewed. Partial least squares (PLS) is introduced as a novel robust method to replace classical methods such as multiple linear regression (MLR). Advantages of PLS compared to MLR are illustrated with typical applications. Genetic algorithm (GA) is a novel optimization technique which can be used as a search engine in variable selection. A novel hybrid approach comprising GA and PLS for variable selection developed in our group (GAPLS) is described. The more advanced method for comparative molecular field analysis (CoMFA) modeling called GA-based region selection (GARGS) is described as well. Applications of GAPLS and GARGS to QSAR and 3D-QSAR problems are shown with some representative examples. GA can be hybridized with nonlinear modeling methods such as artificial neural networks (ANN) for providing useful tools in chemometric and QSAR.

  12. Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors

    PubMed Central

    Cuny, Gregory D.; Yu, Paul B.; Laha, Joydev K.; Xing, Xuechao; Liu, Ji-Feng; Lai, Carol S.; Deng, Donna Y.; Sachidanandan, Chetana; Bloch, Kenneth D.; Peterson, Randall T.

    2008-01-01

    A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g. plasma t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition. PMID:18621530

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

    PubMed

    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.

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

    PubMed

    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 (IC50: 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties.

    PubMed

    Rosa, Mònica; Arsequell, Gemma; Rougeot, Catherine; Calle, Luis P; Marcelo, Filipa; Pinto, Marta; Centeno, Nuria B; Jiménez-Barbero, Jesús; Valencia, Gregorio

    2012-02-09

    Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe(3)-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe(3) derivatives showed that replacing l-Phe(3) for d-Phe(3) increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH-π stacking interactions between the aromatic ring of d-Phe(3) and the Hγ protons of Arg(2). This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues.

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

    PubMed

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

    2017-02-07

    The toxicity data of 90 nitroaromatic compounds related to their 50% lethal dose concentration for rats (LD50) were analyzed to develop quantitative structure-activity relationship (QSAR) models. Quantum-chemically calculated descriptors together with molecular descriptors generated by DRAGON, PaDEL, and HiT-QSAR software were utilized to build QSAR models. Quality and validity of the models were determined by internal and external validation techniques. The results show that the toxicity of nitroaromatic compounds depends on various factors, such as the number of nitro-groups, the topological state, and the presence of certain structural fragments. The developed models based on the largest (to date) dataset of nitroaromatics in vivo toxicity showed a good predictive ability. The results provide important input that could be applied in a preliminary assessment of nitroaromatic compounds' toxicity to mammals. Environ Toxicol Chem 2017;9999:1-7. © 2017 SETAC.

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

    SciTech Connect

    Verhaar, H.J.M.; Seinen, W.; Hermens, J.L.M.; Rorije, E.; Borkent, H.

    1996-06-01

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

  18. Synthesis, Fungicidal Activity, and Structure Activity Relationship of β-Acylaminocycloalkylsulfonamides against Botrytis cinerea

    PubMed Central

    Liu, Chun-Hui; Chen, Xiao-Yuan; Qin, Pei-Wen; Qi, Zhi-Qiu; Ji, Ming-Shan; Liu, Xing-Yu; Babu, P. Vijaya; Li, Xing-Hai; Cui, Zi-Ning

    2017-01-01

    In order to discover new antifungal agrochemicals that could have highly active and novel motifs, thirty-six new 2-acylaminocycloalkylsulfonamides (IV) were synthesized. Their structures were characterized and confirmed by 1H NMR, 13C NMR, IR, MS, elemental analysis and X-ray single crystal diffraction. In vitro and in vivo activities against various Botrytis cinerea strains were evaluated. Bioassay results revealed that most of the title compounds exhibited excellent in vitro fungicidal activity, in which compound IV-26 showed the highest activity against sensitive, low-resistant, moderate-resistant and high-resistant strains of B. cinerea compared with the positive fungicide procymidone. Meanwhile in vivo fungicidal activity of compound IV-31 was better than the commercial fungicides procymidone and chesulfamide in greenhouse trial. The structure activity relationship (SAR) was also discussed and the results were of importance to the structural optimization and development of more potent sulfonamides antifungal agents. PMID:28176837

  19. Olfactory sensitivity and odor structure-activity relationships for aliphatic ketones in CD-1 mice.

    PubMed

    Laska, Matthias

    2014-06-01

    Using a conditioning paradigm, the olfactory sensitivity of CD-1 mice for a homologous series of aliphatic 2-ketones (2-butanone to 2-nonanone) and several of their isomeric forms was investigated. With all 11 odorants, the animals significantly discriminated concentrations as low as 0.01 ppm (parts per million) from the solvent, and with two odorants (2-octanone and 5-nonanone), the best-scoring animals even detected concentrations as low as 3 ppt (parts per trillion). Analysis of odor structure-activity relationships showed that the correlation between olfactory detection thresholds of the mice for the 2-ketones and carbon chain length can best be described as a U-shaped function with the lowest threshold values at 2-octanone. Similarly, the correlation between olfactory sensitivity and carbon chain length of symmetrical ketones (3-pentanone to 6-undecanone) can best be described as a U-shaped function. In contrast, no significant correlation was found between olfactory detection thresholds of the mice and position of the functional carbonyl group attached to a C7 backbone. A comparison between the olfactory detection thresholds obtained here with those obtained in earlier studies suggests that mice are significantly more sensitive for 2-ketones than for n-carboxylic acids of the same carbon chain length. Across-species comparisons suggest that mice are significantly more sensitive for aliphatic ketones than squirrel monkeys and pigtail macaques, whereas the ranges of human olfactory detection threshold values overlap with those of the mice with seven of the 11 ketones tested. Further comparisons suggest that odor structure-activity relationships are both substance class and species specific. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Structure-activity relationship (SAR) analysis of a family of steroids acutely controlling steroidogenesis.

    PubMed

    Midzak, Andrew; Rammouz, Georges; Papadopoulos, Vassilios

    2012-11-01

    Steroids metabolically derive from lipid cholesterol, and vertebrate steroids additionally derive from the steroid pregnenolone. Pregnenolone is derived from cholesterol by hydrolytic cleavage of the aliphatic tail by mitochondrial cytochrome P450 enzyme CYP11A1, located in the inner mitochondrial membrane. Delivery of cholesterol to CYP11A1 comprises the principal control step of steroidogenesis, and requires a series of proteins spanning the mitochondrial double membranes. A critical member of this cholesterol translocation machinery is the integral outer mitochondrial membrane translocator protein (18kDa, TSPO), a high-affinity drug- and cholesterol-binding protein. The cholesterol-binding site of TSPO consists of a phylogenetically conserved cholesterol recognition/interaction amino acid consensus (CRAC). Previous studies from our group identified 5-androsten-3β,17,19-triol (19-Atriol) as drug ligand for the TSPO CRAC motif inhibiting cholesterol binding to CRAC domain and steroidogenesis. To further understand 19-Atriol's mechanism of action as well as the molecular recognition by the TSPO CRAC motif, we undertook structure-activity relationship (SAR) analysis of the 19-Atriol molecule with a variety of substituted steroids oxygenated at positions around the steroid backbone. We found that in addition to steroids hydroxylated at carbon C19, hydroxylations at C4, C7, and C11 contributed to inhibition of cAMP-mediated steroidogenesis in a minimal steroidogenic cell model. However, only substituted steroids with C19 hydroxylations exhibited specificity to TSPO, its CRAC motif, and mitochondrial cholesterol transport, as the C4, C7, and C11 hydroxylated steroids inhibited the metabolic transformation of cholesterol by CYP11A1. We thus provide new insights into structure-activity relationships of steroids inhibiting mitochondrial cholesterol transport and steroidogenic cholesterol metabolic enzymes.

  1. Quantitative structure-activity relationship correlation between molecular structure and the Rayleigh enantiomeric enrichment factor.

    PubMed

    Jammer, S; Rizkov, D; Gelman, F; Lev, O

    2015-08-01

    It was recently demonstrated that under environmentally relevant conditions the Rayleigh equation is valid to describe the enantiomeric enrichment - conversion relationship, yielding a proportional constant called the enantiomeric enrichment factor, εER. In the present study we demonstrate a quantitative structure-activity relationship model (QSAR) that describes well the dependence of εER on molecular structure. The enantiomeric enrichment factor can be predicted by the linear Hansch model, which correlates biological activity with physicochemical properties. Enantioselective hydrolysis of sixteen derivatives of 2-(phenoxy)propionate (PPMs) have been analyzed during enzymatic degradation by lipases from Pseudomonas fluorescens (PFL), Pseudomonas cepacia (PCL), and Candida rugosa (CRL). In all cases the QSAR relationships were significant with R(2) values of 0.90-0.93, and showed high predictive abilities with internal and external validations providing QLOO(2) values of 0.85-0.87 and QExt(2) values of 0.8-0.91. Moreover, it is demonstrated that this model enables differentiation between enzymes with different binding site shapes. The enantioselectivity of PFL and PCL was dictated by electronic properties, whereas the enantioselectivity of CRL was determined by lipophilicity and steric factors. The predictive ability of the QSAR model demonstrated in the present study may serve as a helpful tool in environmental studies, assisting in source tracking of unstudied chiral compounds belonging to a well-studied homologous series.

  2. Toxicity and quantitative structure-activity relationships of nitriles based on Pseudokirchneriella subcapitata.

    PubMed

    Huang, Chun-Pin; Wang, Yun-Ju; Chen, Chung-Yuan

    2007-07-01

    This study presents the toxicity data of various nitriles to Pseudokirchneriella subcapitata using a closed algal toxicity testing technique with no headspace. Two different response endpoints, i.e., dissolved oxygen (DO) production and algal growth rate, were used to evaluate the toxicity of nitriles. In general, the DO endpoint revealed higher inhibitory effects than that from algal growth rate. Furthermore, halogen-substituted nitriles were found to be extremely toxic to P. subcapitata. With increasing numbers of the halogen atoms, stronger toxicity was observed. The bromine substitutent also seems to be more toxic than chlorine substitutent. Quantitative structure-activity relationships (QSARs) were established based on the chemicals' Elumo values and hydrophobicity (logK(ow)). Such relationships may thus be useful in predicting the toxicity of other compounds of the same mode of toxic action. Furthermore, for various aquatic organisms, the relative sensitivity relationship is: Pimephales promelas > or = P. subcapitata> Tetrahymena Pyriformis>Daphnia magna>luminescent bacteria (Microtox). The alga, P. subcapitata, was found to be quite sensitive to nitriles compared to other organisms.

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

    PubMed

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

    2014-08-01

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

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

    SciTech Connect

    Schueuermann, G.; Somashekar, R.K.; Kristen, U.

    1996-10-01

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

  5. Structure-activity relationship between carboxylic acids and T cell cycle blockade.

    PubMed

    Gilbert, Kathleen M; DeLoose, Annick; Valentine, Jimmie L; Fifer, E Kim

    2006-04-04

    This study was designed to examine the potential structure-activity relationship between carboxylic acids, histone acetylation and T cell cycle blockade. Toward this goal a series of structural homologues of the short-chain carboxylic acid n-butyrate were studied for their ability to block the IL-2-stimulated proliferation of cloned CD4+ T cells. The carboxylic acids were also tested for their ability to inhibit histone deacetylation. In addition, Western blotting was used to examine the relative capacity of the carboxlic acids to upregulate the cyclin kinase-dependent inhibitor p21cip1 in T cells. As shown earlier n-butyrate effectively inhibited histone deacetylation. The increased acetylation induced by n-butyrate was associated with the upregulation of the cyclin-dependent kinase inhibitor p21cip1 and the cell cycle blockade of CD4+ T cells. Of the other carboxylic acids studied, the short chain acids, C3-C5, without branching were the best inhibitors of histone deacetylase. This inhibition correlated with increased expression of the cell cycle blocker p21cip1, and the associated suppression of CD4+ T cell proliferation. The branched-chain carboxylic acids tested were ineffective in all the assays. These results underline the relationship between the ability of a carboxylic acid to inhibit histone deacetylation, and their ability to block T cell proliferation, and suggests that branching inhibits these effects.

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

    PubMed

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

    2013-11-08

    The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure-toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure-toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure-activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  7. Development and validation of quantitative structure-activity relationship models for compounds acting on serotoninergic receptors.

    PubMed

    Zydek, Grażyna; Brzezińska, Elżbieta

    2012-01-01

    A quantitative structure-activity relationship (QSAR) study has been made on 20 compounds with serotonin (5-HT) receptor affinity. Thin-layer chromatographic (TLC) data and physicochemical parameters were applied in this study. RP2 TLC 60F(254) plates (silanized) impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids) and their mixtures (denoted as S1-S7 biochromatographic models) were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program) and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R(2) = 0.78-0.84) obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. "Leave-one-out" (LOO) and "leave-N-out" (LNO) cross-validation methods were used to judge the predictive power of final regression equations.

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

    PubMed

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

    2013-02-01

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

  9. Synthesis, structure-activity relationships and biological activity of new isatin derivatives as tyrosinase inhibitors.

    PubMed

    Gencer, Nahit; Sonmez, Fatih; Demir, Dudu; Arslan, Oktay; Kucukislamoglu, Mustafa

    2014-01-01

    A newly series of isatin derivatives (6a-t) containing alkyl/aryl urea groups were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. Tyrosinase was purified from banana on an affinity gel comprised of Sepharose 4B-L-tyrosine-p-aminobenzoic acid. The results showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among them, 1-(2,3-dioxoindolin-5-yl)-3-(4-nitrophenyl)urea (6l) was found to be most active compound (Ki = 24.96 µM). The inhibition kinetics was analysed by Lineweaver-Burk double reciprocal plots. It revealed that compound 6l was a competitive inhibitor. According to results of structure-activity relationship, generally, the compounds electron-donating group bonded to the phenyl ring have higher inhibitory activity against tyrosinase than halogen group bonded to the phenyl ring. The inhibitory activities of alkyl urea substituted compounds decreased with increasing carbon number of the alkyl groups at urea moiety. The halogen series at the para position of the phenyl ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. HOMOLUMO energy levels and dipole moments of some selected compounds (6a, 6d, 6h, 6l and 6o) were also calculated by Gaussian software.

  10. Prediction of compounds in different local structure-activity relationship environments using emerging chemical patterns.

    PubMed

    Namasivayam, Vigneshwaran; Gupta-Ostermann, Disha; Balfer, Jenny; Heikamp, Kathrin; Bajorath, Jürgen

    2014-05-27

    Active compounds can participate in different local structure-activity relationship (SAR) environments and introduce different degrees of local SAR discontinuity, depending on their structural and potency relationships in data sets. Such SAR features have thus far mostly been analyzed using descriptive approaches, in particular, on the basis of activity landscape modeling. However, compounds in different local SAR environments have not yet been predicted. Herein, we adapt the emerging chemical patterns (ECP) method, a machine learning approach for compound classification, to systematically predict compounds with different local SAR characteristics. ECP analysis is shown to accurately assign many compounds to different local SAR environments across a variety of activity classes covering the entire range of observed local SARs. Control calculations using random forests and multiclass support vector machines were carried out and a variety of statistical performance measures were applied. In all instances, ECP calculations yielded comparable or better performance than controls. The approach presented herein can be applied to predict compounds that complement local SARs or prioritize compounds with different SAR characteristics.

  11. Structure-activity relationship of dendrimers engineered with twenty common amino acids in gene delivery.

    PubMed

    Wang, Fei; Hu, Ke; Cheng, Yiyun

    2016-01-01

    Systematic explorations on the structure-activity relationship of surface-engineered dendrimers are essential to design high efficient and safe gene vectors. The chemical diversity of residues in naturally occurring amino acids allows us to generate a library of dendrimers with various surface properties. Here, we synthesized a total number of 40 dendrimers engineered with the twenty common amino acids and investigated their performances in gene delivery. The results show that gene transfection efficacy of the synthesized materials depends on both the type of amino acid and the conjugation ratio. Dendrimers engineered with cationic and hydrophobic amino acids possess relatively higher transfection efficacies. Engineering dendrimers with cationic amino acids such as arginine and lysine facilitates polyplex formation and cellular uptake, with histidine improves endosomal escape of the polyplexes, and with hydrophobic amino acids such as tyrosine and phenylalanine modulates the balance between hydrophobicity and hydrophilicity on dendrimer surface, which is beneficial for efficient cellular internalization. Dendrimers engineered with anionic or hydrophilic amino acids show limited transfection efficacy due to poor DNA binding capacity and/or limited cellular uptake. In the aspect of cytotoxicity, dendrimers engineered with arginine, lysine, tyrosine, phenylalanine and tryptophan show much higher cytotoxicity than other engineered dendrimers. These results are helpful for us to tailor the surface chemistry of dendrimers for efficient gene delivery. Cationic polymers such as dendrimers were widely used as gene vectors but are limited by relatively low delivery efficacy and high toxicity. To achieve efficient and low toxic gene delivery, the polymers were modified with various ligands. However, these ligand-modified polymers in gene delivery are reported by independent researchers using different polymer scaffolds and cell lines. It is hard to provide structure

  12. Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid

    PubMed Central

    Costa, Blaise Mathias; Irvine, Mark W.; Fang, Guangyu; Eaves, Richard J.; Mayo-Martin, Maria Belen; Laube, Bodo; Jane, David E.; Monaghan, Daniel T.

    2012-01-01

    Over-activation of N-methyl-D-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes. 2-Naphthoic acid has low activity at GluN2A-containing receptors and yet lower activity at other NMDA receptors. 3-Amino addition, and especially 3-hydroxy addition, to 2-naphthoic acid increased inhibitory activity at GluN1/GluN2C and GluN1/GluN2D receptors. Further halogen and phenyl substitutions to 2-hydroxy-3-naphthoic acid leads to several relatively potent inhibitors, the most potent of which is UBP618 (1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid) with an IC50 ~ 2 μM at each of the NMDA receptor subtypes. While UBP618 is non-selective, elimination of the hydroxyl group in UBP618, as in UBP628 and UBP608, leads to an increase in GluN1/GluN2A selectivity. Of the compounds evaluated, specifically those with a 6-phenyl substitution were less able to fully inhibit GluN1/GluN2A, GluN1/GluN2B and GluN1/GluN2C responses (maximal % inhibition of 60 – 90%). Such antagonists may potentially have reduced adverse effects by not excessively blocking NMDA receptor signaling. Together, these studies reveal discrete structure-activity relationships for the allosteric antagonism of NMDA receptors that may facilitate the development of NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions. PMID:22155206

  13. Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin.

    PubMed

    Schneider, Elena K; Huang, Johnny X; Carbone, Vincenzo; Han, Meiling; Zhu, Yan; Nang, Sue; Khoo, Keith K; Mak, Johnson; Cooper, Matthew A; Li, Jian; Velkov, Tony

    2017-03-10

    Daptomycin is a lipopeptide antibiotic that is highly bound to plasma proteins. To date, the plasma components and structure-activity relationships responsible for the plasma protein binding profile of daptomycin remain uncharacterized. In the present study we have employed a surface plasmon resonance assay together with molecular docking techniques to investigate the plasma protein binding structure-activity relationships related to the N-terminal fatty acyl of daptomycin. Three compounds were investigated: (1) native daptomycin, which displays an N-terminal n-decanoyl fatty acid side chain, and two analogues with modifications to the N-terminal fatty acyl chain; (2) des-acyl daptomycin; and (3) acetyl-daptomycin. The surface plasmon resonance (SPR) data showed that the binding profile of native daptomycin was in the rank order human serum albumin (HSA) ≫ α-1-antitrypsin > low-density lipoprotein ≥ hemoglobin > sex hormone binding globulin > α-1-acid-glycoprotein (AGP) > hemopexin > fibrinogen > α-2-macroglobulin > β2-microglobulin > high-density lipoprotein > fibronectin > haptoglobulin > transferrin > immunoglobulin G. Notably, binding to fatty acid free HSA was greater than binding to nondelipidated HSA. SPR and ultrafiltration studies also indicated that physiological concentrations of calcium increase binding of daptomycin and acetyl-daptomycin to HSA and AGP. A molecular model of the daptomycin-human serum albumin A complex is presented that illustrates the pivotal role of the N-terminal fatty acyl chain of daptomycin for binding to drug site 1 of HSA. In proof-of-concept, the capacity of physiological cocktails of the identified plasma proteins to inhibit the antibacterial activity of daptomycin was assessed with in vitro microbiological assays. We show that HSA, α-1-antitrypsin, low-density lipoprotein, sex hormone binding globulin, α-1-acid-glycoprotein, and hemopexin are responsible for the majority of the sequestering activity in human plasma

  14. Structure-activity relationships of receptor binding of 1,4-dihydropyridine derivatives.

    PubMed

    Takahashi, Daiki; Oyunzul, Luvsandorj; Onoue, Satomi; Ito, Yoshihiko; Uchida, Shinya; Simsek, Rahime; Gunduz, Miyase Gozde; Safak, Chiat; Yamada, Shizuo

    2008-03-01

    The present study was undertaken to investigate binding activity of synthesized 1,4-dihydropyridine (1,4-DHP) derivatives (Compounds 1--124) to 1,4-DHP calcium channel antagonist receptors in rat brain. Sixteen 1,4-DHP derivatives inhibited specific (+)-[3H]PN 200-110 binding in rat brain in a concentration-dependent manner with IC50 value of 0.43 to 3.49 microM. Scatchard analysis revealed that compounds 54, 69, 85, like nifedipine, caused a significant increase in apparent dissociation constant (Kd) for (+)-[3H]PN 200-110, while compounds 68, 69 and 80 caused a significant decrease in maximal number of bindings sites (Bmax). These data suggest that compounds 68, 69 and 80 exert longer-acting antagonistic effects of 1,4-DHP receptors than compounds 54, 69 and 85. The structure-activity relationship study has revealed that 1) ester groups in 3- and 5-positions are the most effective, 2) the aryl group in the 4-position of 1,4-DHP ring is the basic requirement for optimal activity, 3) position and type of electron-withdrawing groups on phenyl group at position 4 would affect the receptor-binding activity. Furthermore, compound 58 exerted alpha1 receptor binding activity, being 1.6 times greater than 1,4-DHP receptors. Compounds 81, 84, 91, 94, 106, 108 and 109 showed significant binding of ATP-sensitive potassium (K ATP) channel, and the binding activities of compounds 81, 84, 108 and 109 were 1.6--3.8 times greater than the binding activity for 1,4-DHP receptors. Compounds 91 and 106 had similar binding activity for K ATP channel and 1,4-DHP receptors. In conclusion, the present study has shown that novel 1,4-DHP derivatives exert relatively high binding affinity to 1,4-DHP receptors and has revealed new aspect of structure-activity relationships of 1,4-DHP derivatives, especially hexahydroquinoline derivatives.

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

    PubMed

    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.

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

    NASA Astrophysics Data System (ADS)

    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.

  17. [Development and study of structure-activity relationship of drugs against Mycobacterium tuberculosis].

    PubMed

    Baska, Ferenc; Székely, Edina Rita; Szántai-Kis, Csaba; Bánhegyi, Péter; Hegymegi-Barakonyi, Bálint; Németh, Gábor; Breza, Nóra; Zsákai, Lilian; Greff, Zoltán; Pató, János; Kéri, György; Orfi, Lászlo

    2013-01-01

    Tuberculosis is considered to be one of the major health problem not only in the less developed countries but in the economically developed countries as well. Roughly one third of the world's population are infected with Mycobacterium tuberculosis and a significant part of them are carriers of latent tuberculosis. From ten percent of these latent infections are developing the active TB disease and fifty percent of them die from the illness without appropriate treatment. The drug-resistant Mycobacterium tuberculosis (MDR-TB, XDR-TB) and TB-HIV co-infection attracted attention to the most serious infectious disease. Inhibition of alternative signaling pathways were an important part of the research strategies for cancer and inflammatory diseases in recent years. In case of Mycobacterium tuberculosis such pathways were also identified, for example, three serine-threonine kinases (PknA, PknB, PknG) which are necessary and essential for bacterial growth. In this paper we summarize our best anti-TB active compounds, their biological effects and structure-activity relationships using in silico modeling, biochemical measurements and tests on active bacteria.

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

    PubMed

    Beck, Jeremy M; Springer, Clayton

    2014-04-28

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

  19. Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

    PubMed Central

    Joshi, Anand A.; Murray, Thomas F.; Aldrich, Jane V.

    2016-01-01

    The dynorphin (Dyn) A analog zyklophin ([N-benzyl-Tyr1-cyclo(D-Asp5,Dap8)]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR) selective antagonist in vitro, is active in vivo and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogs to explore the structure-activity relationships of this peptide. The synthesis of selected analogs required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications the N-phenethyl and the N-cyclopropylmethyl substitutions resulted in the analogs with the highest KOR affinities. Pharmacological results for the alanine-substituted analogs indicated that Phe4 and Arg6, but interestingly not the Tyr1, phenol are important for zyklophin’s KOR affinity, and Arg7 was important for KOR antagonist activity. In the GTPγS assay while all of the cyclic analogs exhibited negligible KOR efficacy, the N-phenethyl-Tyr1, N-CPM-Tyr1 and the N-benzyl-Phe1 analogs were 8- to 24-fold more potent KOR antagonists than zyklophin. PMID:26491810

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    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.

  2. Quantitative structure-activity relationship analysis of β-amyloid aggregation inhibitors

    NASA Astrophysics Data System (ADS)

    Stempler, Shiri; Levy-Sakin, Michal; Frydman-Marom, Anat; Amir, Yaniv; Scherzer-Attali, Roni; Buzhansky, Ludmila; Gazit, Ehud; Senderowitz, Hanoch

    2011-02-01

    Inhibiting the aggregation process of the β-amyloid peptide is a promising strategy in treating Alzheimer's disease. In this work, we have collected a dataset of 80 small molecules with known inhibition levels and utilized them to develop two comprehensive quantitative structure-activity relationship models: a Bayesian model and a decision tree model. These models have exhibited high predictive accuracy: 87% of the training and test sets using the Bayesian model and 89 and 93% of the training and test sets, respectively, by the decision tree model. Subsequently these models were used to predict the activities of several new potential β-amyloid aggregation inhibitors and these predictions were indeed validated by in vitro experiments. Key chemical features correlated with the inhibition ability were identified. These include the electro-topological state of carbonyl groups, AlogP and the number of hydrogen bond donor groups. The results demonstrate the feasibility of the developed models as tools for rapid screening, which could help in the design of novel potential drug candidates for Alzheimer's disease.

  3. Anti-proliferative activities of terpenoids isolated from Alisma orientalis and their structure-activity relationships.

    PubMed

    Xu, Wen; Li, Ting; Qiu, Jian-Fang; Wu, Shui-Sheng; Huang, Ming-Qing; Lin, Li-Gen; Zhang, Qing-Wen; Chen, Xiu-Ping; Lu, Jin-Jian

    2015-01-01

    This study aimed to isolate terpenoids from Alisma orientalis (Sam.) Juzep. and elucidate their antiproliferative activities, as well as structure-activity relationships. Fourteen protostane-type triterpenoids were isolated from the rhizome of A. orientalis. Among these triterpenoids, alisol A (1), alisol A 24-acetate (2), alisol B (3), alisol B 23-acetate (4), and alisol G (8) presented inhibitory effects on cancer cell lines tested. Compounds 3 and 4 showed the highest potential; IC50 values for HepG2, MDA-MB-231, and MCF-7 cells were 16.28, 14.47, and 6.66 μM for 3 and 18.01, 15.97, and 13.56 μM for 4, respectively. Based on these results, we concluded that the degree of C-16 oxidation and the double bond between C-13 and C-17 may be significant in anti-proliferative activities. Further study showed that 3 and 4 effectively induced apoptosis, as confirmed by flow cytometry. Increased intracellular calcium concentration and endoplasmic reticulum stress were detected after treatment with 4 in HepG2 cells. Although compounds 1 and 2 induced minimal apoptosis, they evidently delayed the G2/M phase in HepG2 cells. Further study showed that 1-4 also enhanced LC3II expression, indicating autophagy is occured.

  4. Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka B.; Spiteller, Michael

    2012-09-01

    A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

  5. Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri

    SciTech Connect

    Schultz, T.W.; Cronin, M.T.D.

    1997-02-01

    Acute toxicity values of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity versus hydrophobicity, measured as the 1-octanol/water partition coefficient (log K{sub ow}), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log pT{sub 30}{sup {minus}1} = 0.489(log K{sub ow}) + 0.126 was found to be a highly predictive model. This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

  6. Biomimetic deiodination of thyroid hormones and iodothyronamines - a structure-activity relationship study.

    PubMed

    Mondal, Santanu; Mugesh, Govindasamy

    2016-10-12

    Mammalian selenoenzymes, iodothyronine deiodinases (DIOs), catalyze the tyrosyl and phenolic ring deiodination of thyroid hormones (THs) and play an important role in maintaining the TH concentration throughout the body. These enzymes also accept the decarboxylated thyroid hormone metabolites, iodothyronamines (TAMs), as substrates for deiodination. Naphthalene-based selenium and/or sulphur-containing small molecules have been shown to mediate the regioselective tyrosyl ring deiodination of thyroid hormones and their metabolites. Herein, we report on the structure-activity relationship studies of a series of peri-substituted selenium-containing naphthalene derivatives for the deiodination of thyroid hormones and iodothyronamines. Single crystal X-ray crystallographic and (77)Se NMR spectroscopic studies indicated that the intramolecular SeX (X = N, O and S) interactions play an important role in the deiodinase activity of the synthetic mimics. Furthermore, the decarboxylated metabolites, TAMs, have been observed to undergo slower tyrosyl ring deiodination than THs by naphthyl-based selenium and/or sulphur-containing synthetic deiodinase mimics and this has been explained on the basis of the strength of SeI halogen bonding formed by THs and TAMs.

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

    PubMed

    Ambure, Pravin; Roy, Kunal

    2014-06-01

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

  8. Structure-activity relationship of the pro- and anticoagulant effects of Fucus vesiculosus fucoidan.

    PubMed

    Zhang, Z; Till, S; Jiang, C; Knappe, S; Reutterer, S; Scheiflinger, F; Szabo, C M; Dockal, M

    2014-03-03

    Fucoidan is a highly complex sulfated polysaccharide commonly extracted from brown seaweed. In addition to their many biological activities, fucoidans have recently been demonstrated to inhibit or increase coagulation at different concentration ranges. Their structural features, i.e. molecular weight (Mw), Mw distribution, degree of sulfation, monosaccharide composition, and different linkages, are known to affect these activities. Therefore, structure-activity relationship (SAR) analysis of fucoidan is crucial for its potential use as a procoagulant. In this study, Fucus vesiculosus (F.v.) fucoidan was fractionated by charge and size as well as over- and desulfated to different degrees to yield preparations with various structural properties. The fractions' pro- and anticoagulant activities were assessed by calibrated automated thrombography (CAT) and activated partial thromboplastin time(aPTT) assays. Binding to and inhibition of the anticoagulant protein tissue factor pathway inhibitor (TFPI) and the ability to activate coagulation via the contact pathway were also investigated. This paper discusses the impact of charge density, size, and sugar composition on fucoidan's pro- and anticoagulant activities. Fucoidan requires a minimal charge density of 0.5 sulfates per sugar unit and a size of 70 sugar units to demonstrate desired procoagulant activities for improvement of haemostasis in factor VIII/factor IX-deficient plasma.

  9. Structure-activity relationship study of spider polyamine toxins as inhibitors of ionotropic glutamate receptors.

    PubMed

    Xiong, Xiao-Feng; Poulsen, Mette H; Hussein, Rama A; Nørager, Niels G; Strømgaard, Kristian

    2014-12-01

    The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.

  10. Application of quantitative structure activity relationship (QSAR) models to predict ozone toxicity in the lung.

    PubMed

    Kafoury, Ramzi M; Huang, Ming-Ju

    2005-08-01

    The sequence of events leading to ozone-induced airway inflammation is not well known. To elucidate the molecular and cellular events underlying ozone toxicity in the lung, we hypothesized that lipid ozonation products (LOPs) generated by the reaction of ozone with unsaturated fatty acids in the epithelial lining fluid and cell membranes play a key role in mediating ozone-induced airway inflammation. To test our hypothesis, we ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and generated LOPs. Confluent human bronchial epithelial cells were exposed to the derivatives of ozonized POPC-9-oxononanoyl, 9-hydroxy-9-hydroperoxynonanoyl, and 8-(5-octyl-1,2,4-trioxolan-3-yl-)octanoyl-at a concentration of 10 muM, and the activity of phospholipases A2 (PLA2), C (PLC), and D (PLD) was measured (1, 0.5, and 1 h, respectively). Quantitative structure-activity relationship (QSAR) models were utilized to predict the biological activity of LOPs in airway epithelial cells. The QSAR results showed a strong correlation between experimental and computed activity (r = 0.97, 0.98, 0.99, for PLA2, PLC, and PLD, respectively). The results indicate that QSAR models can be utilized to predict the biological activity of the various ozone-derived LOP species in the lung.

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

    SciTech Connect

    Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. )

    1991-12-01

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

  12. Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors

    NASA Astrophysics Data System (ADS)

    Xiong, Xiao-Feng; Zhang, Hang; Underwood, Christina R.; Harpsøe, Kasper; Gardella, Thomas J.; Wöldike, Mie F.; Mannstadt, Michael; Gloriam, David E.; Bräuner-Osborne, Hans; Strømgaard, Kristian

    2016-11-01

    G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure-activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.

  13. Quantitative structure-activity relationship models for prediction of the toxicity of polybrominated diphenyl ether congeners.

    PubMed

    Wang, Yawei; Liu, Huanxiang; Zhao, Chunyan; Liu, Hanxia; Cai, Zongwei; Jiang, Guibin

    2005-07-01

    Levels of polybrominated diphenyl ethers (PBDEs) are increasing in the environment and may cause long-term health problems in humans. The similarity in the chemical structures of PBDEs and other halogenated aromatic pollutants hints on the possibility that they might share similar toxicological effects. In this work, three-dimensional quantitative structure activity relationships (3-D-QSAR) models, using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), were built based on calculated structural indices and a reported experimental toxicology index (aryl hydrocarbon receptor relative binding affinities, RBA) of 18 PBDEs congeners, to determine the factors required for the RBA of these PBDEs. After performing leave-one-out cross-validation, satisfactory results were obtained with cross-validation O2 and R2 values of 0.580 and 0.995 by the CoMFA model and 0.680 and 0.982 by the CoMSIA model, respectively. The results showed clearly that the nonplanar conformations of PBDEs result in the lowest energy level and that the electrostatic index was the main factor reflecting the RBA of PBDEs. The two QSAR models were then used to predict the RBA value of 46 PBDEs for which experimental values are unavailable at present.

  14. Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.

    PubMed

    Schiedel, Matthias; Rumpf, Tobias; Karaman, Berin; Lehotzky, Attila; Oláh, Judit; Gerhardt, Stefan; Ovádi, Judit; Sippl, Wolfgang; Einsle, Oliver; Jung, Manfred

    2016-02-25

    Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.

  15. Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies.

    PubMed

    Migliore, Marco; Habrant, Damien; Sasso, Oscar; Albani, Clara; Bertozzi, Sine Mandrup; Armirotti, Andrea; Piomelli, Daniele; Scarpelli, Rita

    2016-02-15

    Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Quantitative structure-activity relationships for the toxicity of chlorophenols to mammalian submitochondrial particles.

    PubMed

    Argese, E; Bettiol, C; Giurin, G; Miana, P

    1999-04-01

    The toxicity of a series of chlorophenols, determined by a short-term in vitro assay utilizing mammalian submitochondrial particles, was related to the physicochemical and structural properties of these compounds. Quantitative Structure-Activity Relationships were defined by correlating EC50 values with six molecular descriptors, chosen to represent lipophilic, electronic and steric effects: the n-octanol/water partition coefficient (log Kow), the constant of Hammett (sigma sigma), the acid dissociation constant (pKa), the first order valence molecular connectivity index (1 chi v), the perimeter of the efficacious section (sigma D) and the melting point (m.p.). The results of regression analysis showed that log Kow is the most successful descriptor, indicating that the ability of chlorophenols to partition into the lipid bilayer of the mitochondrial membrane has an important role in determining their toxic effects. These results are consistent with a molecular mechanism of uncoupling action based on the chemiosmotic theory and on the protonophoric properties of chlorophenols. The quality of the QSAR models confirms the suitability of the SMP assay as a short-term prediction tool for aquatic toxicity of environmental pollutants acting on respiratory functions.

  17. Antimalarial activity of molecules interfering with Plasmodium falciparum phospholipid metabolism. Structure-activity relationship analysis.

    PubMed

    Calas, M; Cordina, G; Bompart, J; Ben Bari, M; Jei, T; Ancelin, M L; Vial, H

    1997-10-24

    A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.

  18. Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

    PubMed

    Jadhavar, Pradeep S; Dhameliya, Tejas M; Vaja, Maulikkumar D; Kumar, Dinesh; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan; Chakraborti, Asit K

    2016-06-01

    2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25μg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78μg/mL and were found to be non-toxic (<50% inhibition at 50μg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40μg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs).

  19. Structure-activity relationships for antibacterial to antifungal conversion of kanamycin to amphiphilic analogues.

    PubMed

    Fosso, Marina; AlFindee, Madher N; Zhang, Qian; Nziko, Vincent de Paul Nzuwah; Kawasaki, Yukie; Shrestha, Sanjib K; Bearss, Jeremiah; Gregory, Rylee; Takemoto, Jon Y; Chang, Cheng-Wei Tom

    2015-05-01

    Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4″ position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3″-NH2 group of kanamycin B was synthesized. FG03's antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4″ position is the optimal site for attaching a linear alkyl chain and that the 3″-NH2 and 6″-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials.

  20. An ecotoxicological study of poly(amidoamine) dendrimers-toward quantitative structure activity relationships.

    PubMed

    Naha, Pratap C; Davoren, Maria; Casey, Alan; Byrne, Hugh J

    2009-09-01

    Polyamidoamine (PAMAM) dendrimers of generation 6-4, G-5 and G-6 were evaluated for their aquatic toxicity using the test models Vibrio fischeri, Daphnia magna, Thamnocephalus platyurus, and two fish cell lines. Physico-chemical characterization of the particles in each of the different test media was performed. A significant eco- and cytotoxicological response was recorded at concentrations from 0.129 microM (7.4 mg L(-1)) to 16.30 microM (231.5 mg L(-1)). Daphnia magna was found to be the most sensitive test model, the RTG-2 fish cell line the least. The toxicological response correlated well with the dendrimer generation and therefore with the particle surface area, increasing surface area leading to increased toxic response. The response also correlated well with changes to the 4 potential in the different media, rather than the actual 4 potential, indicating a potential contribution of changes to the effective composition of the medium. For the cell lines, although spectroscopic studies indicated an interaction with the serum supplement, trends for this interaction do not correlate to those observed for the toxic response. The clear correlations of the observed toxicresponse with themeasured physicochemical properties pointtoward underlying structure activity relationships.

  1. In vitro mammalian cytotoxicological study of PAMAM dendrimers - towards quantitative structure activity relationships.

    PubMed

    Mukherjee, Sourav Prasanna; Davoren, Maria; Byrne, Hugh J

    2010-02-01

    Dendritic polymer nanoparticles such as polyamidoamine dendrimers (PAMAM) show exciting potential for biomedical applications. While the potential commercial applications of such dendrimers have received considerable attention, little is known about their possible adverse effects on both humans and the environment. In this study, the in vitro cytotoxicocity of full generation PAMAM dendrimers to two mammalian cell lines was investigated. Generations G4, G5 and G6 were chosen. Metabolic, lysosomal and mitochondrial activities were evaluated after 24h exposure. Long term toxicity was evaluated using the clonogenic assay. Particle size and zeta potential were measured in all media. In culture medium, the particle size was largely unchanged from that observed in phosphate buffer. The zeta potential changed significantly, however, from positive in deionized water to negative in culture medium. A linear correlation was found between the change in zeta potential of the dendrimers in media and their surface area measured in phosphate buffer. The interaction of the dendrimer nanoparticles with 5% FBS supplemented media was also studied using UV/visible spectroscopy. The data suggest significant interaction of nanoparticles with FBS and other media components which increased with dendrimer generation. The toxicity also correlated linearly with the zeta potential and notably the change in zeta potential in the media, further pointing towards indirect toxic mechanisms. A trend of generation dependent toxic response and interaction of the dendrimers with the cell culture media was observed which may lay the basis of structure activity relationships.

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

    PubMed

    Harper, Jacquie L; Khalil, Iman M; Shaw, Lisa; Bourguet-Kondracki, Marie-Lise; Dubois, Joëlle; Valentin, Alexis; Barker, David; Copp, Brent R

    2015-08-10

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

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

    PubMed

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

    2016-07-25

    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.

  4. Quantitative structure-activity relationships of imidazole-containing farnesyltransferase inhibitors using different chemometric methods.

    PubMed

    Shayanfar, Ali; Ghasemi, Saeed; Soltani, Somaieh; Asadpour-Zeynali, Karim; Doerksen, Robert J; Jouyban, Abolghasem

    2013-05-01

    Farnesyltranseferase inhibitors (FTIs) are one of the most promising classes of anticancer agents, but though some compounds in this category are in clinical trials there are no marketed drugs in this class yet. Quantitative structure activity relationship (QSAR) models can be used for predicting the activity of FTI candidates in early stages of drug discovery. In this study 192 imidazole-containing FTIs were obtained from the literature, structures of the molecules were optimized using Hyperchem software, and molecular descriptors were calculated using Dragon software. The most suitable descriptors were selected using genetic algorithms-partial least squares (GA-PLS) and stepwise regression, and indicated that the volume, shape and polarity of the FTIs are important for their activities. 2D-QSAR models were prepared using both linear methods, i.e., multiple linear regression (MLR), and non-linear methods, i.e., artificial neural networks (ANN) and support vector machines (SVM). The proposed QSAR models were validated using internal and external validation methods. The results show that the proposed 2D-QSAR models are valid and that they can be applied to predict the activities of imidazole-containing FTIs. The prediction capability of the 2D-QSAR (linear and non-linear) models is comparable to and somewhat better than that of previous 3D-QSAR models and the non-linear models are more accurate than the linear models.

  5. Structure- and ligand-based structure-activity relationships for a series of inhibitors of aldolase.

    PubMed

    Ferreira, Leonardo G; Andricopulo, Adriano D

    2012-12-01

    Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment-based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r²=0.98 and q²=0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pKi values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class.

  6. Quantitative structure-activity relationship of organophosphate compounds based on molecular interaction fields descriptors.

    PubMed

    Zhao, Jinsong; Yu, Shuxia

    2013-03-01

    By using multi-block partial least-squares (MBPLS) method, quantitative structure-activity relationship (QSAR) between 35 organophosphate compounds (OP) and their 24h acute toxicities towards the housefly (Musca nebulo L.) was built on the molecular interaction fields (MIF) descriptors, which were obtained with O, N and DRY as probes, and then normalised with block unscaled weights (BUW) technique. The best QSAR model had 8 principal components, with the coefficient of determination R(2)=0.995 and that of leave-one-out cross-validation Q(2)=0.865, and the corresponding standard deviation of error 0.076 and 0.361, respectively. Block importance in the prediction (BIP) for O, N and DRY probe were 1.030, 0.962 and 1.007, respectively. Contour map of variable coefficients showed that hydrogen bonding between the O atom in PO and the NH groups in acetylcholinesterase (AChE) played an important role in the interaction between OP and AChE. Meanwhile, the hydrophobicity of OP also had significant contribution. QSAR based on the MIF descriptors could be a potential means to interpret the mechanisms of ligand-receptor interaction when the receptor was well known.

  7. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    PubMed

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  8. Antagonists at metabotropic glutamate receptor subtype 5: structure activity relationships and therapeutic potential for addiction.

    PubMed

    Carroll, F Ivy

    2008-10-01

    As a result of intensive investigation, particularly in the pharmaceutical industry, a number of potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists have been discovered. The structure activity relationship studies that led to the discovery of these mGluR5 antagonists are presented in this review. Results from studies on selected mGluR5 antagonists in animal models that simulate drug reward, reinforcement, and relapse appear promising. The comorbidity between drug abuse and anxiety and depression make drugs active in these disorders of great interest. Clinical studies showed that the mGluR5 antagonist fenobam was an active anxiolytic drug. Several new mGluR5 antagonists produced anxiolytic and antidepressant-like effects in animal models of these disorders. The results from the clinical and animal studies provide information for new approaches to finding mechanistically distinct pharmacotherapies to help patients achieve and maintain abstinence from cocaine, methamphetamine, opiates, ethanol, and nicotine (smoking).

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

    PubMed

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

    2017-02-01

    Here we report the synthesis of eleven new BODIPYs (14-24) characterized by the presence of an aromatic ring on the 8 (meso) position and of iodine atoms on the pyrrolic 2,6 positions. These molecules, together with twelve BODIPYs already reported by us (1-12), represent a large panel of BODIPYs showing different atoms or groups as substituent of the aromatic moiety. Two physico-chemical features ((1)O2 generation rate and lipophilicity), which can play a fundamental role in the outcome as photosensitizers, have been studied. The in vitro photo-induced cell-killing efficacy of 23 PSs was studied on the SKOV3 cell line treating the cells for 24h in the dark then irradiating for 2h with a green LED device (fluence 25.2J/cm(2)). The cell-killing efficacy was assessed with the MTT test and compared with that one of meso un-substituted compound (13). In order to understand the possible effect of the substituents, a predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, was developed. The results clearly indicate that the presence of an aromatic ring is fundamental for an excellent photodynamic response, whereas the electronic effects and the position of the substituents on the aromatic ring do not influence the photodynamic efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    PubMed

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

    2010-09-01

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

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

    PubMed

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

    2015-01-01

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

  12. Quantum mechanical quantitative structure activity relationships to avoid mutagenicity in dental monomers.

    PubMed

    Yourtee, D; Holder, A J; Smith, R; Morrill, J A; Kostoryz, E; Brockmann, W; Glaros, A; Chappelow, C; Eick, D

    2001-01-01

    The objective of this study was to identify through quantum mechanical quantitative structure activity relationships (Q-QSARs) chemical structures in dental monomers that influence their mutagenicity. AMPAC, a semiempirical computer program that provides quantum mechanical information for chemical structures, was applied to three series of reference chemicals: a set of methacrylates, a set of aromatic and a set of aliphatic epoxy compounds. QSAR models were developed using this chemical information together with mutagenicity data (Salmonella TA 100, Ames Test). CODESSA, a QSAR program that calculates quantum chemical descriptors from information generated by AMPAC and statistically matches these descriptors with observed biological properties was used. QSARs were developed which had r2 values exceeding 0.90 for each study series. These QSARs were used to accurately predict the mutagenicity of BISGMA. a monomer commonly used in dentistry, and two epoxy monomers with developing use in dentistry, GY-281 and UVR-6105. The Q-QSAR quantum mechanical descriptors correctly predicted the level of mutagenicity for all three compounds. The descriptors in the correlation equation pointed to components of structure that may contribute to mutagenesis. The QSARs also provided 'dose windows' for testing mutagenicity, circumventing the need for extensive dose exploration in the laboratory. The Q-QSAR method promises an approach for biomaterials scientists to predict and avoid mutagenicity from the chemicals used in new biomaterial designs.

  13. Applications of Systematic Molecular Scaffold Enumeration to Enrich Structure-Activity Relationship Information.

    PubMed

    Mok, N Yi; Brown, Nathan

    2017-01-23

    Establishing structure-activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion. We describe the development of EnCore, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that EnCore could mimic the scaffold exploration conducted when establishing SAR. When EnCore was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. These results illustrate the potential of EnCore to enrich SAR information. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. EnCore complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping.

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

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  15. Automated Structure-Activity Relationship Mining: Connecting Chemical Structure to Biological Profiles.

    PubMed

    Wawer, Mathias J; Jaramillo, David E; Dančík, Vlado; Fass, Daniel M; Haggarty, Stephen J; Shamji, Alykhan F; Wagner, Bridget K; Schreiber, Stuart L; Clemons, Paul A

    2014-06-01

    Understanding the structure-activity relationships (SARs) of small molecules is important for developing probes and novel therapeutic agents in chemical biology and drug discovery. Increasingly, multiplexed small-molecule profiling assays allow simultaneous measurement of many biological response parameters for the same compound (e.g., expression levels for many genes or binding constants against many proteins). Although such methods promise to capture SARs with high granularity, few computational methods are available to support SAR analyses of high-dimensional compound activity profiles. Many of these methods are not generally applicable or reduce the activity space to scalar summary statistics before establishing SARs. In this article, we present a versatile computational method that automatically extracts interpretable SAR rules from high-dimensional profiling data. The rules connect chemical structural features of compounds to patterns in their biological activity profiles. We applied our method to data from novel cell-based gene-expression and imaging assays collected on more than 30,000 small molecules. Based on the rules identified for this data set, we prioritized groups of compounds for further study, including a novel set of putative histone deacetylase inhibitors. © 2014 Society for Laboratory Automation and Screening.

  16. A review on structure-activity relationship of dietary polyphenols inhibiting α-amylase.

    PubMed

    Xiao, Jianbo; Ni, Xiaoling; Kai, Guoyin; Chen, Xiaoqing

    2013-01-01

    The inhibitory effects of dietary polyphenols against α-amylase have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure-activity relationship of polyphenols inhibiting α-amylase. The molecular structures that influence the inhibition are the following: (1) The hydroxylation of flavonoids improved the inhibitory effect on α-amylase; (2) Presence of an unsaturated 2,3-bond in conjugation with a 4-carbonyl group has been associated with stronger inhibition; (3) The glycosylation of flavonoids decreased the inhibitory effect on α-amylase depending on the conjugation site and the class of sugar moiety; (4) The methylation and methoxylation of flavonoids obviously weakened the inhibitory effect; (5) The galloylated catechins have higher inhibition than nongalloylated catechins; the catechol-type catechins were stronger than the pyrogallol-type catechins; the inhibition activities of the catechins with 2,3-trans structure were higher than those of the catechins with 2,3-cis structure; (6) Cyanidin-3-glucoside showed higher inhibition against than cyanidin and cyanidin-3-galactoside and cyanidin-3,5-diglucoside had no inhibitory activity; (7) Ellagitannins with β-galloyl groups at glucose C-1 positions have higher inhibitory effect than the α-galloyl and nongalloyl compounds and the molecular weight of ellagitannins is not an important element.

  17. Improving Quantitative Structure-Activity Relationship Models using Artificial Neural Networks Trained with Dropout

    PubMed Central

    Mendenhall, Jeffrey; Meiler, Jens

    2016-01-01

    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 (LB-CADD) 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 (FPR) 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. PMID:26830599

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

    PubMed

    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.

  19. Quantitative structure activity relationship (QSAR) of competitive N-methyl-D-aspartate (NMDA) antagonists

    NASA Astrophysics Data System (ADS)

    Korkut, Anil; Varnali, Tereza

    Glutamic acid is an excitatory amino acid neurotransmitter in the mammalian central nervous system and the NMDA molecule binds to NMDA-type glutamic acid receptors as a glutamic acid analogue, in vitro. The NMDA-type glutamic acid receptors are known for their function in many neural processes, such as neural plasticity, learning and memory. In addition, excessive NMDA receptor activity has been shown to be related to neurodegenerative diseases like epilepsy so the design of new NMDA antagonists has extra importance as potent drugs for various neural diseases. Potential antagonist molecules are usually synthesized and their activity is measured by experimental techniques. Here, computational chemistry methods are applied to develop a model, which allows one to predict the activity of potent competitive NMDA antagonists. First, various molecular parameters are calculated for a series of competitive NMDA antagonists with known activity values and those parameters are used to make a regression analysis which provides a model that relates the computationally calculated parameters to experimentally determined activity values. By the quantitative structure activity relationship (QSAR) model developed here, it is possible to predict the activity of a potent drug before its synthesis since only theoretically determined molecular parameters are used for the prediction.

  20. Structure-Activity Relationships on Cinnamoyl Derivatives as Inhibitors of p300 Histone Acetyltransferase.

    PubMed

    Madia, Valentina Noemi; Benedetti, Rosaria; Barreca, Maria Letizia; Ngo, Liza; Pescatori, Luca; Messore, Antonella; Pupo, Giovanni; Saccoliti, Francesco; Valente, Sergio; Mai, Antonello; Scipione, Luigi; Zheng, Yujun George; Tintori, Cristina; Botta, Maurizio; Cecchetti, Violetta; Altucci, Lucia; Di Santo, Roberto; Costi, Roberta

    2017-08-22

    Human p300 is a polyhedric transcriptional coactivator that plays a crucial role in acetylating histones on specific lysine residues. A great deal of evidence shows that p300 is involved in several diseases, including leukemia, tumors, and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale to determine how its modulation could represent an amenable drug target. Several p300 inhibitors (i.e., histone acetyltransferase inhibitors, HATis) have been described so far, but they all suffer from low potency, lack of specificity, or low cell permeability, which thus highlights the need to find more effective inhibitors. Our cinnamoyl derivative, 2,6-bis(3-bromo-4-hydroxybenzylidene)cyclohexanone (RC56), was identified as an active and selective p300 inhibitor and was proven to be a good hit candidate to investigate the structure-activity relationship toward p300. Herein, we describe the design, synthesis, and biological evaluation of new HATis structurally related to our hit; moreover, we investigate the interactions between p300 and the best-emerged hits by means of induced-fit docking and molecular-dynamics simulations, which provided insight into the peculiar chemical features that influence their activity toward the targeted enzyme. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. A structure-activity relationship study of platelet-activating factor

    SciTech Connect

    Surles, J.R.

    1987-01-01

    Several analogues of platelet-activating factor (1-0-alkyl-2-0-acetyl-sn-glycero-3-phosphocholine, PAF), an alkylglycerophospholipid that was found to be a mediator in Type I immediate hypersensitivity and also possessed potent hypotensive properties, were synthesized. These PAF analogues were evaluated in a qualitative structure-activity relationship study for their rabbit neutrophil degranulation properties and their antihypertensive properties in rats. Variations were made in each of the moieties attached to the three glycerol backbone carbons. Variation in sn-1-0-alkyl chain length from fourteen to nineteen carbons and introduction of one or two double bonds revealed that the 1-0-hexadecyl species of PAF was the most active analogue in this series in our assay systems. Substitution of various deoxyalkyl groups for the 2-0-acetyl moiety resulted in severely diminished bioactivities and no inhibition of rat plasma acetylhydrolase activity. Substitution of bulky trialkylammonium moieties for the trimethylammonium portion of the phosphocholine moiety resulted in an analogue (triethylammonium, 41) with reduced immediate hypersensitivity properties and 560% relative antihypertensive potency.

  2. Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

    PubMed Central

    Zarghi, Afshin; Arfaei, Sara

    2011-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. PMID:24250402

  3. Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor.

    PubMed

    Kwiatkowska, Anna; Couture, Frédéric; Levesque, Christine; Ly, Kévin; Desjardins, Roxane; Beauchemin, Sophie; Prahl, Adam; Lammek, Bernard; Neugebauer, Witold; Dory, Yves L; Day, Robert

    2014-01-09

    PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.

  4. Computational Structure-activity Relationship Analysis of Small-Molecule Agonists for Human Formyl Peptide Receptors

    PubMed Central

    Khlebnikov, Andrei I.; Schepetkin, Igor A; Quinn, Mark T.

    2010-01-01

    N-formyl peptide receptors (FPR) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists. PMID:20870313

  5. Quantitative structure-activity relationship study using refractotopological state atom index on some neonicotinoid insecticides.

    PubMed

    Debnath, Bikash; Gayen, Shovanlal; Basu, Anindya; Ghosh, Balaram; Srikanth, Kolluru; Jha, Tarun

    2004-12-01

    Importance of atom-level topological descriptors like electrotopological state atom (E-state) index in QSAR study is increasing. These descriptors help to relate structure and activity at atomic/fragmental level. In view of the earlier success of E-state index on some azidopyridinyl neonicotinoid insecticides, a relatively new atom-level topological descriptor; refractotopological state atom (R-state) index was used in this work. This was used to identify the important atoms/fragments related to dispersive/van der Waals interactions of neonicotinoids with the nicotinic acetylcholine receptor (nAChR). This study showed the structural requirements for the mammal alpha(4)beta(2) and Drosophila nAChR agonistic activity. It also revealed that substituted imine, nitromethylene at X-position were selective to the insecticidal activity. Azido substitution at pyridine ring of neonicotinoids disfavored the binding with the receptors. This study confirmed the validity of the R-state index as a new tool for quantitative structure-activity relationships. It has the ability to find out the required structural features as well as to predict the activity of the neonicotinoids.

  6. The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents

    PubMed Central

    Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2011-01-01

    The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes. PMID:21840723

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

    PubMed

    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.

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

    PubMed

    Butts, Arielle; Martin, Jennifer A; DiDone, Louis; Bradley, Erin K; Mutz, Mitchell; Krysan, Damian J

    2015-01-01

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

  9. Virtual screening for environmental pollutants: structure-activity relationships applied to a database of industrial chemicals.

    PubMed

    Oberg, Tomas

    2006-04-01

    The current risk paradigm calls for individual consideration and evaluation of each separate environmental pollutant, but this does not reflect accurately the cumulative impact of anthropogenic chemicals. In the present study, previously validated structure-activity relationships were used to estimate simultaneously the baseline toxicity and atmospheric persistence of approximately 50,000 compounds. The results from this virtual screening indicate fairly stable statistical distributions among small anthropogenic compounds. The baseline toxicity was not changed much by halogen substitution, but a distinct increase seemed to occur in the environmental persistence with increased halogenation. The ratio of the atmospheric half-lives to the median lethal concentrations provides a continuous scale with which to rank and summarize the incremental environmental impacts in a mixture-exposure situation. Halogenated compounds as a group obtained a high ranking in this data set, with well-known pollutants at the very top: DDT metabolites and derivatives, polychlorinated biphenyls, diphenyl ethers and dibenzofurans, chlorinated paraffins, chlorinated benzenes and derivatives, hydrochlorofluorocarbons, and dichlorononylphenol. Environmentally friendly chemicals that obtained the lowest rank are nearly all hydroxylated and water-soluble. Virtual screening can assist with "green chemistry" in designing safe and degradable products and enable assessment of the efficiency in chemicals risk management.

  10. Structure-activity relationship studies on a novel family of specific HIV-1 reverse transcriptase inhibitors.

    PubMed

    Bonache, María-Cruz; Chamorro, Cristina; Lobatón, Esther; De Clercq, Erik; Balzarini, Jan; Velázquez, Sonsoles; Camarasa, María-José; San-Félix, Ana

    2003-09-01

    We have previously reported the discovery and preliminary structure-activity relationships of a new class of specific HIV-1 reverse transcriptase (RT) inhibitors whose prototype compound is the 1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3-N-[(carboxy) methyl]-thymine. In an attempt to increase the inhibitory efficacy against HIV-1 RT of this new class of nucleosides, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on the prototype compound. These include substitution of the tert-butyldimethylsilyl groups by other liphophilic groups, replacement of the carboxy group at the N-3 position of the nucleobase by other functional groups, change in the length of the spacer between the thymine and the carboxylic acid residue and substitution of the thymine moiety by other pyrimidine (uracil, 5-ethyluracil) or purine (hypoxanthine) nucleobases. In addition, the most salient structural features of this new class of HIV-1-specific nucleosides have been incorporated into classical HIV RT nucleoside inhibitors such as ddl, AZT, d4T. Our studies demonstrate that both the carboxymethyl moiety at the nucleobase and tert-butyldimethylsilyl groups at the sugar are important structural components since deletion of either of them is detrimental to the antiviral activity.

  11. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship.

    PubMed

    Navarro-Retamal, Carlos; Caballero, Julio

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure-activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities.

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

    PubMed Central

    Putz, Mihai V.; Lacrămă, Ana-Maria

    2007-01-01

    A novel quantitative structure-activity (property) relationship model, namely Spectral-SAR, is presented in an exclusive algebraic way replacing the old-fashioned multi-regression one. The actual S-SAR method interprets structural descriptors as vectors in a generic data space that is further mapped into a full orthogonal space by means of the Gram-Schmidt algorithm. Then, by coordinated transformation between the data and orthogonal spaces, the S-SAR equation is given under simple determinant form for any chemical-biological interactions under study. While proving to give the same analytical equation and correlation results with standard multivariate statistics, the actual S-SAR frame allows the introduction of the spectral norm as a valid substitute for the correlation factor, while also having the advantage to design the various related SAR models through the introduced “minimal spectral path” rule. An application is given performing a complete S-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reported eco-toxicity activities among relevant classes of xenobiotics. By representing the spectral norm of the endpoint models against the concerned structural coordinates, the obtained S-SAR endpoints hierarchy scheme opens the perspective to further design the ecotoxicological test batteries with organisms from different species.

  13. Synthesis and structure-activity relationship of oleanolic mono- or di-glycosides against Magnaporthe oryzae.

    PubMed

    Huo, G; Liu, C; Hui, Y; Chen, X; Xiao, D

    2016-09-23

    Saponins are naturally-occurring units with broad diversity and are usually recognized as phytoanticipins. In order to develop new saponin chemical entities with high activity against Magnaporthe oryzae, we selected oleanolic acid (OA), which has wide natural distribution and rich content in plants. We used the ability of OA to act as an aglycone for glycosylation to obtain information on the structure-activity relationship (SAR) for rational molecular pesticide design. Oleanolic mono- or di-glycosides were synthesized at either the C3-hydroxy and/or C28-carboxyl position, using trichloroacetimidate or glycosyl bromide donors, respectively. Structures were confirmed by [(1)H]-,[(13)C]-NMR. Furthermore, the activity of the synthesized glycosides against M. oryzae was assessed in vitro, based on the mycelium growth rate. The twenty five oleanolic mono- or di-glycosides comprised fourteen saponins with 3-monosaccharide residue 1a-1n, six saponins with 28-monosaccharide residue 2a-2f, and five saponins with 3, 28-monosaccharide residue 3a-3e; all showed different activities against M. oryzae according to their different structures. We concluded that the optimal oleanolic mono- and di-glycoside structure for activity against M. oryzae is a C3 connection of a hexose such as mannose, galactose, or glucose, in combination with a C28 connection to a small group such as allyl or a C3 connection to a pentose accompanied by a larger group such as another pentose or heptenyl at C28.

  14. Structure-activity relationships for 1',1'-dimethylalkyl-Delta8-tetrahydrocannabinols.

    PubMed

    Huffman, John W; Miller, John R A; Liddle, John; Yu, Shu; Thomas, Brian F; Wiley, Jenny L; Martin, Billy R

    2003-04-03

    A series of 1',1'-dimethylalkyl-Delta(8)-tetrahydrocannabinol analogues with C-3 side chains of 2-12 carbon atoms has been synthesized and their in vitro and in vivo pharmacology has been evaluated. The lowest member of the series, 1',1'-dimethylethyl-Delta(8)-THC (8, n=0) has good affinity for the CB(1) receptor, but is inactive in vivo. The dimethylpropyl (8, n=1) through dimethyldecyl (8, n=8) all have high affinity for the CB(1) receptor and are full agonists in vivo. 1',1'-Dimethylundecyl-Delta(8)-THC (8, n=9) has significant affinity for the receptor (K(i)=25.8+/-5.8 nM), but has reduced potency in vivo. The dodecyl analogue (8, n=10) has little affinity for the CB(1) receptor and is inactive in vivo. A quantitative structure-activity relationship study of the side chain region of these compounds is consistent with the concept that for optimum affinity and potency the side chain must be of a length which will permit its terminus to loop back in proximity to the phenolic ring of the cannabinoid.

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

    PubMed

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

    2008-06-01

    To measure the toxicity of phenol, aniline, and their derivatives to algae and to assess, model, and predict the toxicity using quantitative structure-activity relationship (QSAR) method. Oxygen production was used as the response endpoint for assessing the toxic effects of chemicals on algal photosynthesis. The energy of the lowest unoccupied molecular orbital (E(LUMO)) and the energy of the highest occupied molecular orbital (E(HOMO)) were obtained from the ChemOffice 2004 program using the quantum chemical method MOPAC, and the frontier orbital energy gap (deltaE) was obtained. The compounds exhibited a reasonably wide range of algal toxicity. The most toxic compound was alpha-naphthol, whereas the least toxic one was aniline. A two-descriptor model was derived from the algal toxicity and structural parameters: log1/EC50 = 0.268,logKow - 1.006deltaE + 11.769 (n = 20, r2 = 0.946). This model was stable and satisfactory for predicting toxicity. CONCLUSION Phenol, aniline, and their derivatives are polar narcotics. Their toxicity is greater than estimated by hydrophobicity only, and addition of the frontier orbital energy gap deltaE can significantly improve the prediction of logKow-dependent models.

  16. Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase.

    PubMed

    Kato, Atsushi; Nasu, Norio; Takebayashi, Kenji; Adachi, Isao; Minami, Yasuhiro; Sanae, Fujiko; Asano, Naoki; Watson, Alison A; Nash, Robert J

    2008-06-25

    Flavonoids are ubiquitous components in vegetables, fruits, tea, and wine. Therefore, they are often consumed in large quantities in our daily diet. Several flavonoids have been shown to have potential as antidiabetic agents. In the present study, we focused on inhibition of glycogen phosphorylase (GP) by flavonoids. 6-Hydroxyluteolin, hypolaetin, and quercetagetin were identified as good inhibitors of dephosphorylated GP (GPb), with IC 50 values of 11.6, 15.7, and 9.7 microM, respectively. Furthermore, a structure-activity relationship study revealed that the presence of the 3' and 4' OH groups in the B-ring and double bonds between C2 and C3 in flavones and flavonols are important factors for enzyme recognition and binding. Quercetagetin inhibited GPb in a noncompetitive manner, with a K i value of 3.5 microM. Multiple inhibition studies by Dixon plots suggested that quercetagetin binds to the allosteric site. In primary cultured rat hepatocytes, quercetagetin and quercetin suppressed glucagon-stimulated glycogenolysis, with IC 50 values of 66.2 and 68.7 microM, respectively. These results suggested that as a group of novel GP inhibitors, flavonoids have potential to contribute to the protection or improvement of control of diabetes type II.

  17. Demystifying Multi-Task Deep Neural Networks for Quantitative Structure-Activity Relationships.

    PubMed

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

    2017-09-05

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

  18. Structure-activity relationships of resveratrol and derivatives in breast cancer cells.

    PubMed

    Lappano, Rosamaria; Rosano, Camillo; Madeo, Antonio; Albanito, Lidia; Plastina, Pierluigi; Gabriele, Bartolo; Forti, Luca; Stivala, Lucia Anna; Iacopetta, Domenico; Dolce, Vincenza; Andò, Sebastiano; Pezzi, Vincenzo; Maggiolini, Marcello

    2009-07-01

    Resveratrol (RSV) is classified as a phytoestrogen due to its ability to interact with estrogen receptors (ERs). We assessed structure-activity relationships of RSV and the analogs 4,4'-dihydroxystilbene (4,4'-DHS), 3,5-dihydroxystilbene (3,5-DHS), 3,4'-dihydroxystilbene (3,4'-DHS), 4-hydroxystilbene (4-HS) using as model systems the ERalpha-positive and negative MCF7 and SkBr3 breast cancer cells, respectively. In binding assays and transfection experiments RSV and the analogs showed the following order of agonism for ERalpha: 3,4'-DHS > 4,4'-DHS > 4-HS > RSV, while 3,5-DHS did not elicit any ligand properties. Computational docking analysis and real-time PCR revealed for each analog a distinct ERalpha binding orientation and estrogen target gene expression profile. Interestingly, the aforementioned order of ligand activity was confirmed in proliferation assays which also showed the lack of growth stimulation by 3,5-DHS. Our data suggest that subtle changes in the structure of the RSV derivatives examined may be responsible for the different ERalpha-mediated biological responses observed in estrogen-sensitive cancer cells.

  19. Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides.

    PubMed

    Agnihotri, Geetanjali; Crall, Breanna M; Lewis, Tyler C; Day, Timothy P; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J; Malladi, Subbalakshmi S; David, Sunil A

    2011-12-08

    Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.

  20. Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides

    PubMed Central

    Agnihotri, Geetanjali; Crall, Breanna M.; Lewis, Tyler C.; Day, Timothy P.; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J.; Malladi, Subbalakshmi S.; David, Sunil A.

    2011-01-01

    Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood. PMID:22007676

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

    PubMed

    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 pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

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

    PubMed

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

    2017-08-10

    For the first time, the structure-activity relationships of thirteen synthesized flavonoids have been investigated by evaluating their ability to modulate horseradish peroxidase (HRP) catalytic activity. Indeed, a modified spectrophotometrically method was carried out and optimized using 4-methylcatechol (4-MC) as peroxidase co-substrate. The results show that these flavonoids exhibit a great capacity to inhibit peroxidase with Ki values ranged from 0.14±0.01 to 65±0.04mM. Molecular docking has been achieved using Auto Dock Vina program to discuss the nature of interactions and the mechanism of inhibition. According to the docking results, all the flavonoids have shown great binding affinity to peroxidase. These molecular modeling studies suggested that pyran-4-one cycle acts as an inhibition key for peroxidase. Therefore, potent peroxidase inhibitors are flavonoids with these structural requirements: the presence of the hydroxyl (OH) group in 7, 5 and 4' positions and the absence of the methoxy (O-CH3) group. Apigenin contributed better in HRP inhibitory activity. The present study has shown that the studied flavonoids could be promising HRP inhibitors, which can help in developing new molecules to control thyroid diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects.

    PubMed

    Takasawa, Ryoko; Takahashi, Saki; Saeki, Kazunori; Sunaga, Satoshi; Yoshimori, Atsushi; Tanuma, Sei-ichi

    2008-04-01

    Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, specific inhibitors of this enzyme have been expected as effective anticancer drugs. The purpose of this study is a good construction of the human GLO I/inhibitor pharmacophore to obtain unique human GLO I inhibitory seed compounds for the development of useful anticancer drugs. Here, we selected natural flavonoid compounds that possess a plane configuration of cis C-4 ketone and C-5 hydroxy groups as the substrate (MG) transition-state mimetic structure. These compounds were examined the inhibitory abilities to human GLO I activity and analyzed their structure-activity relationships to determine an important pharmacophore of flavonoids for the human GLO I binding. Our results point to the contribution of hydroxy groups at the B ring of flavonoids to the effective inhibition of the human GLO I. Based on the binding mode of flavonoids, we constructed the human GLO I/inhibitor pharmacophore. This work delivers the first three-dimensional (3D) structural data and explains certain flavonoids interact specifically with the human GLO I.

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

    PubMed

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

    2016-07-29

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

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

    PubMed

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

    2016-01-01

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

  6. Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

    PubMed Central

    de Araújo, Rodrigo S. A.; Guerra, Felipe Q. S.; de O. Lima, Edeltrudes; de Simone, Carlos A.; Tavares, Josean F.; Scotti, Luciana; Scotti, Marcus T.; de Aquino, Thiago M.; de Moura, Ricardo O.; Mendonça, Francisco J. B.; Barbosa-Filho, José M.

    2013-01-01

    The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity. PMID:23306152

  7. Structure-activity relationship studies of flavonol analogues on pollen germination.

    PubMed

    Forbes, Alaina M; Meier, G Patrick; Haendiges, Stacey; Taylor, Loverine P

    2014-03-12

    Flavonoids are polyphenolic compounds required in the fertilization process in many, if not all, plants. However, the exact biological mechanism(s) and the interacting proteins are unknown. To determine the characteristics important in activating or inhibiting the pollination sequence, a structure-activity relationship analysis of natural and synthetic flavonols was conducted. Flavonol analogues were synthesized through a modified "one-pot" procedure that utilized a Baker-Venkataraman type rearrangement and a Suzuki-Miyaura cross-coupling of a halo-flavonol with an organotrifluoroborate. Of the flavonols tested, kaempferol was the only compound to act as a full agonist. The other smaller, less sterically hindered flavonols (galangin, kaempferide, and 4'-methyl flavonol) acted as partial agonists. Larger more hydrophobic flavonol analogues (3'- and 4'-benzoyl, 3'- and 4'-phenyl, and 3'- and 4'-iodo flavonols) had minimal or no agonist activity. Competition assays between kaempferol and these minimally activating flavonols showed that these analogues inhibited the action of kaempferol in a manner consistent with noncompetitive antagonism. The results suggest that steric hindrance is the most important factor in determining a good agonist. Hydrogen bonding also had a positive effect as long as the substituent did not cause any steric hindrance.

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

    PubMed Central

    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

  9. Macrocyclic inhibitors for peptide deformylase: a structure-activity relationship study of the ring size.

    PubMed

    Hu, Xubo; Nguyen, Kiet T; Jiang, Vernon C; Lofland, Denene; Moser, Heinz E; Pei, Dehua

    2004-09-23

    Peptide deformylase (PDF) catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential role in bacterial cells but not in mammalian cells makes it an attractive target for antibacterial drug design. We have previously reported an N-formylhydroxylamine-based, metal-chelating macrocyclic PDF inhibitor, in which the P(1)' and P(3)' side chains are covalently joined. In this work, we have carried out a structure-activity relationship study on the size of the macrocycle and found that 15-17-membered macrocycles are optimal for binding to the PDF active site. Unlike the acyclic compounds, which are simple competitive inhibitors, the cyclic compounds all act as slow-binding inhibitors. As compared to their acyclic counterparts, the cyclic inhibitors displayed 20-50-fold higher potency against the PDF active site (K(I) as low as 70 pM), improved selectivity toward PDF, and improved the metabolic stability in rat plasma. Some of the macrocyclic inhibitors had potent, broad spectrum antibacterial activity against clinically significant Gram-positive and Gram-negative pathogens. These results suggest that the macrocyclic scaffold provides an excellent lead for the development of a new class of antibiotics.

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

    PubMed

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

    2017-03-19

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

  11. Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

    PubMed Central

    Zaman, Mehfuz; Toth, Istvan

    2013-01-01

    Peptide-based vaccines offer several advantages over conventional whole organism or protein approaches by offering improved purity and specificity in inducing immune response. However, peptides alone are generally non-immunogenic. Concerns remain about the toxicity of adjuvants which are critical for immunogenicity of synthetic peptides. The use of lipopeptides in peptide vaccines is currently under intensive investigation because potent immune responses can be generated without the use of adjuvant (thus are self-adjuvanting). Several lipopeptides derived from microbial origin, and their synthetic versions or simpler fatty acid moieties impart this self-adjuvanting activity by signaling via Toll-like receptor 2 (TLR2). Engagement of this innate immune receptor on antigen-presenting cell leads to the initiation and development of potent immune responses. Therefore optimization of lipopeptides to enhance TLR2-mediated activation is a promising strategy for vaccine development. Considerable structure-activity relationships that determine TLR2 binding and consequent stimulation of innate immune responses have been investigated for a range of lipopeptides. In this mini review we address the development of lipopeptide vaccines, mechanism of TLR2 recognition, and immune activation. An overview is provided of the best studied lipopeptide vaccine systems. PMID:24130558

  12. Progress with peptide scanning to study structure-activity relationships: the implications for drug discovery.

    PubMed

    Eustache, Stéphanie; Leprince, Jérôme; Tufféry, Pierre

    2016-08-01

    Peptides have gained renewed interest as candidate therapeutics. However, to bring them to a broader clinical use, challenges such as the rational optimization of their pharmacological properties remain. Peptide scanning techniques offer a systematic framework to gain information on the functional role of individual amino acids of a peptide. Due to progress in mastering new chemical synthesis routes targeting amino acid backbone, they are currently diversified. Structure-activity relationship (SAR) analyses such as alanine- or enantioneric- scanning can now be supplemented by N-substitution, lactam cyclisation- or aza-amino scanning procedures addressing not only SAR considerations but also the peptide pharmacological properties. This review highlights the different scanning techniques currently available and illustrates how they can impact drug discovery. Progress in peptide scanning techniques opens new perspectives for peptide drug development. It comes with the promise of a paradigm change in peptide drug design in which peptide drugs will be closer to the parent peptides. However, scanning still remains assimilable to a trial and error strategy that could benefit from being combined with specific in silico approaches that start reaching maturity.

  13. Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen

    PubMed Central

    Butts, Arielle; Martin, Jennifer A.; DiDone, Louis; Bradley, Erin K.; Mutz, Mitchell; Krysan, Damian J.

    2015-01-01

    Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold. PMID:26016941

  14. Structure-activity relationship study of novel anticancer aspirin-based compounds.

    PubMed

    Joseph, Stancy; Nie, Ting; Huang, Liqun; Zhou, Hui; Atmakur, Krishnaiah; Gupta, Ramesh C; Johnson, Francis; Rigas, Basil

    2011-01-01

    We performed a structure-activity relationship (SAR) study of a novel aspirin (ASA) derivative, which shows strong anticancer activity in vitro and in vivo. A series of ASA-based benzyl esters (ABEs) were synthesized and their inhibitory activity against human colon (HT-29 and SW480) and pancreatic (BxPC-3 and MIA PaCa-2) cancer cell lines was evaluated. The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the inhibitory activity on cancer cell growth for each ABE. Positional isomerism also played a significant role in this effect. The mechanism of action of these compounds appears consistent with the notion that they generate either a quinone methide or an m-oxybenzyl zwitterion (or an m-hydroxybenzyl cation), which then reacts with a nucleophile, mediating their biological effect. Our SAR study provides an insight into the biological properties of this novel class of compounds and underscores their potential as anticancer agents.

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

    PubMed

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

    2017-03-01

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

  16. Structure-Activity Relationship of a U-Type Antimicrobial Microemulsion System

    PubMed Central

    Zhang, Hui; Taxipalati, Maierhaba; Yu, Liyi; Que, Fei; Feng, Fengqin

    2013-01-01

    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. PMID:24204605

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

    PubMed

    Zhang, Hui; Taxipalati, Maierhaba; Yu, Liyi; Que, Fei; Feng, Fengqin

    2013-01-01

    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.

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

    PubMed

    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.

  19. Quantifying the fingerprint descriptor dependence of structure-activity relationship information on a large scale.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2013-09-23

    It is well-known that different molecular representations, e.g., graphs, numerical descriptors, fingerprints, or 3D models, change the numerical results of molecular similarity calculations. Because the assessment of structure-activity relationships (SARs) requires similarity and potency comparisons of active compounds, this representation dependence inevitably also affects SAR analysis. But to what extent? How exactly does SAR information change when alternative fingerprints are used as descriptors? What is the proportion of active compounds with substantial changes in SAR information induced by different fingerprints? To provide answers to these questions, we have quantified changes in SAR information across many different compound classes using six different fingerprints. SAR profiling was carried out on 128 target-based data sets comprising more than 60,000 compounds with high-confidence activity annotations. A numerical measure of SAR discontinuity was applied to assess SAR information on a per compound basis. For ~70% of all test compounds, changes in SAR characteristics were detected when different fingerprints were used as molecular representations. Moreover, the SAR phenotype of ~30% of the compounds changed, and distinct fingerprint-dependent local SAR environments were detected. The fingerprints we compared were found to generate SAR models that were essentially not comparable. Atom environment and pharmacophore fingerprints produced the largest differences in compound-associated SAR information. Taken together, the results of our systematic analysis reveal larger fingerprint-dependent changes in compound-associated SAR information than would have been anticipated.

  20. Structure-Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives.

    PubMed

    Borgström, Björn; Huang, Xiaoli; Hegardt, Cecilia; Oredsson, Stina; Strand, Daniel

    2017-02-10

    The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure-activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.

  1. Structure-activity relationship study of novel anticancer aspirin-based compounds

    PubMed Central

    JOSEPH, STANCY; NIE, TING; HUANG, LIQUN; ZHOU, HUI; ATMAKUR, KRISHNAIAH; GUPTA, RAMESH C.; JOHNSON, FRANCIS; RIGAS, BASIL

    2013-01-01

    We performed a structure-activity relationship (SAR) study of a novel aspirin (ASA) derivative, which shows strong anticancer activity in vitro and in vivo. A series of ASA-based benzyl esters (ABEs) were synthesized and their inhibitory activity against human colon (HT-29 and SW480) and pancreatic (BxPC-3 and MIA PaCa-2) cancer cell lines was evaluated. The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the inhibitory activity on cancer cell growth for each ABE. Positional isomerism also played a significant role in this effect. The mechanism of action of these compounds appears consistent with the notion that they generate either a quinone methide or an m-oxybenzyl zwitterion (or an m-hydroxybenzyl cation), which then reacts with a nucleophile, mediating their biological effect. Our SAR study provides an insight into the biological properties of this novel class of compounds and underscores their potential as anticancer agents. PMID:21805049

  2. Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

    PubMed Central

    Mojsoska, Biljana; Zuckermann, Ronald N.

    2015-01-01

    The constant emergence of new bacterial strains that resist the effectiveness of marketed antimicrobials has led to an urgent demand for and intensive research on new classes of compounds to combat bacterial infections. Antimicrobial peptoids comprise one group of potential candidates for antimicrobial drug development. The present study highlights a library of 22 cationic amphipathic peptoids designed to target bacteria. All the peptoids share an overall net charge of +4 and are 8 to 9 residues long; however, the hydrophobicity and charge distribution along the abiotic backbone varied, thus allowing an examination of the structure-activity relationship within the library. In addition, the toxicity profiles of all peptoids were assessed in human red blood cells (hRBCs) and HeLa cells, revealing the low toxicity exerted by the majority of the peptoids. The structural optimization also identified two peptoid candidates, 3 and 4, with high selectivity ratios of 4 to 32 and 8 to 64, respectively, and a concentration-dependent bactericidal mode of action against Gram-negative Escherichia coli. PMID:25941221

  3. Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships

    SciTech Connect

    J Beierlein; N Karri; A Anderson

    2011-12-31

    Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

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

    PubMed

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

    2015-12-25

    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.

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

    PubMed

    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.

  6. Quantitative Structure-Activity Relationships for the Nucleophilicity of Trivalent Boron Compounds.

    PubMed

    García-López, Diego; Cid, Jessica; Marqués, Ruben; Fernández, Elena; Carbó, Jorge J

    2017-04-11

    We describe herein the development of quantitative structure-activity relationships (QSAR) for the nucleophilicity of trivalent boron compounds covering boryl fragments bonded to alkali and alkaline-earth metals, to transition metals, and to sp(3) boron units in diboron reagents. We used the charge of the boryl fragment (q[B]) and the boron p/s population ratio (p/s) to describe the electronic structures of boryl moieties, whereas the distance-weighted volume (Vw ) descriptor was used to evaluate the steric effects. The three-term easy-to-interpret QSAR model showed statistical significance and predictive ability (r(2) =0.88, q(2) =0.83). The use of chemically meaningful descriptors has allowed identification of the factors governing the boron nucleophilicity and indicates that the most efficient nucleophiles are those with enhanced the polarization of the B-X bond towards the boron atom and reduced steric bulk. A detailed analysis of the potential energy surfaces of different types of boron substituents has provided insight into the mechanism and established an order of nucleophilicity for boron in B-X: X=Li>Cu>B(sp(3) )>Pd. Finally, we used the QSAR model to make a priori predictions of experimentally untested compounds.

  7. Investigation and prediction of protein precipitation by polyethylene glycol using quantitative structure-activity relationship models.

    PubMed

    Hämmerling, Frank; Ladd Effio, Christopher; Andris, Sebastian; Kittelmann, Jörg; Hubbuch, Jürgen

    2017-01-10

    Precipitation of proteins is considered to be an effective purification method for proteins and has proven its potential to replace costly chromatography processes. Besides salts and polyelectrolytes, polymers, such as polyethylene glycol (PEG), are commonly used for precipitation applications under mild conditions. Process development, however, for protein precipitation steps still is based mainly on heuristic approaches and high-throughput experimentation due to a lack of understanding of the underlying mechanisms. In this work we apply quantitative structure-activity relationships (QSARs) to model two parameters, the discontinuity point m* and the β-value, that describe the complete precipitation curve of a protein under defined conditions. The generated QSAR models are sensitive to the protein type, pH, and ionic strength. It was found that the discontinuity point m* is mainly dependent on protein molecular structure properties and electrostatic surface properties, whereas the β-value is influenced by the variance in electrostatics and hydrophobicity on the protein surface. The models for m* and the β-value exhibit a good correlation between observed and predicted data with a coefficient of determination of R(2)≥0.90 and, hence, are able to accurately predict precipitation curves for proteins. The predictive capabilities were demonstrated for a set of combinations of protein type, pH, and ionic strength not included in the generation of the models and good agreement between predicted and experimental data was achieved.

  8. Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron.

    PubMed

    Wang, Jing; Liu, Huaide; Jin, Weihua; Zhang, Hong; Zhang, Quanbin

    2016-01-01

    Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (P<0.01 or P<0.001) which provides further evidence that DF1 and DF2 also exerts a direct protection against the neuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity.

  9. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    PubMed

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

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

    PubMed

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

    2013-06-28

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

  11. Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias.

    PubMed

    Purohit, Meena K; Chakka, Sai Kumar; Scovell, Iain; Neschadim, Anton; Bello, Angelica M; Salum, Noruê; Katsman, Yulia; Bareau, Madeleine C; Branch, Donald R; Kotra, Lakshmi P

    2014-05-01

    Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.

  12. Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport

    PubMed Central

    Gowda, Raghavendra; Inamdar, Gajanan S.; Kuzu, Omer; Dinavahi, Saketh S.; Krzeminski, Jacek; Battu, Madhu Babu; Voleti, Sreedhara R.; Amin, Shantu; Robertson, Gavin P.

    2017-01-01

    Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development. PMID:28423677

  13. Structure-activity relationships for a new family of sulfonylurea herbicides

    NASA Astrophysics Data System (ADS)

    Wang, Jian-Guo; Li, Zheng-Ming; Ma, Ning; Wang, Bao-Lei; Jiang, Lin; Pang, Siew Siew; Lee, Yu-Ting; Guddat, Luke W.; Duggleby, Ronald G.

    2005-11-01

    Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain amino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the sulfonylurea and imidazolinone herbicides. The commercial sulfonylureas contain a pyrimidine or a triazine ring that is substituted at both meta positions, thus obeying the initial rules proposed by Levitt. Here we assess the activity of 69 monosubstituted sulfonylurea analogs and related compounds as inhibitors of pure recombinant Arabidopsis thaliana AHAS and show that disubstitution is not absolutely essential as exemplified by our novel herbicide, monosulfuron (2-nitro- N-(4'-methyl-pyrimidin-2'-yl) phenyl-sulfonylurea), which has a pyrimidine ring with a single meta substituent. A subset of these compounds was tested for herbicidal activity and it was shown that their effect in vivo correlates well with their potency in vitro as AHAS inhibitors. Three-dimensional quantitative structure-activity relationships were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. For the latter, the best result was obtained when steric, electrostatic, hydrophobic and H-bond acceptor factors were taken into consideration. The resulting fields were mapped on to the published crystal structure of the yeast enzyme and it was shown that the steric and hydrophobic fields are in good agreement with sulfonylurea-AHAS interaction geometry.

  14. Docking and quantitative structure-activity relationship of oxadiazole derivates as inhibitors of GSK3β.

    PubMed

    Quesada-Romero, Luisa; Caballero, Julio

    2014-02-01

    The binding modes of 42 oxadiazole derivates inside glycogen synthase kinase 3 beta (GSK3β were determined using docking experiments; thus, the preferred active conformations of these inhibitors are proposed. We found that these compounds adopt a scorpion-shaped conformation and they accept a hydrogen bond (HB) from the residue Val135 of the GSK3β ATP-binding site hinge region. In addition, quantitative structure-activity relationship (QSAR) models were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. In a first approach, three-dimensional (3D) vectors were calculated using docking conformations and, by using multiple-linear regression, we assessed that GETAWAY vectors were able to describe the reported biological activities. In other QSAR approach, SMILES-based optimal descriptors were calculated. The best model included three-SMILES elements SSSβ leading to the identification of key molecular features that contribute to a high GSK3β inhibitory activity.

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

    PubMed Central

    Murgatroyd, Christopher; Pirrie, Lisa; Tran, Fanny; Smith, Terry K.

    2016-01-01

    ABSTRACT 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. IMPORTANCE 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

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

    NASA Astrophysics Data System (ADS)

    Roberts, Charles A.

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

  17. Chemical graphs, molecular matrices and topological indices in chemoinformatics and quantitative structure-activity relationships.

    PubMed

    Ivanciuc, Ovidiu

    2013-06-01

    Chemical and molecular graphs have fundamental applications in chemoinformatics, quantitative structureproperty relationships (QSPR), quantitative structure-activity relationships (QSAR), virtual screening of chemical libraries, and computational drug design. Chemoinformatics applications of graphs include chemical structure representation and coding, database search and retrieval, and physicochemical property prediction. QSPR, QSAR and virtual screening are based on the structure-property principle, which states that the physicochemical and biological properties of chemical compounds can be predicted from their chemical structure. Such structure-property correlations are usually developed from topological indices and fingerprints computed from the molecular graph and from molecular descriptors computed from the three-dimensional chemical structure. We present here a selection of the most important graph descriptors and topological indices, including molecular matrices, graph spectra, spectral moments, graph polynomials, and vertex topological indices. These graph descriptors are used to define several topological indices based on molecular connectivity, graph distance, reciprocal distance, distance-degree, distance-valency, spectra, polynomials, and information theory concepts. The molecular descriptors and topological indices can be developed with a more general approach, based on molecular graph operators, which define a family of graph indices related by a common formula. Graph descriptors and topological indices for molecules containing heteroatoms and multiple bonds are computed with weighting schemes based on atomic properties, such as the atomic number, covalent radius, or electronegativity. The correlation in QSPR and QSAR models can be improved by optimizing some parameters in the formula of topological indices, as demonstrated for structural descriptors based on atomic connectivity and graph distance.

  18. Design, Synthesis and Qualitative Structure Activity Relationship Evaluations of Quinoline-Based Bisarylimidazoles as Antibacterial Motifs.

    PubMed

    Al-Qawasmeh, Raed A; Huthail, Basil B; Sinnokrot, Mutasem O; Semreen, Mohammad H; Odeh, Raed A; Abu-Zarga, Musa H; Tarazi, Hamadeh; Yousef, Imad A; Al-Tel, Taleb H

    2016-01-01

    The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant (MRSA) and the methicillin-sensitive (MSAA). The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate, into a more complex products with the potential for diversification via functionalization of the resultant acid. We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial structural features needed to enhance

  19. The direct and indirect relationships between alcohol prevention measures and alcoholic liver cirrhosis mortality.

    PubMed

    Xie, X; Mann, R E; Smart, R G

    2000-07-01

    The objective of this article is to investigate direct and indirect relationships between prevention measures and alcoholic liver cirrhosis mortality in Canadian provinces from 1968 to 1986. The data base that was assembled included alcoholic cirrhosis mortality rates, alcohol availability measures (rate of licensed premises, year in which the legal drinking age was reduced), per capita consumption of alcohol, rates of AA members and groups, and economic and demographic measures. This article develops a two-equation analytic model based on the availability theory of alcohol problems and prevention (Single, 1988). The distinction between direct and indirect effects of prevention measures can be made explicitly with this model. Alcohol availability measures, but not AA measures, had a significant direct potential impact on alcohol consumption. AA measures had a significant direct relationship to cirrhosis mortality rates. Alcohol consumption also had a significant direct relationship to cirrhosis mortality, and alcohol availability measures had an important indirect relationship through their influence on per capita alcohol consumption. While these observations need to be interpreted cautiously, the two-equation model shows promise as an approach to understanding direct and indirect influences on alcohol problems. As expected, AA measures and per capita alcohol consumption demonstrated significant direct relationship to cirrhosis mortality. In addition, important indirect influences of drinking-age changes and rates of licensed premises on cirrhosis mortality were observed through their relationships to per capita alcohol consumption.

  20. Structure-activity relationship in binding ligands to library of artificial receptors: the search for biocompatible sensor.

    PubMed

    Frączyk, Justyna; Mrozek, Agnieszka; Kamiński, Zbigniew J

    2010-11-01

    Structure-activity relationship (SAR) analysis was applied for studies of docking of colored ligands to library of artificial receptors formed by self-assembly of N-lipidated amino acids immobilised on the cellulose support. The studies show that the binding depends mainly on the structure of amino acid fragment but influence of N-lipidic fragment is less important.

  1. Structure-activity relationships for saponins from Allium hirtifolium and Allium elburzense and their antispasmodic activity.

    PubMed

    Barile, Elisa; Capasso, Raffaele; Izzo, Angelo A; Lanzotti, Virginia; Sajjadi, S Ebrahim; Zolfaghari, Behzad

    2005-11-01

    A phytochemical study of Allium hirtifolium Boiss flowers has led to the isolation of high amounts of six new furostanol and spirostanol saponins, named hirtifoliosides A1/A2 (1a/ 1b), B (2), C1/C2 ( 3a/ 3b), and D(4) along with three known spirostanol saponins, alliogenin 3- O-beta-D-glucopyranoside, gitogenin 3- O-beta-D-glucopyranosyl-(1-->4)- O-beta-D-glucopyranoside, and agapanthagenin 3- O-beta-D-glucopyranoside. High concentrations of the following known flavonol glycosides have been isolated from both flowers and bulbs: kaempferol 3- O-beta-D-rhamnopyranosyl-(1-->2)-glucopyranoside, kaempferol 3- O-beta-D-glucopyranosyl-(1-->4)-glucopyranoside, kaempferol 3-O-glucopyranoside, kaempferol 7-O-glucopyranoside. The isolated saponins along with the four saponins elburzensosides A1/A2 and C1/C2 and the sapogenin agapanthagenin, previously described from A. elburzense, have been subjected to biological assays for evaluating possible antispasmodic activity in the guinea-pig isolated ileum. The obtained results served as a basis for the establishment of structure-activity relationships within this class of antispasmodic agents. They highlight the positive effects of a hydroxyl group at position 5 and of a glucose unit at position 26 and demonstrate the detrimental effects of both a hydroxyl group at position 6 and of a glucose unit at position 3. Among the tested compounds, elburzensosides C1/C2 and agapanthagenin showed the highest activity in reducing induced contractions as measured by the reduction of histamine release by about 50 %. The observed effect therefore contributes to the explanation of the traditional use of onion and garlic in the treatment of disturbances of the gastrointestinal tract.

  2. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids.

    PubMed

    Nepali, Kunal; Sharma, Sahil; Sharma, Manmohan; Bedi, P M S; Dhar, K L

    2014-04-22

    A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part(.) The present review article offers a detailed account of the design strategies employed for the synthesis of anticancer agents via molecular hybridization techniques. Over the years, the researchers have employed this technique to discover some promising chemical architectures displaying significant anticancer profiles. Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as exemplified through the number of research papers. The microtubule inhibitors such as taxol, colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as one of the functionality of the hybrids and promising results have been obtained in most of the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion of pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs), a family of DNA interactive antitumor antibiotics derived from Streptomyces species in hybrid structure based drug design has also emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and coumarins have also been designed and reported to posses' remarkable inhibitory potential. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the hybrids. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. Structure-activity relationship study on the binding of PBDEs with thyroxine transport proteins.

    PubMed

    Yang, Weihua; Shen, Shide; Mu, Lailong; Yu, Hongxia

    2011-11-01

    Molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) were used to develop models to predict binding affinity of polybrominated diphenyl ether (PBDE) compounds to the human transthyretin (TTR). Based on the molecular conformations derived from the molecular docking, predictive comparative molecular similarity indices analysis (CoMSIA) models were developed. The results of CoMSIA models were as follows: leave-one-out (LOO) cross-validated squared coefficient q² (LOO) = 0.827 (full model, for all 28 compounds); q² (LOO) = 0.752 (split model, for 22 compounds in the training set); leave-many-out (LMO) cross-validated squared coefficient q² (LMO, two groups) = 0.723 ± 0.100 (full model, for all 28 compounds); q² (LMO, five groups) = 0.795 ± 0.030 (full model, for all 28 compounds); and the predictive squared correlation coefficient r²(pred)  = 0.928 (for six compounds in the test set). The developed CoMSIA models can be used to infer the activities of compounds with similar structural characteristics. In addition, the interaction mechanism between hydroxylated polybrominated diphenyl ethers (HO-PBDEs) and the TTR was explored. Hydrogen bonding with amino acid residues Asp74, Ala29, and Asn27 may be an important determinant for HO-PBDEs binding to TTR. Among them, forming hydrogen bonds with amino acid residues Asp74 might exert a more important function.

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

    PubMed Central

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

    2014-01-01

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

  5. Structure-activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations

    NASA Astrophysics Data System (ADS)

    Hao, Ge-Fei; Tan, Ying; Yu, Ning-Xi; Yang, Guang-Fu

    2011-03-01

    Protoporphyrinogen oxidase (PPO, EC 1.3.3.4), which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenyl-ether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure-activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental k i data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier ( e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO2 group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors.

  6. Enteric neuronal ablation: structure-activity relationship in a series of alkyldimethylbenzylammonium chlorides.

    PubMed

    Herman, J R; Bass, P

    1989-10-01

    Serosal application of a commercial solution of benzalkonium chloride (BAC) has been shown to selectively ablate myenteric neurons in the rat jejunum. This experimental model has proven useful in the study of the role of the myenteric plexus in intestinal function. The commercial BAC is a mixture of at least three homologous N-alkyldimethylbenzylammonium chlorides (ADBAC). The purpose of this study was to determine neuronal ablative activity in a series of ADBAC homologs when applied on the serosa of rat jejunum. Homologs not commercially available were synthesized and purified. Seven ADBAC homologs with alkyl chain lengths ranging from C6 to C18 were tested. A solution of each homolog (2 mM in saline) was applied directly on the serosa of an exteriorized portion of jejunum from anesthetized rats. Fifteen days after treatment, animals were sacrificed and treated tissues were processed for neuronal cell counts and muscle thickness determinations. All ADBAC homologs, except C18, ablated neurons of the myenteric plexus and produced thickening of intestinal smooth muscle. The number of submucosal neurons was not affected by any of the homologs. The structure-activity relationship observed in this study paralleled that of the reported antimicrobial activity of the ADBAC homologs, and is related to the aqueous solubility and relative surface activities of the homologs. The C14 homolog was found to be the most effective ablative agent, and reduced the number of myenteric neurons in a concentration-dependent manner. Thus, the C14 homolog can be used to produce a selectively denervated jejunal model for use in acute or chronic in vitro or in vivo studies of intestinal function.

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

    PubMed

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

    2007-11-01

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

  8. Quantitative structure-activity relationships (QSARs) for estrogen binding to the estrogen receptor: predictions across species.

    PubMed Central

    Tong, W; Perkins, R; Strelitz, R; Collantes, E R; Keenan, S; Welsh, W J; Branham, W S; Sheehan, D M

    1997-01-01

    The recognition of adverse effects due to environmental endocrine disruptors in humans and wildlife has focused attention on the need for predictive tools to select the most likely estrogenic chemicals from a very large number of chemicals for subsequent screening and/or testing for potential environmental toxicity. A three-dimensional quantitative structure-activity relationship (QSAR) model using comparative molecular field analysis (CoMFA) was constructed based on relative binding affinity (RBA) data from an estrogen receptor (ER) binding assay using calf uterine cytosol. The model demonstrated significant correlation of the calculated steric and electrostatic fields with RBA and yielded predictions that agreed well with experimental values over the entire range of RBA values. Analysis of the CoMFA three-dimensional contour plots revealed a consistent picture of the structural features that are largely responsible for the observed variations in RBA. Importantly, we established a correlation between the predicted RBA values for calf ER and their actual RBA values for human ER. These findings suggest a means to begin to construct a more comprehensive estrogen knowledge base by combining RBA assay data from multiple species in 3D-QSAR based predictive models, which could then be used to screen untested chemicals for their potential to bind to the ER. Another QSAR model was developed based on classical physicochemical descriptors generated using the CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) program. The predictive ability of the CoMFA model was superior to the corresponding CODESSA model. Images Figure 2. Figure 3. Figure 4. Figure 5. PMID:9353176

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

    PubMed

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

    2002-11-07

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

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

    PubMed

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

    2013-10-01

    REACH regulation requires ecotoxicological data to characterize industrial chemicals. To limit in vivo testing, Quantitative Structure-Activity Relationships (QSARs) are advocated to predict toxicity of a molecule. In this context, the topic of this work was to develop a reliable QSAR explaining the experimental acute toxicity of organic solvents for fish trophic level. Toxicity was expressed as log(LC50), the concentration in mmol.L(-1) producing the 50% death of fish. The 141 chemically heterogeneous solvents of the dataset were described by physico-chemical descriptors and quantum theoretical parameters calculated via Density Functional Theory. The best subsets of solvent descriptors for LC50 prediction were chosen both through the Kubinyi function associated with Enhanced Replacement Method and a stepwise forward multiple linear regressions. The 4-parameters selected in the model were the octanol-water partition coefficient, LUMO energy, dielectric constant and surface tension. The predictive power and robustness of the QSAR developed were assessed by internal and external validations. Several techniques for training sets selection were evaluated: a random selection, a LC50-based selection, a balanced selection in terms of toxic and non-toxic solvents, a solvent profile-based selection with a space filling technique and a D-optimality onions-based selection. A comparison with fish LC50 predicted by ECOSAR model validated for neutral organics confirmed the interest of the QSAR developed for the prediction of organic solvent aquatic toxicity regardless of the mechanism of toxic action involved. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity.

    PubMed

    Kagechika, H; Kawachi, E; Hashimoto, Y; Himi, T; Shudo, K

    1988-11-01

    Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids. The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring. The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other. Substitution at the ring position ortho to the amide group or N-methylation of the amide group caused loss of activity, presumably owing to the resultant change of conformation. It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity. Among the synthesized compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (Am80) and 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido] benzoic acid (Am580) were several times more active than retinoic acid in the assay. They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).

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

    PubMed

    Lee, Yunho; von Gunten, Urs

    2012-12-01

    Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(·) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. [Perspective of predictive toxicity assessment of in vivo repeated dose toxicity using structural activity relationship].

    PubMed

    Ono, Atsushi

    2010-01-01

    Tens of thousands of existing chemicals have been widely used for manufacture, agriculture, household and other purposes in worldwide. Only approximately 10% of chemicals have been assessed for human health hazard. The health hazard assessment of residual large number of chemicals for which little or no information of their toxicity is available is urgently needed for public health. However, the conduct of traditional toxicity tests which involves using animals for all of these chemicals would be economically impractical and ethically unacceptable. (Quantitative) Structure-Activity Relationships [(Q)SARs] are expected as method to have the potential to estimate hazards of chemicals from their structure, while reducing time, cost and animal testing currently needed. Therefore, our studies have been focused on evaluation of available (Q)SAR systems for estimating in vivo repeated toxicity on the liver. The results from our preliminary analysis showed the distribution for LogP of the chemicals which have potential to induce liver toxicity was bell-shape and indicating the possibility to estimate liver toxicity of chemicals from their physicochemical property. We have developed (Q)SAR models to in vivo liver toxicity using three commercially available systems (DEREK, ADMEWorks and MultiCASE) as well as combinatorial use of publically available chemoinformatic tools (CDK, MOSS and WEKA). Distinct data-sets of the 28-day repeated dose toxicity test of new and existing chemicals evaluated in Japan were used for model development and performance test. The results that concordances of commercial systems and public tools were almost same which below 70% may suggest currently attainable knowledge of in silico estimation of complex biological process, though it possible to obtain complementary and enhanced performance by combining predictions from different programs. In future, the combinatorial application of in silico and in vitro tests might provide more accurate

  14. Structure-activity relationship of synthetic branched-chain distearoylglycerol (distearin) as protein kinase C activators

    SciTech Connect

    Zhou, Qingzhong; Raynor, R.L.; Wood, M.G. Jr.; Menger, F.M.; Kuo, J.F. )

    1988-09-20

    Several representative branched-chain analogues of distearin (DS) were synthesized and tested for their abilities to activate protein kinase C (PKC) and to compete for the binding of ({sup 3}H)phorbol 12,13-dibutyrate (PDBu) to the enzyme. Substitutions of stearoyl moieties at sn-1 and sn-2 with 8-methylstearate decreased activities on these parameters, relative to those of the parental diacylglycerol DS, a weak PKC activator. Substitutions with 8-butyl, 4-butyl, or 8-phenyl derivatives, on the other hand, increased activities of the resulting analogues to levels comparable to those seen for diolein (DO), a diacylglycerol prototype shown to be a potent PKC activator. Kinetic analysis indicated that 8-methyldistearin (8-MeDS) acted by decreasing, whereas 8-butyldistearin (8-BuDS) and 8-phenyldistearin (8-PhDS) acted by increasing, the affinities of PKC for phosphatidylserine (PS, a phospholipid cofactor) and Ca{sup 2+} compared to the values seen in the absence or presence of DS. The stimulatory effect of 8-BuDS and 8-PhDS on PKC, as DO, was additive to that of 1,2-(8-butyl)distearoylphosphatidylcholine (1,2(8-Bu)DSPC) and, moreover, they abolished the marked inhibition of the enzyme activity caused by high concentrations of 1,2(8-Bu)DSPC. The present findings demonstrated a structure-activity relationship of the branched-chain DS analogues in the regulation of PKC, perhaps related to their abilities to specifically modify interactions of PKC with PS and/or Ca{sup 2+} critically involved in enzyme activation/inactivation.

  15. Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids.

    PubMed

    Resul, B; Stjernschantz, J; Selén, G; Bito, L

    1997-02-01

    A novel series of prostaglandin F (PGF) analogues have been prepared and evaluated in vivo and in vitro. Their intraocular pressure (IOP) lowering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogues were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF2 alpha (C#1). Based on the structure-activity relationship investigations, inversion of the configuration, at carbon-9 (C#3) or carbon-11 (C#4), changes the potency and the receptor profile of PGF2 alpha. Replacement part of the omega-chain of PGF2 alpha with a benzene ring changes the potency and receptor profile of PGF2 alpha. The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (C#8), and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studied. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologically more active than the methyl group at the 4-position (C#18). Furthermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (latanoprost), has been found in clinical studies to be a highly potent and efficacious IOP-reducing agent for the treatment of glaucoma.

  16. Quantitative Structure Activity Relationship Models for the Antioxidant Activity of Polysaccharides

    PubMed Central

    Nie, Kaiying; Wang, Zhaojing

    2016-01-01

    In this study, quantitative structure activity relationship (QSAR) models for the antioxidant activity of polysaccharides were developed with 50% effective concentration (EC50) as the dependent variable. To establish optimum QSAR models, multiple linear regressions (MLR), support vector machines (SVM) and artificial neural networks (ANN) were used, and 11 molecular descriptors were selected. The optimum QSAR model for predicting EC50 of DPPH-scavenging activity consisted of four major descriptors. MLR model gave EC50 = 0.033Ara-0.041GalA-0.03GlcA-0.025PC+0.484, and MLR fitted the training set with R = 0.807. ANN model gave the improvement of training set (R = 0.96, RMSE = 0.018) and test set (R = 0.933, RMSE = 0.055) which indicated that it was more accurately than SVM and MLR models for predicting the DPPH-scavenging activity of polysaccharides. 67 compounds were used for predicting EC50 of the hydroxyl radicals scavenging activity of polysaccharides. MLR model gave EC50 = 0.12PC+0.083Fuc+0.013Rha-0.02UA+0.372. A comparison of results from models indicated that ANN model (R = 0.944, RMSE = 0.119) was also the best one for predicting the hydroxyl radicals scavenging activity of polysaccharides. MLR and ANN models showed that Ara and GalA appeared critical in determining EC50 of DPPH-scavenging activity, and Fuc, Rha, uronic acid and protein content had a great effect on the hydroxyl radicals scavenging activity of polysaccharides. The antioxidant activity of polysaccharide usually was high in MW range of 4000–100000, and the antioxidant activity could be affected simultaneously by other polysaccharide properties, such as uronic acid and Ara. PMID:27685320

  17. Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis.

    PubMed

    Brenzan, Mislaine Adriana; Nakamura, Celso Vataru; Dias Filho, Benedito Prado; Ueda-Nakamura, Tânia; Young, Maria Claudia M; Côrrea, Arlene Gonçalves; Alvim, Joel; dos Santos, Adriana Oliveira; Cortez, Diógenes Aparício Garcia

    2008-11-01

    To study the structure-activity relationship of coumarin (-) mammea A/BB isolated from the CH(2)Cl(2) extract of Calophyllum brasiliense leaves, we evaluated the antileishmanial activity of natural, synthetic and derivatives of this coumarin, against promastigote and intracellular amastigote forms of Leishmania amazonensis, and their cytotoxicity to J774G8 murine macrophages. The derivatives were obtained by hydrogenation and methoxylation reactions. The compound structures were elucidated on the basis of spectroscopic data. The compounds 5,7-dihydroxy-8-(2-methylbutanoyl)-6-(3-methylbutyl)-4-phenyl-chroman-2-one (3), 7-hydroxy-5-methoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (4) and 5,7-dimethoxy-8-(1-methoxy-2-methylbutyl)-6-(3-methylbut-2-en-1-yl)-4 phenylcoumarin (6) were more biologically active than the compound (-) mammea A/BB (1) (7.4 microM), with IC(50) values from 0.9, 2.4 and 1.9 microM respectively; compound (3) displayed the highest activity. The compounds mammea B/BB (2), 5,7-dimethoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (5) and 5,7-dihydroxy-4-phenylcoumarin (7) were less active than (-) mammea A/BB (1), with IC(50) of 30.1, 15.1 and 60.2 microM respectively; compound (7) showed the lowest antileishmanial activity of all. Compounds (1), (3), (4) and (6) were active not only against promastigote forms of L. amazonensis, but also against intracellular amastigote forms with IC(50) of 14.3, 0.6, 34.0 and 22.2 microM, respectively. Interestingly, compound (3) showed the most antileishmanial activity of all. This study demonstrated that several aspects of the structure were important for antileishmanial activity.

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

    PubMed Central

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

    2011-01-01

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

  19. Conceptualizing the Suicide-Alcohol Relationship.

    ERIC Educational Resources Information Center

    Rogers, James R.

    Despite the strong empirical evidence linking alcohol use across varying levels to suicidal behavior, the field is lacking a unifying theoretical framework in this area. The concept of alcohol induced myopia to explain the varied effects of alcohol on the behaviors of individuals who drink has been proposed. The term "alcohol myopia" refers to its…

  20. A Study of the Relationship Between Alcoholism and Character Disorder.

    ERIC Educational Resources Information Center

    Wolfley, Virgil L.

    Studies have shown that sociopaths and alcoholics tend to come from similar social backgrounds and that they share several characteristics. To investigate the relationship between alcoholism and character disorder syndrome in adult males, 20 males who had a history of alcohol problems and displayed characteristics of character disorder were…

  1. Relationships Between Local Enforcement, Alcohol Availability, Drinking Norms, and Adolescent Alcohol Use in 50 California Cities

    PubMed Central

    Paschall, Mallie J.; Grube, Joel W.; Thomas, Sue; Cannon, Carol; Treffers, Ryan

    2012-01-01

    Objective: This study investigated relationships between local alcohol policies, enforcement, alcohol outlet density, adult alcohol use, and underage drinking in 50 California cities. Method: Eight local alcohol policies (e.g., conditional use permit, social host ordinance, window/billboard advertising) were rated for each city based on their comprehensiveness. Local alcohol enforcement was based on grants received from the California Alcoholic Beverage Control agency for enforcement of underage drinking laws. Outlet density was based on the number of on- and off-premise outlets per roadway mile. Level of adult alcohol use was ascertained from a survey of 8,553 adults and underage drinking (frequency of past-year alcohol use and heavy drinking) from surveys of 1,312 adolescents in 2009 and 2010. Multilevel regression analyses were conducted to examine the effects of policies, enforcement, and other community-level variables on adolescent drinking, controlling for youth demographic characteristics. Mediating effects of adolescents' perceived ease of obtaining alcohol, perceived enforcement, and perceived acceptability of alcohol use also were examined. Results: None of the eight local alcohol-policy ratings were associated with adolescent drinking. Funding for underage drinking enforcement activities was inversely related to frequency of past-year alcohol use, whereas outlet density and adult drinking were positively related to both past-year alcohol use and heavy drinking. These relationships were attenuated when controlling for perceived ease of obtaining alcohol, enforcement, and acceptability of alcohol use, providing evidence for mediation. Conclusions: Adolescent alcohol use and heavy drinking appear to be influenced by enforcement of underage drinking laws, alcohol outlet density, and adult alcohol use. These community-level influences may be at least partially mediated through adolescents' perceptions of alcohol availability, acceptability of alcohol use

  2. Chronological relationship between antisocial personality disorder and alcohol dependence.

    PubMed

    Bahlmann, M; Preuss, U W; Soyka, M

    2002-11-01

    Personality disorders, and particularly antisocial personality disorder (ASPD), frequently co-occur with alcohol dependence. ASPD is considered to be an important cofactor in the pathogenesis and clinical course of alcohol dependence. The chronological relationship between the onset of symptoms of ASPD and alcohol-dependence characteristics has not yet been studied in great detail and the role of ASPD in classification schemes of alcohol dependence as suggested by Cloninger and Schuckit has yet to be determined. We studied 55 alcohol-dependent patients to assess the prevalence and age at manifestation of ASPD, conduct disorder characteristics as well as alcohol dependence by employing the Semi-Structured Assessment for the Genetics of Alcoholism and the Structured Clinical Interview for DSM-III-R. Results indicate that the onset of ASPD characteristics precede that of alcohol dependence by some 4 years. This finding suggests that in patients with ASPD, alcohol dependence might be a secondary syndrome as suggested by previous research.

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

  4. Ranking of hair dye substances according to predicted sensitization potency: quantitative structure-activity relationships.

    PubMed

    Søsted, H; Basketter, D A; Estrada, E; Johansen, J D; Patlewicz, G Y

    2004-01-01

    Allergic contact dermatitis following the use of hair dyes is well known. Many chemicals are used in hair dyes and it is unlikely that all cases of hair dye allergy can be diagnosed by means of patch testing with p-phenylenediamine (PPD). The objectives of this study are to identify all hair dye substances registered in Europe and to provide their tonnage data. The sensitization potential of each substance was then estimated by using a quantitative structure-activity relationship (QSAR) model and the substances were ranked according to their predicted potency. A cluster analysis was performed in order to help select a number of chemically diverse hair dye substances that could be used in subsequent clinical work. Various information sources, including the Inventory of Cosmetics Ingredients, new regulations on cosmetics, data on total use and ChemId (the Chemical Search Input website provided by the National Library of Medicine), were used in order to identify the names and structures of the hair dyes. A QSAR model, developed with the help of experimental local lymph node assay data and topological sub-structural molecular descriptors (TOPS-MODE), was used in order to predict the likely sensitization potential. Predictions for sensitization potential were made for the 229 substances that could be identified by means of a chemical structure, the majority of these hair dyes (75%) being predicted to be strong/moderate sensitizers. Only 22% were predicted to be weak sensitizers and 3% were predicted to be extremely weak or non-sensitizing. Eight of the most widely used hair dye substances were predicted to be strong/moderate sensitizers, including PPD - which is the most commonly used hair dye allergy marker in patch testing. A cluster analysis by using TOPS-MODE descriptors as inputs helped us group the hair dye substances according to their chemical similarity. This would facilitate the selection of potential substances for clinical patch testing. A patch-test series

  5. Antifungal activity of organobismuth compounds against the yeast Saccharomyces cerevisiae: structure-activity relationship.

    PubMed

    Murafuji, Toshihiro; Miyoshi, Youhei; Ishibashi, Motoko; Mustafizur Rahman, A F M; Sugihara, Yoshikazu; Miyakawa, Isamu; Uno, Hidemitsu

    2004-03-01

    Antifungal activity of organobismuth(III) and (V) compounds 1-9 was examined against the yeast, Saccharomyces cerevisiae. A clear structure-activity relationship was observed in these compounds. Thus, triarylbismuth dichlorides 2 [(4-YC6H4)3BiCl2: Y=MeO, F, Cl, CF3, CN, NO2] and halobismuthanes 6 [2-(t)BuSO2C6H4(4-YC6H4)BiX: Y=MeO, Me, H, Cl; X=Cl, Br, I], 7 [Bi(X)(C6H4-2-SO2C6H4-1'-): X=Cl, Br, I], 8 [2-Me2NCH2C6H4(Ph)BiX: X=Cl, Br] and 9 [4-MeC6H4(8-Me2NC10H6-1-)BiCl] showed the growth inhibition effect, while triarylbismuth difluorides 3 [(4-YC6H4)3BiF2] and triarylbismuthanes 1 [(4-YC6H4)3Bi], 4 [2-(t)BuSO2C6H4(4-YC6H4)2Bi] and 5 [4-YC6H4Bi(C6H4-2-SO2C6H4-1'-)] were not active at all irrespective of the nature of the substituents. Generation of the inhibition effect is governed by the facility of nucleophilic reaction at the bismuth center and the Lewis acidic bismuth center is an active site. Of all the bismuth compounds attempted, halobismuthanes 7 derived from diphenyl sulfone exhibited the highest activities. An X-ray crystallographic study of 7a [Bi(Cl)(C6H4-2-SO2C6H4-1'-)] revealed that the bismuth center adopts a seven-coordinated geometry, which is unusual in organobismuth(III) compounds, through the intramolecular and intermolecular coordination between the bismuth and oxygen atoms. The marked inhibition effect of 7 may be attributed to such a highly coordinated geometry, which allows the bismuth center to bind tightly with some biomolecules playing important roles in the growth of S. cerevisiae.

  6. Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

    PubMed Central

    Tyssen, David; Henderson, Scott A.; Johnson, Adam; Sterjovski, Jasminka; Moore, Katie; La, Jennifer; Zanin, Mark; Sonza, Secondo; Karellas, Peter; Giannis, Michael P.; Krippner, Guy; Wesselingh, Steve; McCarthy, Tom; Gorry, Paul R.; Ramsland, Paul A.; Cone, Richard; Paull, Jeremy R. A.; Lewis, Gareth R.; Tachedjian, Gilda

    2010-01-01

    Background Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. Methods and Findings Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. Conclusions Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as Viva

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

    NASA Astrophysics Data System (ADS)

    Oprea, Tudor I.; García, Angel E.

    1996-06-01

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

  8. Structure-activity relationship of reversibly lipidized peptides: studies of fatty acid-desmopressin conjugates.

    PubMed

    Wang, Jeff; Wu, Daphne; Shen, Wei-Chiang

    2002-05-01

    To synthesize a series of reversible fatty acid-desmopressin (DDAVP) conjugates and to study their structure-activity relationship as anti-diuretic drugs. Seven fatty acid conjugates of DDAVP were prepared using various reversible lipidization reagents as described in our previous reports. All products were purified by acid precipitation and/or size-exclusion chromatography. Reversed-phase HPLC was used to evaluate their purity and lipophilicity. The anti-diuretic efficacy of these fatty acid conjugates was assessed in vasopressin-deficient Brattleboro rats. Four selected conjugates, i.e., DPA, DPH, DPD and DPP (acetic, hexanoic. decanoic, and palmitic acid conjugate, respectively), along with DDAVP itself were used in Caco-2 cell uptake studies and their degradation and the regeneration of active DDAVP were investigated using an in vitro liver slice metabolic system coupled with a HPLC assay. All fatty acid-DDAVP conjugates were more lipophilic than DDAVP as examined by HPLC analyses. When cysteine was used as the linker, the capacity index (k', a measure of lipophilicity) of the conjugates was linearly correlated with the number of carbons in the fatty acid chain. The anti-diuretic activity of the conjugates was correlated with the length of the fatty acid chain, with C10 as the minimal requirement for possessing the enhanced anti-diuretic activity. Among the seven fatty acid conjugates, palmitic acid conjugate was the most potent DDAVP derivative. Removal of carboxyl group from the cysteine linker completely abolished the enhancement of the activity. The extent of cellular uptake also positively correlated with the lipophilicity of the conjugates. The metabolism of DDAVP, DPH, DPD, and DPP by liver slices all followed first order kinetics with half-life of 0.30, 0.01, 0.06 and 3.44 hr, respectively. The degradation rates of DPH and DPD in the liver slice incubation were much faster than that of DDAVP and therefore an accumulation of regenerated DDAVP in the

  9. Young People and Alcohol in Italy: An Evolving Relationship

    ERIC Educational Resources Information Center

    Beccaria, Franca; Prina, Franco

    2010-01-01

    In Italy, commonly held opinions and interpretations about the relationship between young people and alcohol are often expressed as generalizations and approximations. In order to further understanding of the relationship between young people and alcohol in contemporary Italy, we have gathered, compared and discussed all the available data, both…

  10. Young People and Alcohol in Italy: An Evolving Relationship

    ERIC Educational Resources Information Center

    Beccaria, Franca; Prina, Franco

    2010-01-01

    In Italy, commonly held opinions and interpretations about the relationship between young people and alcohol are often expressed as generalizations and approximations. In order to further understanding of the relationship between young people and alcohol in contemporary Italy, we have gathered, compared and discussed all the available data, both…

  11. Relocating alcohol advertising research: examining socially mediated relationships with alcohol.

    PubMed

    Cherrington, Jane; Chamberlain, Kerry; Grixti, Joe

    2006-03-01

    This article reviews, critiques and politicises the positivist approaches that presently dominate alcohol advertising health research, and considers the benefits of a culturalist alternative. Positivist research in this area is identified as: (1) atheoretical and methods-driven; (2) restricted in focus, leaving critical issues unconsidered; and (3) inappropriately conceptualizing the 'normal' drinking person as rational and safe. The culturist alternative proposed is argued to present a more adequate framework, which can include and address problematic issues that are presently excluded, including: the pleasures associated with alcohol use, the involvements of 'normal' people in problem drinking, the inadequacy of present risk categories and the complexities of wider mediatory processes about alcohol in society. We argue for the adoption of more informed, culturalist approaches to alcohol advertising research.

  12. Drinking motives mediate the relationship between alcohol reward value and alcohol problems in military veterans.

    PubMed

    Dennhardt, Ashley A; Murphy, James G; McDevitt-Murphy, Meghan E; Williams, Joah L

    2016-12-01

    Elevated alcohol reward value (RV) has been linked to higher levels of drinking and alcohol-related consequences, and there is evidence that specific drinking motives may mediate the relationship between demand and problematic alcohol use in college students, making these variables potentially important indicators of risk for high RV and alcohol problems. The present study evaluated these relationships in a high-risk sample of military veterans. Heavy-drinking (N = 68) veterans of Operations Enduring Freedom or Iraqi Freedom (OEF/OIF) completed the alcohol purchase task (APT) measure of alcohol demand (RV), and standard assessments of alcohol consumption, alcohol-related problems, and drinking motives. RV was associated with overall alcohol consequences, interpersonal alcohol consequences, social responsibility consequences and impulse control consequences. Mediation analyses indicated significant mediation of the relationships between RV and a number of problem subscales by social motives, coping-anxiety motives, coping-depression motives and enhancement motives. This suggests that individuals who have a high valuation of alcohol may have increased motivation to drink in social, mood-enhancement, and coping situations, resulting in increased alcohol-related consequences. Demand and drinking motives should be examined as potential indicators of need for intervention services and as treatment targets in veterans. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure-Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors.

    PubMed

    Sharma, Alka; Luxami, Vijay; Saxena, Sanjai; Paul, Kamaldeep

    2016-03-01

    A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 μM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer.

  14. Structure-activity relationships and sub-type selectivity in an oxabicyclic estrogen receptor alpha/beta agonist scaffold.

    PubMed

    Hamann, Lawrence G; Meyer, J Hoyt; Ruppar, Daniel A; Marschke, Keith B; Lopez, Francisco J; Allegretto, Elizabeth A; Karanewsky, Donald S

    2005-03-01

    An oxabicyclic template for estrogen receptor alpha and beta agonists has been identified which can be tuned to provide moderate levels of selectivity for either receptor sub-type. Structure-activity relationships within this phenol-substituted oxabicyclo[3.3.1]nonene series are described. Select compounds from the present series showed activity in vivo after oral dosing in rodent models of uterine proliferation.

  15. Synthesis, antimicrobial activity and advances in structure-activity relationships (SARs) of novel tri-substituted thiazole derivatives.

    PubMed

    Reddy, Guda Mallikarjuna; Garcia, Jarem Raul; Reddy, Vemulapati Hanuman; de Andrade, Ageo Meier; Camilo, Alexandre; Pontes Ribeiro, Renan Augusto; de Lazaro, Sergio Ricardo

    2016-11-10

    Trisubstituted thiazoles were synthesized and studied for their antimicrobial activity and supported by theoretical calculations. In addition, MIC, MBC and MFC were also tested. Moreover, the present study was analyzed to scrutinize comprehensive structure-activity relationships. In fact, LUMO orbital energy and orbital orientation was reliable to explain their antibacterial and antifungal assay. Amongst the tested compounds, tri-methyl-substituted thiazole compound showed higher antimicrobial activity and low MIC value due to highest LUMO energy.

  16. Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.

    PubMed

    Riether, Doris; Zindell, Renee; Wu, Lifen; Betageri, Raj; Jenkins, James E; Khor, Someina; Berry, Angela K; Hickey, Eugene R; Ermann, Monika; Albrecht, Claudia; Ceci, Angelo; Gemkow, Mark J; Nagaraja, Nelamangala V; Romig, Helmut; Sauer, Achim; Thomson, David S

    2015-02-01

    Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.

  17. Quantitative structure-activity relationship study of the biophysicochemical behavior of nitrosamine.

    PubMed

    Vera, A; Montes, M; Usero, J L; Casado, J

    1992-08-01

    The partition coefficients of 14 aliphatic nitrosamines were measured in six water-organic solvent systems. Correlations between Hansch's hydrophobic parameter (pi) and Kier and Hall's topological index (1 chi) allowed pi to be substituted by 1 chi in the structure-activity correlations of the carcinogenicity data of the nitrosamines studied. The use of high-performance liquid chromatographic capacity factors of nitrosamines in these correlations is also discussed.

  18. Integration of graph theory and quantum chemistry for structure-activity relationships.

    PubMed

    Balasubramanian, K

    1994-01-01

    The objective of this article is to outline both graph-theoretically based and quantum chemically based structural indices of potential use in quantitative structure activity correlations. We consider graph-theoretical indices such as the connectivity index, topological index, Wiener index and molecular ID indices. Several structural and geometry-dependent indices can be derived from semiempirical and ab initio quantum calculations based on the charge densities, overlap matrices, frontier orbitals, molecular hardness, free valence, density matrices, quantum spectral difference indices, quantum spectral indices and bond matrices. Finally, the use of electrostatic potentials and charge densities for the prediction of reactive sites will be discussed.

  19. Bringing "Booze" Back In: The Relationship between Alcohol and Homicide.

    ERIC Educational Resources Information Center

    Parker, Robert Nash

    1995-01-01

    Tested hypotheses concerning the relationship between alcohol and homicide from four major theoretical perspectives; specific predictions on the causes of types of homicide were also derived. Findings revealed that alcohol consumption rates change the way important predictors, such as poverty and deterrence, are related to specific types of…

  20. Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.

    PubMed

    Singh, Kurnvir; Tanui, Rose; Gameiro, Armanda; Eisenberg, Gilad; Colas, Claire; Schlessinger, Avner; Grewer, Christof

    2017-02-01

    The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.

  1. Structure-activity relationships for the inhibition of DNA polymerase alpha by aphidicolin derivatives.

    PubMed Central

    Prasad, G; Edelson, R A; Gorycki, P D; Macdonald, T L

    1989-01-01

    Aphidicolin and 17 derivatives that have been structurally modified in the A- and D-rings were assessed for their ability to inhibit DNA polymerase alpha. No derivative surpassed the activity of aphidicolin; derivatives with structural alterations in the A-ring exhibited significantly greater loss of activity relative to derivatives with structural alterations in the D-ring. The conclusions of these studies indicate a critical role for the C-18 function in the interaction of aphidicolin with polymerase alpha. Molecular modelling studies could not identify structural features of the aphidicolin-dCTP "overlap" that is unique to dCTP, relative to the remaining dNTPs, and that is consistent with the extant structure-activity data. PMID:2505232

  2. Structure-activity relationships in the free-radical metabolism of xenobiotics

    SciTech Connect

    Chignell, C.F.

    1985-09-01

    Many xenobiotics, including naturally occurring compounds, drugs, and environmental agents, are metabolized both in vivo and in vitro to free-radical intermediates. The one-electron reduction of nitroaromatic compounds, quinones, and a wide variety of other chemicals is catalyzed enzymatically by a number of reductases and dehydrogenases. Structure-activity studies have shown that the cytotoxicities of nitroaromatic compounds and quinones are related to their one-electron reduction potentials (E/sub 7//sup 1/). Other factors such as oil:water partition coefficients may also be important. Xenobiotics may also be oxidized to free radicals by peroxidases and oxidases. Hammett's rules apply to the one-electron oxidation of simple meta- and para-substituted phenols and amines by horseradish peroxidase, compound I.

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

    PubMed

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

    2013-01-01

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

  4. Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure-Activity Relationships.

    PubMed

    Satz, Alexander L

    2016-07-11

    Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

  5. College Student Dating Partner Drinking Profiles: Differences in Relationship Functioning and Relationship-Specific Alcohol Expectancies.

    PubMed

    Linden-Carmichael, Ashley N; Lau-Barraco, Cathy; Kelley, Michelle L

    2016-06-06

    Although the majority of research on partner drinking styles has examined married couples, dating partners may influence one another's problem behaviors including alcohol use. This study identified patterns of at-risk alcohol use in college women and their dating partners using a person-centered statistical approach (i.e., latent profile analysis). Participants were 286 college student women in dating relationships. They completed questionnaires regarding their own and their partners' drinking, alcohol use severity, intimate partner violence (IPV), relationship satisfaction, and relationship-specific alcohol expectancies. Data were collected in 2012 through 2013. Results revealed three distinct, latent classes based on both partners' alcohol outcomes. The "Low-Risk" group (58%) consisted of non-heavy drinking partners. In the "High-Risk - Higher Men" class (27%), men drank more than women; however, both men and women were high-risk drinkers. The "High-Risk - Higher Women" group (15%) consisted of high-risk drinking partners but women consumed more alcohol than men. Both high-risk couple groups were more dissatisfied in their relationships and experienced more IPV, but held stronger beliefs about how alcohol influenced their relationship. Findings indicate that there are several distinct classes of dating couples that differ in relationship problems and beliefs about alcohol's impact on their relationship. Riskier couples differ in behaviors and alcohol-related beliefs from low-risk couples. These findings may inform the development of more efficacious alcohol interventions tailored toward high-risk drinking dating couples.

  6. Kinetics and quantitative structure-activity relationship study on the degradation reaction from perfluorooctanoic acid to trifluoroacetic acid.

    PubMed

    Gong, Chen; Sun, Xiaomin; Zhang, Chenxi; Zhang, Xue; Niu, Junfeng

    2014-08-14

    Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of 200~500 K. The Arrhenius equations of rate constants of elementary reactions are fitted. The decarboxylation is role step in the degradation mechanism of PFOA. For the perfluorinated carboxylic acids from perfluorooctanoic acid to trifluoroacetic acid, the quantitative structure-activity relationship of the decarboxylation was analyzed with the genetic function approximation method and the structure-activity model was constructed. The main parameters governing rate constants of the decarboxylation reaction from the eight-carbon chain to the two-carbon chain were obtained. As the structure-activity model shows, the bond length and energy of C1-C2 (RC1-C2 and EC1-C2) are positively correlated to rate constants, while the volume (V), the energy difference between EHOMO and ELUMO (ΔE), and the net atomic charges on atom C2 (QC2) are negatively correlated.

  7. Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure-Activity Relationships.

    PubMed

    Albu, Silvia A; Koteva, Kalinka; King, Andrew M; Al-Karmi, Salma; Wright, Gerard D; Capretta, Alfredo

    2016-10-10

    The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo-β-lactamases NDM-1 and VIM-2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM-1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.

  8. Synthesis and structure-activity relationship of beta-defensins, multi-functional peptides of the immune system.

    PubMed

    Klüver, Enno; Adermann, Knut; Schulz, Axel

    2006-04-01

    beta-defensins are a large family of multiple disulfide-bonded peptides occurring in mammals and birds. They play an important role in the innate immune system, directly killing microbial organisms. Recent research has demonstrated that beta-defensins are important for other biological functions beyond antimicrobial effects, including inhibition of viral infection, interaction with Toll-like receptors, chemotactic effects, and sperm function. The corresponding broad spectrum of activities makes this peptide class an important subject and tool in immunologic research. In this review, we summarize the current status of the routes to obtain synthetic beta-defensins, their major structural properties and structure-activity relationship.

  9. Glucal-conjugated sterols as novel vascular leakage blocker: structure-activity relationship focusing on the C17-side chain.

    PubMed

    Kim, Kyeojin; Maharjan, Sony; Lim, Changjin; Kim, Nam-Jung; Agrawal, Vijayendra; Han, Young Taek; Lee, Sujin; An, Hongchan; Yun, Hwayoung; Choi, Hyun-Jung; Kwon, Young-Guen; Suh, Young-Ger

    2014-03-21

    A series of glucal-conjugated sterols as novel vascular leakage blocker were identified through design, synthesis and biologically evaluation. In addition, the structure-activity relationship (SAR) of the glucal-conjugated sterols focusing on the C17-side chain was also established. The sterol analogs linked with the rigid C17-side chain side chains exhibited potent cell survival activities. In particular, analog 21l, which possesses a cyclopentyl oxime moiety, was shown to have excellent pharmacological effects on retinal vascular leakage in a diabetic mouse model. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Structure-activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate synthase.

    PubMed

    Mao, Jialin; Eoh, Hyungjin; He, Rong; Wang, Yuehong; Wan, Baojie; Franzblau, Scott G; Crick, Dean C; Kozikowski, Alan P

    2008-10-01

    We report on a target-based approach to identify possible Mycobacterium tuberculosis DXS inhibitors from the structure of a known transketolase inhibitor. A small focused library of analogs was assembled in order to begin elucidating some meaningful structure-activity relationships of 3-(4-chloro-phenyl)-5-benzyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Ultimately we found that 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one, although still weak, was able to inhibit M. tuberculosis DXS with an IC(50) of 10.6 microM.

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

    PubMed

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

    2007-03-01

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

  12. Structure-activity relationship study of 2,4-diaminothiazoles as cdk5/p25 kinase inhibitors

    PubMed Central

    Laha, Joydev K.; Zhang, Xuemei; Qiao, Lixin; Liu, Min; Chatterjee, Snigdha; Robinson, Shaughnessy; Kosik, Kenneth S.; Cuny, Gregory D.

    2011-01-01

    Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure-activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved. PMID:21353545

  13. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.

    PubMed

    Soares de Melo, Candice; Candice, Soares de Melo; Feng, Tzu-Shean; van der Westhuyzen, Renier; Gessner, Richard K; Street, Leslie J; Morgans, Garreth L; Warner, Digby F; Moosa, Atica; Naran, Krupa; Lawrence, Nina; Boshoff, Helena I M; Barry, Clifton E; Harris, C John; Gordon, Richard; Chibale, Kelly

    2015-11-15

    Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified.

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

    PubMed Central

    Chen, Hong; Zhong, Lili; Long, Yuhua; Li, Jia; Wu, Jueheng; Liu, Lan; Chen, Shengping; Lin, Yongcheng; Li, Mengfeng; Zhu, Xun; She, Zhigang

    2012-01-01

    A series of new derivatives (5–29) of marine-derived bostrycin (1) were synthesized. The in vitro cytotoxic activities of all compounds were evaluated against MCF-7, MDA-MB-435, A549, HepG2, HCT-116 and MCF-10A cells using the MTT method. The compounds 7, 8, 22, 23, 25, 28 and 29 of the total showed comparable activity to epirubicin, the positive control, against the tested cancer cell lines. However, these compounds also exhibited cytotoxicity towards MCF-10A cells. The structure-activity relationship (SAR) of bostrycin derivatives was also discussed based on the obtained experimental data. PMID:22690152

  15. Therapeutic journey of 2,4-thiazolidinediones as a versatile scaffold: An insight into structure activity relationship.

    PubMed

    Naim, Mohd Javed; Alam, Md Jahangir; Ahmad, Shujauddin; Nawaz, Farah; Shrivastava, Neelima; Sahu, Meeta; Alam, Ozair

    2017-03-31

    Thiazolidinedione is an important heterocyclic ring system, a pharmacophore and a privileged scaffold in medicinal chemistry; is a derivative of thiazolidine ring which came into existence for its role as antihyperglycemic agent and a specific ligand of PPAR's (Peroxisome proliferator activated receptor). Exhaustive research has led to determination of its vast biological profile with wide range of therapeutic applications. This review covers recent pharmacological advancements of thiazolidinedione moiety along with structure activity relationship so as to provide better correlation among different structures and their receptor interactions.

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

    PubMed

    Salmina, Elena S; Haider, Norbert; Tetko, Igor V

    2015-12-23

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

  17. Discovery of potent CCR4 antagonists: Synthesis and structure-activity relationship study of 2,4-diaminoquinazolines.

    PubMed

    Yokoyama, Kazuhiro; Ishikawa, Noriko; Igarashi, Susumu; Kawano, Noriyuki; Hattori, Kazuyuki; Miyazaki, Takahiro; Ogino, Shin-ichi; Matsumoto, Yuzo; Takeuchi, Makoto; Ohta, Mitsuaki

    2008-07-15

    A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM).

  18. Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents.

    PubMed

    Matos, Maria J; Vazquez-Rodriguez, Saleta; Santana, Lourdes; Uriarte, Eugenio; Fuentes-Edfuf, Cristina; Santos, Ysabel; Muñoz-Crego, Angeles

    2013-01-24

    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.

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

    PubMed

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

    2017-02-07

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

  20. Structure-activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels.

    PubMed

    Yamamoto, Takashi; Niwa, Seiji; Ohno, Seiji; Onishi, Tomoyuki; Matsueda, Hiroyuki; Koganei, Hajime; Uneyama, Hisayuki; Fujita, Shin-ichi; Takeda, Tomoko; Kito, Morikazu; Ono, Yukitsugu; Saitou, Yuki; Takahara, Akira; Iwata, Seinosuke; Shoji, Masataka

    2006-02-15

    Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure-activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.

  1. Novel structure-activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators.

    PubMed

    Coburger, Claudius; Wollmann, Jörg; Krug, Martin; Baumert, Christiane; Seifert, Marianne; Molnár, Joséf; Lage, Hermann; Hilgeroth, Andreas

    2010-07-15

    Synthesized series of cage dimeric 1,4-dihydropyridines have been systematically evaluated as MDR modulators in in vitro assays to investigate structure-dependent selectivity properties of inhibiting most cancer-relevant efflux pump proteins. Structure-activity relationships of each P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP) 1 and MRP2 inhibition are discussed and prove to be mainly determined by certain aromatic substitution patterns. The characterization of breast cancer resistance protein (BCRP) inhibition results in the discovery of benzyloxy substituted derivatives as selective P-gp inhibitors.

  2. MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Abstract
    One reasonable approach to the analysis of the relationships between molecular structure and toxic activity is through the investigation of the forces and intermolecular interactions responsible for chemical toxicity. The interaction between the xenobiotic and the bio...

  3. Tobacco and alcohol tax relationships with suicide in Switzerland.

    PubMed

    Yamasaki, Akiko; Chinami, Masanobu; Suzuki, Masao; Kaneko, Yoshihiro; Fujita, Daisuke; Shirakawa, Taro

    2005-08-01

    Previous research has shown an empirical link between tobacco and alcohol use and suicide. If tobacco and alcohol use contribute to suicidal behaviors, then policies designed to reduce the tobacco and alcohol consumption may succeed in reducing suicides as well. To test this hypothesis, correlations for suicide rates with alcohol consumption, taxes on alcohol and tobacco in Switzerland were examined using sets of time-series data from Switzerland in 1965-1994. The tax on tobacco correlated significantly negatively with male standardized suicide rate. The tax on alcohol also correlated significantly with male standardized suicide rate in an autoregressive model. On the other hand, significant relationships with female suicide rate were not found. Policies designed to reduce tobacco consumption are consistent with a benefit of reducing suicides, particularly for men in this sample.

  4. Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

    PubMed Central

    Singh, Kurnvir; Tanui, Rose; Gameiro, Armanda; Eisenberg, Gilad; Colas, Claire; Schlessinger, Avner; Grewer, Christof

    2017-01-01

    The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors. PMID:28057420

  5. Harmful and beneficial relationships between alcohol consumption and subclinical atherosclerosis.

    PubMed

    Kim, M K; Shin, J; Kweon, S-S; Shin, D H; Lee, Y-H; Chun, B-Y; Choi, B Y

    2014-07-01

    Arterial stiffness and increased intima-media wall thickness are two of the main predictors of cardiovascular disease (CVD). We evaluated whether brachial-ankle pulse wave velocity (baPWV) and common carotid artery intima-media wall thickness (CCA-IMT) are correlated with alcohol consumption in a cross-sectional study among Korean men and women aged 40 years and over. All 5539 subjects (2121 men and 3418 women) were participants in the Multi-Rural Communities cohort (MRcohort) study, a part of the Korean Genome Epidemiology Study (KoGES). The baPWV was positively correlated with alcohol consumption in men (p for trend <0.0001). Age (middle-aged versus elderly) modified the effect of alcohol consumption on PWV. On the other hand CCA-IMT decreased with alcohol consumption in men. There was no favorable zone of alcohol consumption in terms of baPWV and CCA-IMT. Adjustment for lipid profiles substantially attenuated the relationship between alcohol consumption and CCA-IMT. There was no clear relation between alcohol consumption and baPWV/CCA-IMT in women. Along with a linear harmful relationship between alcohol consumption and arterial stiffness in men there may also be a beneficial relationship between alcohol consumption and carotid intima-wall thickness. The effect of alcohol on arterial stiffness may be slightly stronger in elderly men, and the effect of alcohol on CCA-IMT may be mediated by lipid factors. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Directional relationships between alcohol use and antisocial behavior across adolescence.

    PubMed

    Cho, Seung-Bin; Heron, Jon; Aliev, Fazil; Salvatore, Jessica E; Lewis, Glyn; Macleod, John; Hickman, Matthew; Maughan, Barbara; Kendler, Kenneth S; Dick, Danielle M

    2014-07-01

    The co-occurrence of alcohol use and antisocial behavior is well established, but different hypotheses exist regarding the direction of effects between the 2 behaviors. We used longitudinal data to examine the directional relationship between the 2 behaviors across adolescence. A cross-lagged model was applied to longitudinal data from the Avon Longitudinal Study of Parents and Children. The sample used in the present study consisted of 4,354 females and 3,984 males. Alcohol use and antisocial behavior were measured with multiple items collected at 12, 13, 15, and 17 years of age. Both alcohol use and antisocial behavior were highly stable, as evidenced by highly significant autoregressive paths. Regarding the cross-lagged paths, neither behavior was predictive of the other during early adolescence (between ages 12 and 13). During mid-to late adolescence (from ages 13 to 17), antisocial behavior was predictive of subsequent alcohol use. Alcohol use was predictive of antisocial behavior in late adolescence (between ages 15 and 17), although this relationship was mainly driven by males and was not significant in the female subgroup. The result generally supported the direction from antisocial behavior to alcohol use, especially during mid- to late adolescence. However, there was also a suggestion that the direction of relationship between the 2 behaviors changes across adolescence. The results highlight the importance of considering developmental stages to understand the directional relationships between the 2 behaviors. Copyright © 2014 by the Research Society on Alcoholism.

  7. Cellular localization of dieldrin and structure-activity relationship of dieldrin analogues in dopaminergic cells.

    PubMed

    Allen, Erin M G; Florang, Virginia R; Davenport, Laurie L; Jinsmaa, Yunden; Doorn, Jonathan A

    2013-07-15

    The incidence of Parkinson's disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structure-activity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity.

  8. Oxidative folding and preparation of α-conotoxins for use in high-throughput structure-activity relationship studies.

    PubMed

    Gyanda, Reena; Banerjee, Jayati; Chang, Yi-Pin; Phillips, Angela M; Toll, Lawrence; Armishaw, Christopher J

    2013-01-01

    α-Conotoxins are peptide neurotoxins that selectively inhibit various subtypes of nicotinic acetylcholine receptors. They are important research tools for studying numerous pharmacological disorders, with profound potential for developing drug leads for treating pain, tobacco addiction, and other conditions. They are characterized by the presence of two disulfide bonds connected in a globular arrangement, which stabilizes a bioactive helical conformation. Despite extensive structure-activity relationship studies that have produced α-conotoxin analogs with increased potency and selectivity towards specific nicotinic acetylcholine receptor subtypes, the efficient production of diversity-oriented α-conotoxin combinatorial libraries has been limited by inefficient folding and purification procedures. We have investigated the optimized conditions for the reliable folding of α-conotoxins using simplified oxidation procedures for use in the accelerated production of synthetic combinatorial libraries of α-conotoxins. To this end, the effect of co-solvent, redox reagents, pH, and temperature on the proportion of disulfide bond isomers was determined for α-conotoxins exhibiting commonly known Cys loop spacing frameworks. In addition, we have developed high-throughput 'semi-purification' methods for the quick and efficient parallel preparation of α-conotoxin libraries for use in accelerated structure-activity relationship studies. Our simplified procedures represent an effective strategy for the preparation of large arrays of correctly folded α-conotoxin analogs and permit the rapid identification of active hits directly from high-throughput pharmacological screening assays. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

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

    PubMed

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

    2015-01-01

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

  10. Quantitative structure-activity relationship analysis of acute toxicity of diverse chemicals to Daphnia magna with whole molecule descriptors.

    PubMed

    Moosus, M; Maran, U

    2011-10-01

    Quantitative structure-activity relationship analysis and estimation of toxicological effects at lower-mid trophic levels provide first aid means to understand the toxicity of chemicals. Daphnia magna serves as a good starting point for such toxicity studies and is also recognized for regulatory use in estimating the risk of chemicals. The ECOTOX database was queried and analysed for available data and a homogenous subset of 253 compounds for the endpoint LC50 48 h was established. A four-parameter quantitative structure-activity relationship was derived (coefficient of determination, r (2) = 0.740) for half of the compounds and internally validated (leave-one-out cross-validated coefficient of determination, [Formula: see text] = 0.714; leave-many-out coefficient of determination, [Formula: see text] = 0.738). External validation was carried out with the remaining half of the compounds (coefficient of determination for external validation, [Formula: see text] = 0.634). Two of the descriptors in the model (log P, average bonding information content) capture the structural characteristics describing penetration through bio-membranes. Another two descriptors (energy of highest occupied molecular orbital, weighted partial negative surface area) capture the electronic structural characteristics describing the interaction between the chemical and its hypothetic target in the cell. The applicability domain was subsequently analysed and discussed.

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

    PubMed

    Potůčková, Eliška; Hrušková, Kateřina; Bureš, Jan; Kovaříková, Petra; Špirková, Iva A; Pravdíková, Kateřina; Kolbabová, Lucie; Hergeselová, Tereza; Hašková, Pavlína; Jansová, Hana; Macháček, Miloslav; Jirkovská, Anna; Richardson, Vera; Lane, Darius J R; Kalinowski, Danuta S; Richardson, Des R; Vávrová, Kateřina; Šimůnek, Tomáš

    2014-01-01

    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.

  12. Quantitative structure-activity relationship modeling of antioxidant activities of hydroxybenzalacetones using quantum chemical, physicochemical and spatial descriptors.

    PubMed

    Mitra, Indrani; Saha, Achintya; Roy, Kunal

    2009-05-01

    We have modeled antioxidant activities of hydroxybenzalacetones against lipid peroxidation induced by t-butyl hydroperoxide (pC1), gamma-irradiation (pC2) and also their 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging activity (pC3) using quantitative structure-activity relationship technique. The quantitative structure-activity relationship models were developed using different statistical methods like stepwise multiple linear regression, genetic function approximation and genetic partial least squares with descriptors of different categories (quantum chemical, physicochemical, spatial and substituent constants). The models were validated by internal validation and randomization techniques. The model predictivity was judged on the basis of their cross-validated squared correlation coefficient (Q2) and modified r2 (r m 2) values. The best models for the two responses, pC1 and pC2, were obtained by genetic partial least squares technique while the best model for the third response, pC3, was obtained by genetic function approximation technique. The developed models suggest that the distribution of charges on the phenolic nucleus and the phenolic oxygen as well as the charged surface areas of the molecules together with the geometry and orientation of the substituents significantly influence all the three types of responses (pC1, pC2 and pC3). The developed models may be used to design hydroxybenzalacetones with better antioxidant activities.

  13. Alexander the Great's relationship with alcohol.

    PubMed

    Liappas, J A; Lascaratos, J; Fafouti, S; Christodoulou, G N

    2003-05-01

    This study sought to clarify if Alexander the Great indulged pathologically in alcohol and whether it contributed to his death. The texts of the historians Diodorus of Sicily, Plutarch, Arrian, Curtius Rufus, Athenaeus, Aelian and Justin were studied, with their information concerning wine consumption by Macedonians, and especially Alexander, and were evaluated. The surviving historical texts, all later than Alexander's epoch, are based on a series of contemporary histories and especially on the 'Royal Journals', an official diary written in the imperial court. Alexander consumed large quantities of undiluted wine periodically, reaching pathological intoxication. However, the existing data do not provide convincing evidence that Alexander the Great manifested abuse of or dependence on alcohol according to DSM-IV or ICD-10 criteria and it seems unlikely that alcohol was involved in his untimely death.

  14. Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.

    PubMed

    Doiron, Jérémie A; Leblanc, Luc M; Hébert, Martin J G; Levesque, Natalie A; Paré, Aurélie F; Jean-François, Jacques; Cormier, Marc; Surette, Marc E; Touaibia, Mohamed

    2016-09-26

    Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition. Caffeoyl alcohol and ethers (6, 7a-b) as well as caffeoyl aldehyde and ketones (8a-e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10-30 μm). After preliminary anti-LTs activity screening in HEK293 cell models, 5-LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration-dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a-b being roughly eight-, seven-, and 16-fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 μm, respectively.

  15. Synthesis, antimicrobial evaluation, and structure-activity relationship of α-pinene derivatives.

    PubMed

    Dhar, Preeti; Chan, PuiYee; Cohen, Daniel T; Khawam, Fadi; Gibbons, Sarah; Snyder-Leiby, Teresa; Dickstein, Ellen; Rai, Prashant Kumar; Watal, Geeta

    2014-04-23

    Several (+)- and (-)-α-pinene derivatives were synthesized and evaluated for their antimicrobial activity toward Gram-positive bacteria Micrococcus luteus and Staphylococcus aureus, Gram-negative bacterium Escherichia coli, and the unicellular fungus Candida albicans using bioautographic assays. (+)-α-Pinene 1a showed modest activity against the test organisms, whereas (-)-α-pinene 1b showed no activity at the tested concentration. Of all the α-pinene derivatives evaluated, the β-lactam derivatives (10a and 10b) were the most antimicrobial. The increase in the antimicrobial activity of 10a compared to 1a ranged from nearly 3.5-fold (C. albicans) to 43-fold (S. aureus). The mean ± standard deviation for the zone of inhibition (mm) for 10a (C. albicans) was 31.9 ± 4.3 and that for S. aureus was 51.1 ± 2.9. Although (-)-α-pinene 1b was not active toward the test microorganisms, the corresponding β-lactam 10b, amino ester 13b, and amino alcohol 14b showed antimicrobial activity toward the test microorganisms. The increase in the antimicrobial activity of 10b compared to 1b ranged from 32-fold (S. aureus) to 73-fold (M. luteus). The mean ± standard deviation for the zone of inhibition (mm) for 10b (S. aureus) was 32.0 ± 0.60 and that for M. luteus was 73.2 ± 0.30.

  16. A Combinational Strategy of Model Disturbance and Outlier Comparison to Define Applicability Domain in Quantitative Structural Activity Relationship.

    PubMed

    Yan, Jun; Zhu, Wei-Wei; Kong, Bo; Lu, Hong-Bing; Yun, Yong-Huan; Huang, Jian-Hua; Liang, Yi-Zeng

    2014-08-01

    In order to define an applicability domain for quantitative structure-activity relationship modeling, a combinational strategy of model disturbance and outlier comparison is developed. An indicator named model disturbance index was defined to estimate the prediction error. Moreover, the information of the outliers in the training set was used to filter the unreliable samples in the test set based on "structural similarity". Chromatography retention indices data were used to investigate this approach. The relationship between model disturbance index and prediction error can be found. Also, the comparison between the outlier set and the test set could provide additional information about which unknown samples should be paid more attentions. A novel technique based on model population analysis was used to evaluate the validity of applicability domain. Finally, three commonly used methods, i.e. Leverage, descriptor range-based and model perturbation method, were compared with the proposed approach. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. The relationship between prenatal care, personal alcohol abuse and alcohol abuse in the home environment.

    PubMed

    Grekin, Emily R; Ondersma, Steven J

    2009-01-01

    Nearly one-fourth of African-American women receive no prenatal care during the first trimester of pregnancy. The aim of the current study is to identify factors that underlie inadequate prenatal care among African-American women. Maternal alcohol abuse has been examined as one risk factor for inadequate prenatal care, but findings have been inconsistent, perhaps because (a) alcohol use during pregnancy is substantially under-reported and (b) studies have not considered the wider social network in which maternal alcohol use takes place. The current study attempts to clarify relationships between personal alcohol use, alcohol use in the home environment, and prenatal care in a sample of post-partum women. Participants were 107 low-income, primarily African-American women. All participants completed a computer-based screening which assessed personal and environmental alcohol use, prenatal care and mental health. Environmental alcohol use was related to delayed prenatal care while personal alcohol use was not. More specifically, after controlling for demographic variables, the presence of more than three person-episodes of binge drinking in a woman's home environment increased the odds of seriously compromized prenatal care by a factor of seven. Findings suggest the need to further assess environmental alcohol use and to examine the reliability of personal alcohol use measures.

  18. Does Technology Use Moderate the Relationship Between Parental Alcoholism and Adolescent Alcohol and Cigarette Use?

    PubMed Central

    Ohannessian, Christine McCauley

    2009-01-01

    The primary goals of this study were to examine the associations between technology use and alcohol and cigarette use during adolescence and to explore whether technology use moderates the relationship between parental alcoholism and substance use (alcohol and cigarette use). The sample included 328 14-16 year-old adolescent boys and girls. The adolescents completed a battery of self-report questionnaires which included measures that assessed their substance use, their use of technology, and their parents' alcohol use (including alcoholism). Results indicated that adolescents who had an alcoholic parent reported relatively higher levels of alcohol consumption. Heavier use of technology (particularly text messaging, e-mailing/IMing, and watching television) also was related to earlier and heavier substance use during adolescence. Moreover, these effects tended to be more pronounced in adolescents with an alcoholic parent. Results from this study suggest that high levels of technology use during adolescence may be related to an increased risk of alcohol and cigarette use, particularly for children of alcoholic parents (COAs). PMID:19223123

  19. Does technology use moderate the relationship between parental alcoholism and adolescent alcohol and cigarette use?

    PubMed

    Ohannessian, Christine McCauley

    2009-01-01

    The primary goals of this study were to examine the associations between technology use and alcohol and cigarette use during adolescence and to explore whether technology use moderates the relationship between parental alcoholism and substance use (alcohol and cigarette use). The sample included 328 14-16 year-old adolescent boys and girls. The adolescents completed a battery of self-report questionnaires which included measures that assessed their substance use, their use of technology, and their parents' alcohol use (including alcoholism). Results indicated that adolescents who had an alcoholic parent reported relatively higher levels of alcohol consumption. Heavier use of technology (particularly text messaging, e-mailing/IMing, and watching television) also was related to earlier and heavier substance use during adolescence. Moreover, these effects tended to be more pronounced in adolescents with an alcoholic parent. Results from this study suggest that high levels of technology use during adolescence may be related to an increased risk of alcohol and cigarette use, particularly for children of alcoholic parents (COAs).

  20. Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates.

    PubMed

    Lee, H T; Roark, W H; Picard, J A; Sliskovic, D R; Roth, B D; Stanfield, R L; Hamelehle, K L; Bousley, R F; Krause, B R

    1998-02-03

    Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.

  1. Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives.

    PubMed

    Zurwerra, Didier; Glaus, Florian; Betschart, Leo; Schuster, Julia; Gertsch, Jürg; Ganci, Walter; Altmann, Karl-Heinz

    2012-12-21

    A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred-fold less potent than 1. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Directional Relationships Between Alcohol Use and Antisocial Behavior Across Adolescence

    PubMed Central

    Cho, Seung-Bin; Heron, Jon; Aliev, Fazil; Salvatore, Jessica E.; Lewis, Glyn; Macleod, John; Hickman, Matthew; Maughan, Barbara; Kendler, Kenneth S.; Dick, Danielle M.

    2014-01-01

    Background The co-occurrence of alcohol use and antisocial behavior is well established, but different hypotheses exist regarding the direction of effects between the 2 behaviors. We used longitudinal data to examine the directional relationship between the 2 behaviors across adolescence. Methods A cross-lagged model was applied to longitudinal data from the Avon Longitudinal Study of Parents and Children. The sample used in the present study consisted of 4,354 females and 3,984 males. Alcohol use and antisocial behavior were measured with multiple items collected at 12, 13, 15, and 17 years of age. Results Both alcohol use and antisocial behavior were highly stable, as evidenced by highly significant autoregressive paths. Regarding the cross-lagged paths, neither behavior was predictive of the other during early adolescence (between ages 12 and 13). During mid-to late adolescence (from ages 13 to 17), antisocial behavior was predictive of subsequent alcohol use. Alcohol use was predictive of antisocial behavior in late adolescence (between ages 15 and 17), although this relationship was mainly driven by males and was not significant in the female subgroup. Conclusions The result generally supported the direction from antisocial behavior to alcohol use, especially during mid-to late adolescence. However, there was also a suggestion that the direction of relationship between the 2 behaviors changes across adolescence. The results highlight the importance of considering developmental stages to understand the directional relationships between the 2 behaviors. PMID:24930394

  3. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    PubMed

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  4. Marihuana, Alcohol and Tobacco: Reassessment of a Presumed Relationship.

    ERIC Educational Resources Information Center

    Dull, R. Thomas; Williams, Franklin P., III

    1981-01-01

    Concludes little relationship exists between the three substances marihuana, alcohol and tobacco. Youthful subjects tend to overestimate the relationships between the three substances and cannot be generalized to other populations. Suggests an explanation of this youthful association focuses on simultaneous experimentation rather than causal…

  5. Marihuana, Alcohol and Tobacco: Reassessment of a Presumed Relationship.

    ERIC Educational Resources Information Center

    Dull, R. Thomas; Williams, Franklin P., III

    1981-01-01

    Concludes little relationship exists between the three substances marihuana, alcohol and tobacco. Youthful subjects tend to overestimate the relationships between the three substances and cannot be generalized to other populations. Suggests an explanation of this youthful association focuses on simultaneous experimentation rather than causal…

  6. Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate

    PubMed Central

    Goyanka, Ritu; Das, Sharmistha; Samuels, Herbert H.; Cardozo, Timothy

    2010-01-01

    Nuclear receptors (NRs) comprise the second largest protein family targeted by currently available drugs, acting via specific ligand interactions within the ligand binding domain (LBD). Recently, farnesyl pyrophosphate (FPP) was shown to be a unique promiscuous NR ligand, activating a subset of NR family members and inhibiting wound healing in skin. The current study aimed at visualizing the unique basis of FPP interaction with multiple receptors in order to identify general structure–activity relationships that operate across the NR family. Docking of FPP to the 3D structures of the LBDs of a diverse set of NRs consistently revealed an electrostatic FPP pyrophosphate contact with an NR arginine conserved in the NR family, a hydrophobic farnesyl contact with NR helix-12 and a ligand binding pocket volume between 300 and 430 Å3 as the minimal requirements for FPP activation of any NR. Lack of any of these structural features appears to render a given NR resistant to FPP activation. We used these structure–activity relationships to rationally design and successfully engineer several mutant human estrogen receptors that retain responsiveness to estradiol but no longer respond to FPP. PMID:20817759

  7. Violent crime and alcohol availability: relationships in an urban community.

    PubMed

    Speer, P W; Gorman, D M; Labouvie, E W; Ontkush, M J

    1998-01-01

    The relationship between violent crime, neighborhood sociodemographic characteristics, and alcohol outlet densities in Newark, New Jersey is reported, thus extending previous research of municipalities at more refined levels of analysis. Alcohol outlet densities were significant predictors in regression models, but rates of violent crime were better predicted in larger units (R2 = .673 for the census tract level vs. .543 at the census block group level). Alcohol outlet densities, however, were more predictive of violent crime at smaller units of analysis (change in R2 with the addition of alcohol outlet densities was .194 at the census tract level vs. .278 at the census block group level). Findings suggest that alcohol outlets represent a form of "undesirable land use" in urban neighborhoods that are a manifestation of increasingly concentrated economic disadvantage in the United States.

  8. Provincial alcohol index and its relationship to alcohol-related harm in Thailand: implications for subnational alcohol policy development.

    PubMed

    Chaiyasong, Surasak; Thamarangsi, Thaksaphon

    2016-07-11

    The Provincial Alcohol Index (PAI) is one of the efforts to develop a composite measurement to operationalize the situation of alcohol consumption and related risk behaviors. The index offers a means for national and subnational alcohol control committees to address alcohol-related problems in their responsible jurisdiction areas. The objective of this study is to assess the relationship between PAI scores and alcohol-related problems using Thailand as an example. Cross-sectional analyses of PAI scores based on the 2007 National Cigarette Smoking and Alcohol Drinking Behavior Survey (CSAD) and the National Statistical Office data were conducted. CSAD data were collected from 168,285 Thai residents aged 15 years and above in 76 provinces of Thailand (population range 180,787 to 5,716,248). The PAI scores were generated using three different methods based on five indicators: 1) prevalence of adult (≥15 years) drinkers, 2) prevalence of underage drinkers, 3) proportion of regular drinkers, 4) proportion of binge drinkers and 5) proportion of drink-drivers. Alcohol-related injuries and violent events together with provincial level covariates (age, gender, income and region) were assessed. Correlational and linear regression analyses were performed to examine the relationship between PAI scores and alcohol-related problems. The PAI scores generated from the three methods were significantly correlated with one another (r > 0.7, p < 0.05) and significantly related to alcohol-related problems after adjusting for the provincial level covariates. Based on the normalized method, PAI scores had a significant and positive relationship with prevalence of alcohol-related injuries (beta = 562 cases per million population, p = 0.027) and violence (beta = 451 events per million population, p = 0.013). PAI scores were highest in the north and lowest in the south of the country. The findings of this study illustrate the relationship between the PAI and

  9. Synthesis, antioxidant and cytoprotective evaluation of potential antiatherogenic phenolic hydrazones. A structure-activity relationship insight.

    PubMed

    Vanucci-Bacqué, Corinne; Carayon, Chantal; Bernis, Corinne; Camare, Caroline; Nègre-Salvayre, Anne; Bedos-Belval, Florence; Baltas, Michel

    2014-08-01

    A novel series of hydrazones derived from substituted benzaldehydes have been synthesized as potential antiatherogenic agents. Several methods were used for exploring their antioxidant and cytoprotective properties, such as their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, the inhibition of superoxide anion (O₂(·-)) generation and the measurement of cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS). The cytoprotective efficacy was also evaluated by measuring the cell viability (monitored by the MTT assay) in the presence of cytotoxic oxidized LDL. In this report, we discuss the relationship between the chemical structure of phenolic hydrazones and their antioxidant and cytoprotective activities, for subsequent application as antiatherogenic agents. This SAR study confirms that the phenolic frame is not the only prerequisite for antioxidant activity and N-methylbenzothiazole hydrazone moiety magnifies the dual required properties in two most interesting derivatives.

  10. Antioxidant properties of phenolic Schiff bases: structure-activity relationship and mechanism of action.

    PubMed

    Anouar, El Hassane; Raweh, Salwa; Bayach, Imene; Taha, Muhammad; Baharudin, Mohd Syukri; Di Meo, Florent; Hasan, Mizaton Hazizul; Adam, Aishah; Ismail, Nor Hadiani; Weber, Jean-Frédéric F; Trouillas, Patrick

    2013-11-01

    Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

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

    PubMed

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

    2017-02-15

    The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by (1)H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC50 = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.

  12. Study of structure-activity relationship in Aurein 1.2 analogs.

    PubMed

    Soufian, Safieh; Hassani, Leila

    2011-07-15

    Two new analogs of Aurein 1.2 antimicrobial peptide were synthesized and the antimicrobial activities were investigated. The results showed that the activity of G1R/F3W analog was higher than the native peptide and the F3W analog. Circular dichroism studies also showed that the secondary structure of the F3W was concentration-dependent, whereas, there was no such relationship seen in the case of G1R/F3W analog. It has been proposed that G1R/F3W activity was based on a single mechanism (snorkeling), while Aurein 1.2 and F3W utilized the snorkeling mechanism at low concentrations (0-0.01 mM) and the carpet mechanism at higher concentrations (0.01-0.1 mM). This study suggests that one pay attention to the concentration of biomolecules in peptide-based drug design.

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

    PubMed

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

    2012-03-01

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

  14. Antioxidant properties of phenolic Schiff bases: structure-activity relationship and mechanism of action

    NASA Astrophysics Data System (ADS)

    Anouar, El Hassane; Raweh, Salwa; Bayach, Imene; Taha, Muhammad; Baharudin, Mohd Syukri; Di Meo, Florent; Hasan, Mizaton Hazizul; Adam, Aishah; Ismail, Nor Hadiani; Weber, Jean-Frédéric F.; Trouillas, Patrick

    2013-11-01

    Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

  15. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles.

    PubMed

    Denny, W A; Atwell, G J; Baguley, B C; Cain, B F

    1979-02-01

    Quantitative relationships between physicochemical drug properties and antileukemic (L1210) efficacy have been examined for a series of bisquaternary ammonium heterocycles employing multiple variable regression analysis. Three measures of biologic response were examined: ILSmax, the percentage increase in mean life span of leukemic animals at the LD10 dose; D40, the drug dose necessary to provide 40% increase in life span; and CI (=LD 10/D40), the chemotherapeutic index. A cross correlation matrix between these three measures and the LD10 values demonstrates ILSmax and CI to be independent of toxicity. D40 is highly inversely correlated with LD10 and positively correlated with ILSmax, suggesting that this parameter measures a composite of both drug selectivity and toxicity. Superior regression equations resulted at all stages employing ILSmax as a measure of antitumor selectivity. Acceptable equations modeling LD10 could not be obtained. There was a parabolic relationship between agent lipophilic-hydrophilic balance, measured as chromatographic Rm values, and ILSmax. To reduce residual variance in the L1210 screening data, not accepted by this parabolic equation, measures of agent-DNA interaction were investigated as possible indices of site fit. Relative levels of drug-DNA interaction were obtained by spectrofluorimetric quantitation of drug displacement of DNA-bound ethidium. Addition to regression equations of agent C50 values for calf thymus DNA, those micromolar drug concentrations necessary to displace 50% of the ethidium bound to that DNA, provided a significant reduction in the screening data variance. C50 values for drug interactions with poly[d(A-T)] and poly[d(G-C)] were also investigated as possible indicators of drug selectivity towards different DNA sites. Marked differences were observed in the C50 values for the two synthetic nucleic acids, with those for calf thymus DNA and poly[d(G-C)] proving highly covariant. A regression equation containing a

  16. Relationships among Alcohol Outlet Density, Alcohol Use, and Intimate Partner Violence Victimization among Young Women in the United States

    ERIC Educational Resources Information Center

    Waller, Martha W.; Iritani, Bonita J.; Christ, Sharon L.; Clark, Heddy Kovach; Moracco, Kathryn E.; Halpern, Carolyn Tucker; Flewelling, Robert L.

    2012-01-01

    Greater access to alcohol has been widely found to be associated with many negative outcomes including violence perpetration. This study examines the relationship between alcohol outlet density, alcohol use, and intimate partner violence (IPV) victimization among young women in the United States. A direct association between alcohol outlet density…

  17. Relationships among Alcohol Outlet Density, Alcohol Use, and Intimate Partner Violence Victimization among Young Women in the United States

    ERIC Educational Resources Information Center

    Waller, Martha W.; Iritani, Bonita J.; Christ, Sharon L.; Clark, Heddy Kovach; Moracco, Kathryn E.; Halpern, Carolyn Tucker; Flewelling, Robert L.

    2012-01-01

    Greater access to alcohol has been widely found to be associated with many negative outcomes including violence perpetration. This study examines the relationship between alcohol outlet density, alcohol use, and intimate partner violence (IPV) victimization among young women in the United States. A direct association between alcohol outlet density…

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

    PubMed

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

    2016-01-01

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

  19. Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.

    PubMed

    Sahu, Pramod K

    2016-10-04

    New fourteen 3,4-dihydropyrimidine derivatives/analogues of curcumin (2a-2n) were designed, synthesized and biologically evaluated for their cytotoxicity and antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines HeLa, HCT-116 and QG-56 by MTT assay method. From SAR study, it has been revealed that particularly, compound 2e and 2j (IC50 value 12.5 μM) have shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 3,4-dihydropyrimidines of curcumin, 2c, 2d, 2j and 2n exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. Therefore, we conclude that physico-chemical analyses may prove structural features of curcumin analogues with their promising combined cytotoxicity/antioxidant activity and it is also concluded from virtual and practical screening that the compounds were varied to possess a broad range of lipophilic character, revealed by Log P values.

  20. CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats.

    PubMed

    Toropova, A P; Toropov, A A; Benfenati, E; Gini, G; Leszczynska, D; Leszczynski, J

    2011-09-01

    For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/). The total number of considered compounds is 689. New additional global attributes of the simplified molecular input line entry system (SMILES) have been examined for improvement of the optimal SMILES-based descriptors. These global SMILES attributes are representing the presence of some chemical elements and different kinds of chemical bonds (double, triple, and stereochemical). The "classic" scheme of building up quantitative structure-property/activity relationships and the balance of correlations (BC) with the ideal slopes were compared. For all six random splits, best prediction takes place if the aforementioned BC along with the global SMILES attributes are included in the modeling process. The average statistical characteristics for the external test set are the following: n = 119 ± 6.4, R(2) = 0.7371 ± 0.013, and root mean square error = 0.360 ± 0.037. Copyright © 2011 Wiley Periodicals, Inc.

  1. Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines.

    PubMed

    Shrestha, Anurupa; Sil, Diptesh; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; David, Sunil A

    2009-05-01

    We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH(2)-(CH(2))(3)-NH-(CH(2))(4)-NH(2)] and norspermidine [NH(2)-(CH(2))(3)-NH-(CH(2))(3)-NH(2)] backbones, with the N-alkyl group being held constant at C(16) in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.

  2. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship

    PubMed Central

    Navarro-Retamal, Carlos

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure–activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities. PMID:27517610

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

    PubMed

    Barratt, Martin D

    2004-11-01

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

  4. Disubstituted amino-, nitroso-, and nitrofluorenes: a physicochemical basis for structure-activity relationships in Salmonella typhimurium

    SciTech Connect

    Vance, W.A.; Wang, Y.Y.; Okamoto, H.S.

    1987-01-01

    Twenty-nine derivatives of fluorene were tested for mutagenic potency in four strains of Salmonella typhimurium with and/or without S9 microsomal activation. The effects of a second functional group on the mutagenic activity of an amino-nitroso-, and nitrofluorene were correlated with its physical and chemical properties. When the functional group is conjugated by resonance, both inductive and resonance effects are determinants of mutagenic potency. Electron-withdrawing groups such as the halogens (F, Cl, Br, and I), nitro, nitroso, and cyano at C-7 increased the mutagenic potency of 2-nitrofluorene. Acetylation of a hydroxy or an amino group at C-7 increased the mutagenic potency of 2-nitrofluorene. The physical properties of a second functional group are expected to exert their effect(s) at three points in the metabolic activation of 2,7-disubstituted fluorene derivatives: 1) initial reduction of the nitro group (redox effect), 2) stabilization of the hydroxylamine (inductive effect), and 3) stabilization/destabilization of the nitrenium ion (resonance and inductive effects). The relationships between the physical properties of a second functional group and their effects on biological activities of nitro- and aminofluorenes in the Ames Salmonella assay may be of predictive value in a first approximation of both the mutagenic and carcinogenic potency of chemicals with comparable structures such as fluoranthene and biphenyl.

  5. Antimicrobial structure activity relationship of five anthraquinones of emodine type isolated from Vismia laurentii.

    PubMed

    Kemegne, Gislaine Aurelie; Mkounga, Pierre; Essia Ngang, Jean Justin; Sado Kamdem, Sylvain Leroy; Nkengfack, Augustin Ephrem

    2017-02-22

    Antimicrobial activity of anthraquinone compounds of emodine type has been reported by many authors. These compounds are found in Vismia laurentii (Clusiaceae), a plant used in traditional pharmacopoeia for treatment of microbial infections among others affections. The continuous identification of new compounds has raised the problem of the relation between the structure and antimicrobial properties. The yeast growth kinetics parameters were not influenced by the pH variation as it was the case for the other tested bacteria. Fungicidal activities were noted for all molecules while only few of them had bactericidal activities, mostly on Gram positive bacteria. Mathematical model establishing a quantitative relationship between physicochemical properties of molecules and their fungicidal activities were obtained for Candida albicans and showed that physicochemical properties impacting on antifungal activity were polarizability, partition coefficient, molecular weight and hydrogen bond acceptor. This work demonstrated that the presence of a long aliphatic chain methoxy group substituted in position two of the emodine structure increased the antibacterial properties of the studied compounds. Moreover this antimicrobial property depends on the pH of the environment, and specifically on the polarizability and number of hydrogen bond acceptors of the compound.

  6. Antimicrobial Photodynamic Therapy with Functionalized Fullerenes: Quantitative Structure-activity Relationships

    PubMed Central

    Mizuno, Kazue; Zhiyentayev, Timur; Huang, Liyi; Khalil, Sarwat; Nasim, Faria; Tegos, George P; Gali, Hariprasad; Jahnke, Ashlee; Wharton, Tim; Hamblin, Michael R

    2011-01-01

    Photosensitive dyes or photo sensitizers (PS) in combination with visible light and oxygen produce reactive oxygen species that kill cells in the process known as photodynamic therapy (PDT). Antimicrobial PDT employs PS that is selective for microbial cells and is a new treatment for infections. Most antimicrobial PS is based on tetrapyrrole or phenothiazinium structures that have been synthesized to carry quaternary cationic charges or basic amino groups. However we recently showed that cationic-substituted fullerene derivative were highly effective in killing a broad spectrum of microbial cells after illumination with white light. In the present report we compared a new group of synthetic fullerene derivatives that possessed either basic or quaternary amino groups as antimicrobial PS against Gram-positive (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans). Quantitative structure-function relationships were derived with LogP and hydrophilic lipophilic balance parameters. Compounds with non-quaternary amino groups tended to form nanoaggregates in water and were only effective against S. aureus. The most important determinant of effectiveness was an increased number of quaternary cationic groups that were widely dispersed around the fullerene cage to minimize aggregation. S. aureus was most susceptible; E. coli was intermediate, while C. albicans was the most resistant species tested. The high effectiveness of antimicrobial PDT with quaternized fullerenes suggest they may have applications in treatment of superficial infections (for instance in wounds and burns) where light penetration into tissue is not problematic. PMID:21743839

  7. Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.

    PubMed

    Zhang, Chongqian; Du, Chunmiao; Feng, Zhiwei; Zhu, Jingyu; Li, Youyong

    2015-02-01

    CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.

  8. Structure-activity relationship among purpurinimides and bacteriopurpurinimides: trifluoromethyl substituent enhanced the photosensitizing efficacy.

    PubMed

    Gryshuk, Amy; Chen, Yihui; Goswami, Lalit N; Pandey, Suresh; Missert, Joseph R; Ohulchanskyy, Tymish; Potter, William; Prasad, Paras N; Oseroff, Allan; Pandey, Ravindra K

    2007-04-19

    At similar lipophilicity, compared to the nonfluorinated purpurinimide 11, the corresponding fluorinated analog 8 with a trifluoromethyl substituent at the lower half (position-132) of the molecule showed enhanced photosensitizing efficacy. The structural parameters established in purpurinimides (lambdamax: 700 nm) were successfully translated to the bacteriopurpurin imide system 19 (lambdamax: 792 nm) and within both series, a monotonic relationship between the lipophilicity and the in vivo PDT activity was observed. For preparing water-soluble compounds, the photosensitizers 8 and 19 were converted into the corresponding aminobenzyl-diethylenetriamine pentaacetate conjugates 23 and 26. Acid treatment of purpurinimide 23 produced the corresponding water-soluble analog 24. Bacteriochlorin 26 under acidic or basic conditions mainly gave the decomposition products. At similar in vivo treatment conditions (C3H mice with RIF tumors and BALB-C mice with colon-26 tumors) the water-soluble purpurinimide 24 was found to be more effective than the methyl ester analog 8. These results suggest that besides overall lipophilicity the inherent charge of the photosensitizer also influences the PDT efficacy.

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

    SciTech Connect

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. )

    1988-02-01

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

  10. Design and structure-activity relationships of C-terminal cyclic neurotensin fragment analogues.

    PubMed

    Sefler, A M; He, J X; Sawyer, T K; Holub, K E; Omecinsky, D O; Reily, M D; Thanabal, V; Akunne, H C; Cody, W L

    1995-01-20

    Neurotensin (NT) is a linear tridecapeptide with a broad range of central and peripheral pharmacological effects. The C-terminal hexapeptide of NT (NT8-13) has been shown to possess similar properties to NT itself, and in fact, an analogue of NT8-13 (N alpha MeArg8-Lys-Pro-Trp-Tle-Leu13, Tle = tert-leucine) has been reported to possess central activity after peripheral administration. Cyclic derivatives of this hexapeptide were synthesized by a combination of solution and solid-phase peptide synthetic methodologies, and several analogues had low nanomolar binding affinity for the NT receptor. In particular, cyclo[Arg-Lys-Pro-Trp-Glu]-Leu (cyclized between the alpha amine of Arg and the gamma carboxylate of Glu) possessed 16 nM NT receptor affinity and was determined to be an agonist in vitro. 1H-NMR and 13C-edited 1H-NMR spectroscopy were performed on this and related cyclic analogues to help identify structural properties which may be important for receptor recognition. These cyclic peptides represent novel molecular probes to further investigate NT receptor pharmacology, as well as to advance our understanding of the structure-conformation relationships of NT and to help establish a working basis for additional pharmacophore mapping studies.

  11. Mutagenic nitrenes/nitrenium ions from azido-imidazoarenes and their structure-activity relationships.

    PubMed

    Wild, D; Dirr, A

    1989-11-01

    New heterocyclic arylazides (azido-imidazoarenes) structurally related to the food mutagen/carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) have been prepared. Their photolysis yields nitrenes and/or nitrenium ions which induce mutations in Salmonella typhimurium. The relationships between the chemical structure and mutagenic activity of these species are the same as those found in our previous studies of the amino- and nitro-imidazoarenes. Therefore the efficiency of the reaction with DNA of the ultimate metabolite, the nitrene/nitrenium ion, is the critical step governing the mutagenic potency of the amino- and nitro-imidazoarenes. The efficiency of DNA-binding depends on the delocalization of the positive charge of the nitrenium ion or of the electron deficiency of the nitrene. It is typical of the N-1-substituted and N-3-substituted arenimidazolyl-nitrenium ions that they can form another nitrenium resonance structure very similar to the parent nitrenium ion structure. We suggest that this property of the nitrene/nitrenium ion, in combination with its aromatic structure facilitating carbonium ion resonance structures, is the basic reason for the extremely potent mutagenic activity of IQ and related food mutagens/carcinogens.

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

    PubMed

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

    2012-01-01

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

  13. Estimating the persistence of organic contaminants in indirect potable reuse systems using quantitative structure activity relationship (QSAR).

    PubMed

    Lim, Seung Joo; Fox, Peter

    2012-09-01

    Predictions from the quantitative structure activity relationship (QSAR) model EPI Suite were modified to estimate the persistence of organic contaminants in indirect potable reuse systems. The modified prediction included the effects of sorption, biodegradation, and oxidation that may occur during sub-surface transport. A retardation factor was used to simulate the mobility of adsorbed compounds during sub-surface transport to a recovery well. A set of compounds with measured persistent properties during sub-surface transport was used to validate the results of the modifications to the predictions of EPI Suite. A comparison of the predicted values and measured values was done and the residual sum of the squares showed the importance of including oxidation and sorption. Sorption was the most important factor to include in predicting the fates of organic chemicals in the sub-surface environment.

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

    PubMed

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

    2015-08-28

    The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition.

    PubMed

    Ng, Wai-Lung; Li, Ho-Chuen; Lau, Kit-Man; Chan, Anthony K N; Lau, Clara Bik-San; Shing, Tony K M

    2017-07-17

    Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.

  16. Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists.

    PubMed

    Chen, Zhixiang; Ning, Mengmeng; Zou, Qingan; Cao, Hua; Ye, Yangliang; Leng, Ying; Shen, Jianhua

    2016-01-01

    A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methyl-thiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.

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

    PubMed

    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 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 of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective Gq inhibitory activity. This provides pertinent information for the understanding of the Gq 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.

  18. Cellular uptake of transportan 10 and its analogs in live cells: Selectivity and structure-activity relationship studies.

    PubMed

    Song, Jingjing; Kai, Ming; Zhang, Wei; Zhang, Jindao; Liu, Liwei; Zhang, Bangzhi; Liu, Xin; Wang, Rui

    2011-09-01

    Transportan 10 (TP10) is an amphipathic cell-penetrating peptide with high translocation ability. In order to obtain more details of structure-activity relationship of TP10, we evaluated the effects of structure and charge on its translocation ability. Our results demonstrated that disrupting the helical structure or Arg substitution could remarkably decrease the cellular uptake of TP10. However, increasing the number of positive charge was an effective strategy to enhance translocation ability of TP10. Furthermore, the molecular dynamics simulation supported the results derived from experiments, suggesting that higher membrane disturbance leads to higher cellular uptake of peptides. In addition, our study also demonstrated TP10 and its analogs preferentially entered cancer cells rather than normal cells. The uptake selectivity toward cancer cells makes TP10 and its analogs as potent CPPs for drug delivery. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Cationic Membrane Peptides: Atomic-Level Insight of Structure-Activity Relationships from Solid-State NMR

    PubMed Central

    Su, Yongchao; Li, Shenhui; Hong, Mei

    2012-01-01

    Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this mini-review we will summarize high-resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane. PMID:23108593

  20. Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.

    PubMed

    Stokes, Neil R; Baker, Nicola; Bennett, James M; Chauhan, Pramod K; Collins, Ian; Davies, David T; Gavade, Maruti; Kumar, Dushyant; Lancett, Paul; Macdonald, Rebecca; Macleod, Leanne; Mahajan, Anu; Mitchell, Jeffrey P; Nayal, Narendra; Nayal, Yashodanand Nandan; Pitt, Gary R W; Singh, Mahipal; Yadav, Anju; Srivastava, Anil; Czaplewski, Lloyd G; Haydon, David J

    2014-01-01

    The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.

  1. Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

    PubMed Central

    Shehata, Mohamed A.; Nøhr, Anne C.; Lissa, Delphine; Bisig, Christoph; Isberg, Vignir; Andersen, Kirsten B.; Harpsøe, Kasper; Björkling, Fredrik; Bräuner-Osborne, Hans; Gloriam, David E.

    2016-01-01

    GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson’s disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization. PMID:27830715

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

    PubMed

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

    2015-06-05

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

  3. Studies of Staphylococcus aureus FabI inhibitors: fragment-based approach based on holographic structure-activity relationship analyses.

    PubMed

    Kronenberger, Thales; Asse, Leonardo Rander; Wrenger, Carsten; Trossini, Gustavo Henrique Goulart; Honorio, Kathia Maria; Maltarollo, Vinicius Gonçalves

    2017-02-01

    FabI is a key enzyme in the fatty acid metabolism of Gram-positive bacteria such as Staphylococcus aureus and is an established drug target for known antibiotics such as triclosan. However, due to increasing antibacterial resistance, there is an urgent demand for new drug discovery. Recently, aminopyridine derivatives have been proposed as promising competitive inhibitors of FabI. In the present study, holographic structure-activity relationship (HQSAR) analyses were employed for determining structural contributions of a series containing 105 FabI inhibitors. The final HQSAR model was robust and predictive according to statistical validation (q(2) and r(2)pred equal to 0.696 and 0.854, respectively) and could be further employed to generate fragment contribution maps. Then, final HQSAR model together with FabI active site information can be useful for designing novel bioactive ligands.

  4. Modeling structure-activity relationships of prodiginines with antimalarial activity using GA/MLR and OPS/PLS.

    PubMed

    de Campos, Luana Janaína; de Melo, Eduardo Borges

    2014-11-01

    In the present study, we performed a multivariate quantitative structure-activity relationship (QSAR) analysis of 52 prodiginines with antimalarial activity. Variable selection was based on the genetic algorithm (GA) and ordered predictor selection (OPS) approaches, and the models were built using the multiple linear regression (MLR) and partial least squares (PLS) regression methods. The leave-N-out crossvalidation and y-randomization tests showed that the models were robust and free from chance correlation. The mechanistic interpretation of the results was supported by earlier findings. In addition, the comparison of our models with those previously described indicated that the OPS/PLS-based model had a higher quality of external prediction. Thus, this study provides a comprehensive approach to the evaluation of the antimalarial activity of prodiginines, which may be used as a support tool in designing new therapeutic agents for malaria.

  5. A quantitative structure-activity relationship study on a few series of anti-hepatitis C virus agents.

    PubMed

    Varshney, Jonish; Sharma, Anjana; Gupta, Satya P

    2012-05-01

    A 2-Dimensional Quantitative Structure-Activity Relationship study has been performed on 2 series of hepatitis C virus (HCV) inhibitors, i.e., Isothiazoles and Thiazolones. In each case significant correlations are found between the anti-HCV potencies and some physicochemical, electronic and steric properties of the compounds, indicating that for the first series the activity is controlled by density and two indicator parameters (one for halogen and other for methyl), while for the second series density, Hammett constant and Kier's first order valence molecular connectivity index are important for anti-HCV activity. The validity of the correlation has been judged by leave-one-out jackknife procedure and predicting the activity of some test compounds. Using the correlations obtained, some new compounds of high potency have been predicted in each series.

  6. [Inhibition of oxygen consumption by annonaceous acetogenins in liver cell respiration and their structure-activity relationship].

    PubMed

    Xu, Zhi-Fang; Wei, Xiao-yi; Xie, Hai-hui; Yang, Ren-zhou

    2002-10-01

    To study the inhibition of oxygen consumption by annonaceous acetogenins (ACG) and their structure-activity relationship (SAR). The inhibition of oxygen consumption in chicken liver cell respiration by different structural ACG was studied by using oxygen electrode technique. Six ACG showed potent inhibitory effects like rotenone which was a classical inhibitor of mitochondrial complex I, and was more potent than complex IV inhibitor KCN. The IC50 values of six ACG for inhibiting oxygen consumption suggested that bistetrahydrofuran (THF) ACG was 7-11 times more active than non-THF ACG, and A1-type ACG was more potent than A2-type ACG. The terminal gamma-lactone was crucial for the inhibition of oxygen consumption. The distance between THF and gamma-lactone, the hydroxyl groups in the alkyl chain, were the important factors of SAR, but the 4-OH group possibly played some negative role in the exhibit of potent activity.

  7. Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies.

    PubMed

    Denèfle, Thomas; Boullet, Héloise; Herbi, Linda; Newton, Clara; Martinez-Torres, Ana-Carolina; Guez, Alexandre; Pramil, Elodie; Quiney, Claire; Pourcelot, Marilyne; Levasseur, Mikail D; Lardé, Eva; Moumné, Roba; Ogi, François-Xavier; Grondin, Pascal; Merle-Beral, Hélène; Lequin, Olivier; Susin, Santos A; Karoyan, Philippe

    2016-09-22

    Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies.

  8. Chromanyl-isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies.

    PubMed

    Singh, Gagandeep; Sharma, Anuradha; Kaur, Harpreet; Ishar, Mohan Paul S

    2016-02-01

    Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities.

  9. In vitro inhibition effect and structure-activity relationships of some saccharin derivatives on erythrocyte carbonic anhydrase I and II.

    PubMed

    Sonmez, Fatih; Bilen, Cigdem; Sumersan, Sinem; Gencer, Nahit; Isik, Semra; Arslan, Oktay; Kucukislamoglu, Mustafa

    2014-02-01

    In this study, in vitro inhibitory effects of some saccharin derivatives on purified carbonic anhydrase I and II were investigated using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among the compounds, 6-(p-tolylthiourenyl) saccharin (6m) was found to be the most active one for hCA I activity (IC50=13.67 μM) and 6-(m-methoxyphenylurenyl) saccharin (6b) was found to be the most active one for hCA II activity (IC50=6.54 μM). Structure-activity relationships (SARs) study showed that, generally, thiourea derivatives (6l--v) inhibited more hCA I and hCA II than urea derivatives (6a-k). All compounds (excluding 6c and 6r) have higher inhibitory activity on hCA II than on hCA I.

  10. Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors.

    PubMed

    Zhang, Yu; Xu, Lei; Zhang, Zhiqiang; Zhang, Zhiyu; Zheng, Longtai; Li, Dan; Li, Youyong; Liu, Feng; Yu, Kunqian; Hou, Tingjun; Zhen, Xuechu

    2015-09-28

    Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl]amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure-activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.

  11. Protegrin structure-activity relationships: using homology models of synthetic sequences to determine structural characteristics important for activity.

    PubMed

    Ostberg, Nathan; Kaznessis, Yiannis

    2005-02-01

    The protegrin family of antimicrobial peptides is among the shortest in sequence length while remaining very active against a variety of microorganisms. The major goal of this study is to characterize easily calculated molecular properties, which quantitatively show high correlation with antibacterial activity. The peptides studied have high sequence similarity but vary in activity over more than an order of magnitude. Hence, sequence analysis alone cannot be used to predict activity for these peptides. We calculate structural properties of 62 protegrin and protegrin-analogue peptides and correlate them to experimental activities against six microbe species, as well as hemolytic and cytotoxic activities. Natural protegrins structures were compared with synthetic derivatives using homology modeling, and property descriptors were calculated to determine the characteristics that confer their antimicrobial activity. A structure-activity relationship study of all these peptides provides information about the structural properties that affect activity against different microbial species.

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

    PubMed

    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

    2016-04-14

    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 report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.

  13. Quantitative structure-activity relationship studies of a series of sulfa drugs as inhibitors of Pneumocystis carinii dihydropteroate synthetase.

    PubMed

    Johnson, T; Khan, I A; Avery, M A; Grant, J; Meshnick, S R

    1998-06-01

    Sulfone and sulfanilamide sulfa drugs have been shown to inhibit dihydropteroate synthetase (DHPS) isolated from Pneumocystis carinii. In order to develop a pharmacophoric model for this inhibition, quantitative structure-activity relationships (QSAR) for sulfa drugs active against DHPS have been studied. Accurate 50% inhibitory concentrations were collected for 44 analogs, and other parameters, such as partition coefficients and molar refractivity, were calculated. Conventional multiple regression analysis of these data did not provide acceptable QSAR. However, three-dimensional QSAR provided by comparative molecular field analysis did give excellent results. Upon removal of poorly correlated analogs, a data set of 36 analogs, all having a common NHSO2 group, provided a cross-validated r2 value of 0.699 and conventional r2 value of 0.964. The resulting pharmacophore model should be useful for understanding and predicting the binding of DHPS by new sulfa drugs.

  14. Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents.

    PubMed

    Ling, Chenyu; Fu, Liqiang; Gao, Suo; Chu, Wenjing; Wang, Hui; Huang, Yanqin; Chen, Xiaoyan; Yang, Yushe

    2014-06-12

    A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

  15. [A new SVRDF 3D-descriptor of amino acids and its application to peptide quantitative structure activity relationship].

    PubMed

    Tong, Jian-Bo; Zhang, Sheng-Wan; Cheng, Su-Li; Li, Gai-Xian

    2007-01-01

    To establish a new amino acid structure descriptor that can be applied to polypeptide quantitative structure activity relationship (QSAR) studies, a new descriptor, SVRDF, was derived from a principal components analysis of a matrix of 150 radial distribution function index of amino acids. The scale was then applied in three panels of peptide QSAR that were molded by partial least squares regression. The obtained models with the correlation coefficients (R2(cum)), cross-validation correlation coefficients (Q2(cum)) were 0.766 and 0.724 for 48 bitter tasting dipeptides; 0.941 and 0.811 for 21 oxytocin analogues; 0.996 and 0.919 for 20 thromboplastin inhibitors. Satisfactory results showed that information related to biological activity can be systemically expressed by SVRDF scales, which may be an useful structural expression methodology for the study of peptides QSAR.

  16. Neuroprotective peptide-macrocycle conjugates reveal complex structure-activity relationships in their interactions with amyloid β.

    PubMed

    Yu, Mingfeng; Ryan, Timothy M; Ellis, Samantha; Bush, Ashley I; Triccas, James A; Rutledge, Peter J; Todd, Matthew H

    2014-10-01

    Interactions between amyloid β (Aβ) and metal ions are thought to mediate the neuropathogenic effects of Aβ in Alzheimer's disease. The construction of small molecules capable of synergistically chelating metal ions and recognizing Aβ would allow new insights into the biology of this disease and provide a possible therapeutic approach. We report herein the synthesis and biological evaluation of tetraazamacrocycle-(G)KLVFF hybrids and their metal complexes. The results obtained from ThT and bis-ANS extrinsic fluorescence assays, tyrosine intrinsic fluorescence assay and proteolytic assay imply complex, multifaceted structure-activity relationships in the interaction of these conjugates with Aβ. Many of the compounds tested rescued cells from Aβ-induced cytotoxicity. The attendant simplicity and ready diversification of the synthesis of these conjugates makes them attractive for further investigation.

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

    PubMed Central

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

    2016-01-01

    In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600EB-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site. PMID:28003837

  18. Theoretical investigations and density functional theory based quantitative structure-activity relationships model for novel cytotoxic platinum(IV) complexes.

    PubMed

    Varbanov, Hristo P; Jakupec, Michael A; Roller, Alexander; Jensen, Frank; Galanski, Markus; Keppler, Bernhard K

    2013-01-10

    Octahedral platinum(IV) complexes are promising candidates in the fight against cancer. In order to rationalize the further development of this class of compounds, detailed studies on their mechanisms of action, toxicity, and resistance must be provided and structure-activity relationships must be drawn. Herein, we report on theoretical and QSAR investigations of a series of 53 novel bis-, tris-, and tetrakis(carboxylato)platinum(IV) complexes, synthesized and tested for cytotoxicity in our laboratories. The hybrid DFT functional wb97x was used for optimization of the structure geometry and calculation of the descriptors. Reliable and robust QSAR models with good explanatory and predictive properties were obtained for both the cisplatin sensitive cell line CH1 and the intrinsically cisplatin resistant cell line SW480, with a set of four descriptors.

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

    PubMed

    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.

  20. Quantitative structure-activity relationships by evolved neural networks for the inhibition of dihydrofolate reductase by pyrimidines.

    PubMed

    Landavazo, Dana G; Fogel, Gary B; Fogel, David B

    2002-02-01

    Evolutionary computation provides a useful method for training neural networks in the face of multiple local optima. This paper begins with a description of methods for quantitative structure activity relationships (QSAR). An overview of artificial neural networks for pattern recognition problems such as QSAR is presented and extended with the description of how evolutionary computation can be used to evolve neural networks. Experiments are conducted to examine QSAR for the inhibition of dihydrofolate reductase by pyrimidines using evolved neural networks. Results indicate the utility of evolutionary algorithms and neural networks for the predictive task at hand. Furthermore, results that are comparable or perhaps better than those published previously were obtained using only a small fraction of the previously required degrees of freedom.

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

    NASA Astrophysics Data System (ADS)

    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.

  2. Evaluation and structure-activity relationship study of acute toxicity of naphthoquinones to Photobacterium phosphoreum, Photobacterium T3B.

    PubMed

    Ding, Feng; Guo, Jing; Li, Zhen; Li, Li Ying; Zhang, Jin Yang; Zhang, Jin Hua; Lian, Jie; Song, Wen Hua; Zhu, Lin

    2010-08-01

    The acute toxicities of five naphthoquinone compounds to Photobacterium phosphoreum were determined. We evaluated the mechanism of toxicity using the structure-activity relationship technique. The results showed that some factors, including the species of substituents, shape/size of molecule and oil-water partition coefficient (log P) played the important roles in the interaction between the naphthoquinones and the target. Among of these, the toxicities of Atovaquone and Buparvaquone were lower than the other naphthoquinones we tested because of the alkyl-substitution with the bigger volume and strong hydrophobicity. Conversely, Menadione had the highest toxicity because of the appropriate log P and shape/size of molecule resulting in the easier interaction with the target.

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

    PubMed

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

    2013-09-01

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

  4. [The manipulation of information of developed formulas for the study of structure-activity relationships. Application to antiparasitic agents].

    PubMed

    Doré, J C; Lacroix, J; Lacroix, R; Viel, C

    1990-01-01

    Beside traditional univariate methods of pharmacochemical (pharmacomodulation...), and of molecular pharmacology ("binding"...) most global approach (multivariate) of structure-activity and structure-toxicity relationships may been in action with processing implement. Developed formula may been treated by different algorithmic methods as molecular connectivity matrix which use atoms, bindings, chemical functions, fragments, of any molecule. This technique allows to research and to automatically count structural fragments of molecule, different in their chemical aspect but having the same port of activity. So, with this profile of fragments it is possible to build a spanning tree (PRIM'S arborescent skeleton) and to place a priori on it, new structures with other properties to value their activity level in the designed field. We applied these techniques to 50 most prescribed antiparasitic active principles.

  5. Structure-activity relationship for hydrophobic salts as viscosity-lowering excipients for concentrated solutions of monoclonal antibodies.

    PubMed

    Guo, Zheng; Chen, Alvin; Nassar, Roger A; Helk, Bernhard; Mueller, Claudia; Tang, Yu; Gupta, Kapil; Klibanov, Alexander M

    2012-11-01

    To discover, elucidate the structure-activity relationship (SAR), and explore the mechanism of action of excipients able to drastically lower the viscosities of concentrated aqueous solutions of humanized monoclonal antibodies (MAbs). Salts prepared from hydrophobic cations and anions were dissolved into humanized MAbs solutions. Viscosities of the resulting solutions were measured as a function of the nature and concentration of the salts and MAbs. Even at moderate concentrations, some of the salts prepared herein were found to reduce over 10-fold the viscosities of concentrated aqueous solutions of several MAbs at room temperature. To be potent viscosity-lowering excipients, the ionic constituents of the salts must be hydrophobic, bulky, and aliphatic. A mechanistic hypothesis explaining the observed salt effects on MAb solutions' viscosities was proposed and verified.

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

    SciTech Connect

    Sadat Hayatshahi, Sayyed Hamed; Khajeh, Khosro

    2005-12-16

    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 {sub 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%.

  7. Phomentrioloxin, a fungal phytotoxin with potential herbicidal activity, and its derivatives: a structure-activity relationship study.

    PubMed

    Cimmino, Alessio; Andolfi, Anna; Zonno, Maria Chiara; Boari, Angela; Troise, Ciro; Motta, Andrea; Vurro, Maurizio; Ash, Gavin; Evidente, Antonio

    2013-10-09

    Phomentrioloxin is a phytotoxic geranylcyclohexenetriol produced in liquid culture by Phomopsis sp. (teleomorph: Diaporthe gulyae), a potential mycoherbicide proposed for the control of the annual weed Carthamus lanatus. In this study, seven derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on nonhost weedy and agrarian plants, fungi, Gram+ and Gram- bacteria, and on brine shrimp larvae. The results provide insights into an investigation of the structural requirements for activity. The hydroxy groups at C-2 and C-4 appeared to be important features for the phytotoxicity, as well as an unchanged cyclohexentriol ring. A role seemed also to be played by the unsaturations of the geranyl side chain. These findings could be useful for understanding the mechanisms of action of new natural products, for identifying the active sites, and possibly in devising new herbicides of natural origin.

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

    PubMed

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

    2013-07-08

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

  9. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.

    PubMed

    Adam, Julia M; Bennett, D Jonathan; Bom, Anton; Clark, John K; Feilden, Helen; Hutchinson, Edward J; Palin, Ronald; Prosser, Alan; Rees, David C; Rosair, Georgina M; Stevenson, Donald; Tarver, Gary J; Zhang, Ming-Qiang

    2002-04-25

    A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.

  10. Synthesis and structure-active relationship of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline anticonvulsants.

    PubMed

    Gitto, Rosaria; De Luca, Laura; Ferro, Stefania; Agnello, Stefano; Russo, Emilio; De Sarro, Giovanbattista; Chimirri, Alba

    2010-12-01

    We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticonvulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported analogues. This novel series of isoquinolines was designed on the basis of well defined structure-active relationship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2) mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-1-(4'-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6d) that displayed significant anticonvulsant activity. Computational studies helped to rationalize these obtained pharmacological results.

  11. Enzymatic Methylation and Structure-Activity-Relationship Studies on Polycarcin V, a Gilvocarcin-Type Antitumor Agent

    PubMed Central

    Chen, Jhong-Min; Shepherd, Micah D.; Horn, Jamie; Leggas, Markos; Rohr, Jürgen

    2014-01-01

    Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure-activity-relationships of the gilvocarcin group of antitumor antibiotics, because of a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O-methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2’-OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important H-bond donor for the interaction with histone H3, while converting 3'-OH into an OCH3 group improved the bioactivity. Bis-methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two H-bond donors in the sugar are necessary for optimal binding. PMID:25366963

  12. AutoQSAR: an automated machine learning tool for best-practice quantitative structure-activity relationship modeling.

    PubMed

    Dixon, Steven L; Duan, Jianxin; Smith, Ethan; Von Bargen, Christopher D; Sherman, Woody; Repasky, Matthew P

    2016-10-01

    We introduce AutoQSAR, an automated machine-learning application to build, validate and deploy quantitative structure-activity relationship (QSAR) models. The process of descriptor generation, feature selection and the creation of a large number of QSAR models has been automated into a single workflow within AutoQSAR. The models are built using a variety of machine-learning methods, and each model is scored using a novel approach. Effectiveness of the method is demonstrated through comparison with literature QSAR models using identical datasets for six end points: protein-ligand binding affinity, solubility, blood-brain barrier permeability, carcinogenicity, mutagenicity and bioaccumulation in fish. AutoQSAR demonstrates similar or better predictive performance as compared with published results for four of the six endpoints while requiring minimal human time and expertise.

  13. Quantitative Structure Activity Relationship for Inhibition of Human Organic Cation/Carnitine Transporter (OCTN2)

    PubMed Central

    Diao, Lei; Ekins, Sean; Polli, James E.

    2010-01-01

    Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L-carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure–activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and Cmax/Ki ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates and their diminished elimination by other drugs is concluded not to be mediated by OCTN2. PMID:20831193

  14. Structure-activity relationships in Ni-Fe (oxy)hydroxide oxygen evolution electrocatalysts

    NASA Astrophysics Data System (ADS)

    Batchellor, Adam S.

    The oxygen evolution reaction (OER) is kinetically slow and hence a significant efficiency loss in electricity-driven water electrolysis. Understanding the relationships between architecture, composition, and activity in high-performing catalyst systems are critical for the development of better catalysts. This dissertation discusses areas both fundamental and applied that seek to better understand how to accurately measure catalyst activity as well as ways to design higher performing catalysts. Chapter I introduces the work that has been done in the field to date. Chapter II compares various methods of determining the electrochemically active surface area of a film. It further discusses how pulsed and continuous electrodepostition techniques effect film morphology and behavior, and shows that using a simple electrodeposition can create high loading films with architectures that outperform those deposited onto inert substrates. The reversibility of the films, a measure of the films transport efficiency, is introduced and shown to correlate strongly with performance. Chapter III uses high energy x-ray scattering to probe the nanocrystalline domains of the largely amorphous NiFe oxyhydroxide catalysts, and shows that significant similarities in the local structure are not responsible for the change in performance for the films synthesized under different conditions. Bond lengths for oxidized and reduced catalysts are determined, and show no significant phase segregation occurs. Chapter IV seeks to optimize the deposition conditions introduced in Chapter II and to provide a physical representation of how tuning each of the parameters affects film morphology. The deposition current density is shown to be the most important factor affecting film performance at a given loading. Chapter V highlights the different design considerations for films being used in a photoelectrochemical cell, and how in situ techniques can provide information that may otherwise be unobtainable

  15. Evaluation and Structure-Activity Relationship Analysis of a New Series of Arylnaphthalene lignans as Potential Anti-Tumor Agents

    PubMed Central

    Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

    2014-01-01

    Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6′-hydroxy justicidin A (HJA), 6′-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6′ significantly increased the antiproliferative activity of

  16. Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties

    PubMed Central

    Potůčková, Eliška; Hrušková, Kateřina; Bureš, Jan; Kovaříková, Petra; Špirková, Iva A.; Pravdíková, Kateřina; Kolbabová, Lucie; Hergeselová, Tereza; Hašková, Pavlína; Jansová, Hana; Macháček, Miloslav; Jirkovská, Anna; Richardson, Vera; Lane, Darius J. R.; Kalinowski, Danuta S.; Richardson, Des R.; Vávrová, Kateřina; Šimůnek, Tomáš

    2014-01-01

    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. PMID:25393531

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

    PubMed

    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.

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

    PubMed Central

    2013-01-01

    Background 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. Results 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. Conclusions 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. PMID:24171724

  19. Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents.

    PubMed

    Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

    2014-01-01

    Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6'-hydroxy justicidin A (HJA), 6'-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6' significantly increased the antiproliferative activity of

  20. Inhibitory effects of dietary flavonoids on purified hepatic NADH-cytochrome b5 reductase: structure-activity relationships.

    PubMed

    Çelik, Haydar; Koşar, Müberra

    2012-05-30

    The structure-activity relationships of flavonoids with regard to their inhibitory effects on NADH-cytochrome b5 reductase (E.C. 1.6.2.2), a clinically and toxicologically important enzyme, are not known. In the present study, the inhibitory effects of fourteen selected flavonoids of variable structure on the activity of purified bovine liver cytochrome b5 reductase, which shares a high degree of homology with the human counterpart, were investigated and the relationship between structure and inhibition was examined. Of all the compounds tested, the flavone luteolin was the most potent in inhibiting b5 reductase with an IC50 value of 0.11 μM, whereas naringenin, naringin and chrysin were inactive within the concentration range tested. Most of the remaining flavonoids (morin, quercetin, quercitrin, myricetin, luteolin-7-O-glucoside, (-)-epicatechin, and (+)-catechin) produced a considerable inhibition of enzyme activity with IC50 values ranging from 0.81 to 4.5 μM except apigenin (36 μM), rutin (57 μM) and (+)-taxifolin (IC50 not determined). The magnitude of inhibition was found to be closely related to the chemical structures of flavonoids. Analysis of structure-activity data revealed that flavonoids containing two hydroxyl groups in ring B and a carbonyl group at C-4 in combination with a double bond between C-2 and C-3 produced a much stronger inhibition, whereas substitution of a hydroxyl group at C-3 was associated with a less inhibitory effect. The physiologically relevant IC50 values for most of the flavonoids tested regarding b5 reductase inhibition indicate a potential for significant flavonoid-drug and/or flavonoid-xenobiotic interactions which may have important therapeutic and toxicological outcomes for certain drugs and/or xenobiotics. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. Structure-activity relationship of natural flavonoids in hydroxyl radical-scavenging effects.

    PubMed

    Chen, Ji-Wu; Zhu, Zhen-Qin; Hu, Tian-Xi; Zhu, Da-Yuan

    2002-07-01

    To study the relationship between the structure and hydroxyl radical (*OH)-scavenging activity of twelve natural flavonoids. The hydroxyl radical-generating chemiluminescence system with ascorbate-CuSO4-yeast-H2O2 was used to determine the hydroxyl radical-scavenging activity of twelve natural flavonoids. Guercetin, heliosin, hyperoside, kaempferol, baicalin, corylifolin, lysionotin, matteucinol, corylifolinin, and genistein could effectively scavenge. OH and inhibit the chemiluminescence of the system. The IC50 values (95 % confidence limits) of the flavonoids were 12.1 (9.9-14.5) g/L, 15.8(14.0-19.2) g/L, 19.5 (16.8-27.4) g/L, 20.1 (13.6-29.0) g/L, 34.6 (28.4-43.4) g/L, 66.8 (63.2-74.4) g/L, 187 (147-235) g/L, 211 (165-284) g/L, 262 (190-346) g/L, and 708 (498-994) g/L, respectively; whereas nobilelin and corylifolin-Ac could not scavenge *OH. (1) Phenolic hydroxyls in flavonoids were the main active groups capable of scavenging *OH; (2) Hydroxyl groups in ring B and A were important *OH-scavenging active groups; (3) The ortho-dihydroxyl groups in ring A and/or B could greatly enhance the *OH-scavenging activity of the rings; (4) Comparing the IC50 values of guercetin, heliosin, hyperoside, baicalin, lysionotin, and matteucinol, it was suggested that the hydroxyl groups on 3',4' position of ring B possessed high *OH-scavenging activity and the scavenging activity of hydroxyl groups in ring B was higher than that of hydroxyl groups in ring A. The hydroxyl group or glucoside on 3 position of ring C of the above mentioned 6 flavonoids was also related to the. OH-scavenging ability. (5) The structural types of flavonoids themselves could influence their *OH-scavenging activity.

  2. Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection

    PubMed Central

    Li, Bin; Zhang, Bingyu; Miao, Fang

    2017-01-01

    A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure−activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4–28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure−activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly. PMID:28423022

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

    PubMed

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

    2014-07-14

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

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

    SciTech Connect

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

    1985-02-01

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

  5. Quantitative structure-activity relationship of botanical sesquiterpenes: spatial and contact repellency to the yellow fever mosquito, Aedes aegypti.

    PubMed

    Paluch, Gretchen; Grodnitzky, Justin; Bartholomay, Lyric; Coats, Joel

    2009-08-26

    The plant terpenoids encompass a diversity of structures and have many functional roles in nature, including protection against pest arthropods. Previous studies in this laboratory have identified naturally occurring sesquiterpenes contained in essential oils from two plants, amyris (Amyris balsamifera) and Siam-wood (Fokienia hodginsii), that are significantly repellent to a spectrum of arthropod pests. In efforts to further examine the biological activity of this class of compounds 12 of these plant-derived sesquiterpenes have been isolated, purified, and assayed for spatial and contact repellency against the yellow fever mosquito, Aedes aegypti . These data were used to develop quantitative structure-activity relationships that identified key properties of the sesquiterpene molecule, including electronic and structural parameters that were used to predict optimal repellent activity. There were notable similarities in the models developed for spatial repellency over five time points and for contact repellency. Vapor pressure was an important component of all repellency models. Initial levels of spatial repellency were also related to polarizability of the molecule and lowest unoccupied molecular orbital (LUMO) energy, whereas the equation for late spatial repellency was dependent on other electronic features, including Mulliken population and electrotopological state descriptors. The model identified for contact repellency was the best fit and most significant model in this analysis and showed a relationship with vapor pressure, Mulliken population, and total energy.

  6. Plant-derived flavones as inhibitors of aurora B kinase and their quantitative structure-activity relationships.

    PubMed

    Jung, Yearam; Shin, Soon Young; Yong, Yeonjoong; Jung, Hyeryoung; Ahn, Seunghyun; Lee, Young Han; Lim, Yoongho

    2015-05-01

    Although several plant-derived flavones inhibit aurora B kinase (aurB), quantitative relationships between the structural properties of plant-derived flavones and their inhibitory effects on aurB remain unclear. In this report, these quantitative structure-activity relationships were obtained. For quercetagetin, found in the Eriocaulon species, showing the best IC50 value among the flavone derivatives tested in this report, further biological tests were performed using cell-based assays, including Western blot analysis, flow cytometry, and immunofluorescence microscopy. In vitro cellular experiments demonstrated that quercetagetin inhibits aurB. The molecular-binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB, aurA, and aurC and prevents the active phosphorylation of all three aurora kinases. In addition, quercetagetin triggers mitotic arrest and caspase-mediated apoptosis. These observations suggest that quercetagetin is an aurora kinase inhibitor. Induction of mitosis-associated tumor cell death by quercetagetin is a promising strategy for developing novel chemotherapeutic anticancer agents.

  7. SARANEA: a freely available program to mine structure-activity and structure-selectivity relationship information in compound data sets.

    PubMed

    Lounkine, Eugen; Wawer, Mathias; Wassermann, Anne Mai; Bajorath, Jürgen

    2010-01-01

    We introduce SARANEA, an open-source Java application for interactive exploration of structure-activity relationship (SAR) and structure-selectivity relationship (SSR) information in compound sets of any source. SARANEA integrates various SAR and SSR analysis functions and utilizes a network-like similarity graph data structure for visualization. The program enables the systematic detection of activity and selectivity cliffs and corresponding key compounds across multiple targets. Advanced SAR analysis functions implemented in SARANEA include, among others, layered chemical neighborhood graphs, cliff indices, selectivity trees, editing functions for molecular networks and pathways, bioactivity summaries of key compounds, and markers for bioactive compounds having potential side effects. We report the application of SARANEA to identify SAR and SSR determinants in different sets of serine protease inhibitors. It is found that key compounds can influence SARs and SSRs in rather different ways. Such compounds and their SAR/SSR characteristics can be systematically identified and explored using SARANEA. The program and source code are made freely available under the GNU General Public License.

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

    PubMed Central

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

    2011-01-01

    While the synthetic utility of asymmetric phase transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product. PMID:21446723

  9. College Student Dating Partner Drinking Profiles: Differences in Relationship Functioning and Relationship-Specific Alcohol Expectancies

    PubMed Central

    Linden-Carmichael, Ashley N; Kelley, Michelle L.

    2016-01-01

    Background Although the majority of research on partner drinking styles has examined married couples, dating partners may influence one another's problem behaviors including alcohol use. Objectives This study identified patterns of at-risk alcohol use in college women and their dating partners using a person-centered statistical approach (i.e., latent profile analysis). Methods Participants were 286 college student women in dating relationships. They completed questionnaires regarding their own and their partners’ drinking, alcohol use severity, intimate partner violence (IPV), relationship satisfaction, and relationship-specific alcohol expectancies. Data were collected in 2012 through 2013. Results Results revealed three distinct, latent classes based on both partners’ alcohol outcomes. The “Low-Risk” group (58%) consisted of non-heavy drinking partners. In the “High-Risk – Higher Men” class (27%), men drank more than women; however, both men and women were high-risk drinkers. The “High-Risk – Higher Women” group (15%) consisted of high-risk drinking partners but women consumed more alcohol than men. Both high-risk couple groups were more dissatisfied in their relationships and experienced more IPV, but held stronger beliefs about how alcohol influenced their relationship. Conclusions/Importance Findings indicate that there are several distinct classes of dating couples that differ in relationship problems and beliefs about alcohol’s impact on their relationship. Riskier couples differ in behaviors and alcohol-related beliefs from low-risk couples. These findings may inform the development of more efficacious alcohol interventions tailored toward high-risk drinking dating couples. PMID:27096223

  10. Reconsidering the Relationship between Alcohol and Lethal Violence

    ERIC Educational Resources Information Center

    Phillips, Scott; Matusko, Jacqueline; Tomasovic, Elizabeth

    2007-01-01

    Prior event-based research regarding the relationship between alcohol and violence suffers from important limitations, including the absence of a comparison group, an inappropriate comparison group, or a comparison group that could be considered appropriate but does not control for potential confounders. To overcome such limitations, we use a…

  11. Reconsidering the Relationship between Alcohol and Lethal Violence

    ERIC Educational Resources Information Center

    Phillips, Scott; Matusko, Jacqueline; Tomasovic, Elizabeth

    2007-01-01

    Prior event-based research regarding the relationship between alcohol and violence suffers from important limitations, including the absence of a comparison group, an inappropriate comparison group, or a comparison group that could be considered appropriate but does not control for potential confounders. To overcome such limitations, we use a…

  12. Toxicity of substituted anilines to Pseudokirchneriella subcapitata and quantitative structure-activity relationship analysis for polar narcotics.

    PubMed

    Chen, Chung-Yuan; Ko, Chia-Wen; Lee, Po-I

    2007-06-01

    This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e., dissolved oxygen production [DO] and algal growth rate) were used to evaluate the toxicity of anilines. Both DO and growth rate endpoints revealed similar sensitivity to the effects of anilines. However, trichloroanilines showed stronger inhibitory effects on microalgal photosynthetic reactions than that on algal growth. For various aquatic organisms, the relative sensitivity relationship for anilines is Daphnia magna > luminescent bacteria (Microtox) > or = Pocelia reticulata > or = Pseudokirchneriella subcapitata > or = fathead minnow > Tetrahymena pyriformis. The susceptibility of P. subcapitata to anilines is similar to fish, but P. subcapitata is apparently less sensitive than the water flea. The lack of correlation between the toxicity revealed by different aquatic organisms (microalgae, D. magna, luminescent bacteria, and P. reticulata) suggests that anilines might have different metabolic routes in these organisms. Both hydrogen bonding donor capacity (the lowest unoccupied molecular orbital energy, Elumo) and hydrophobicity (1-octanol:water partition coefficient, Kow) were found to provide satisfactory descriptions for the toxicity of polar narcotics (substituted anilines and chlorophenols). Quantitative structure-activity relationships (QSARs) based on Elumo, log Kow, or both values were established with r2 values varying from 0.75 to 0.92. The predictive power for the QSAR models were found to be satisfactory through leave-one-out cross-validation. Such relationships could provide useful information for the estimation of toxicity for other polar narcotic compounds.

  13. The moderating role of social networks in the relationship between alcohol consumption and treatment utilization for alcohol-related problems

    PubMed Central

    Mowbray, Orion

    2014-01-01

    Many individuals wait until alcohol use becomes severe before treatment is sought. However, social networks, or the number of social groups an individual belongs to, may play a moderating role in this relationship. Logistic regression examined the interaction of alcohol consumption and social networks as a predictor of treatment utilization while adjusting for sociodemographic and clinical variables among 1,433 lifetime alcohol-dependent respondents from wave 2 of the National Epidemiologic Survey on Alcohol Related Conditions (NESARC). Results showed that social networks moderate the relationship between alcohol consumption and treatment utilization such that for individuals with few network ties, the relationship between alcohol consumption and treatment utilization was diminished, compared to the relationship between alcohol consumption and treatment utilization for individuals with many network ties. Findings offer insight into how social networks, at times, can influence individuals to pursue treatment, while at other times, influence individuals to stay out of treatment, or seek treatment substitutes. PMID:24462223

  14. The moderating role of social networks in the relationship between alcohol consumption and treatment utilization for alcohol-related problems.

    PubMed

    Mowbray, Orion

    2014-01-01

    Many individuals wait until alcohol use becomes severe before treatment is sought. However, social networks, or the number of social groups an individual belongs to, may play a moderating role in this relationship. Logistic regression examined the interaction of alcohol consumption and social networks as a predictor of treatment utilization while adjusting for sociodemographic and clinical variables among 1,433 lifetime alcohol-dependent respondents from wave 2 of the National Epidemiologic Survey on Alcohol Related Conditions (NESARC). Results showed that social networks moderate the relationship between alcohol consumption and treatment utilization such that for individuals with few network ties, the relationship between alcohol consumption and treatment utilization was diminished, compared to the relationship between alcohol consumption and treatment utilization for individuals with many network ties. Findings offer insight into how social networks, at times, can influence individuals to pursue treatment, while at other times, influence individuals to stay out of treatment, or seek treatment substitutes.

  15. Structure-activity relationship study of biflavonoids on the Dengue virus polymerase DENV-NS5 RdRp.

    PubMed

    Coulerie, Paul; Nour, Mohammed; Maciuk, Alexandre; Eydoux, Cécilia; Guillemot, Jean-Claude; Lebouvier, Nicolas; Hnawia, Edouard; Leblanc, Karine; Lewin, Guy; Canard, Bruno; Figadère, Bruno

    2013-09-01

    Dengue virus is the world's most prevalent human pathogenic arbovirus. There is currently no treatment or vaccine, and solutions are urgently needed. We previously demonstrated that biflavonoids from Dacrydium balansae, an endemic gymnosperm from New Caledonia, are potent inhibitors of the Dengue virus NS5 RNA-dependent RNA polymerase. Herein we describe the structure-activity relationship study of 23 compounds: biflavonoids from D. balansae (1-4) and from D. araucarioides (5-10), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (13-23). We conclude that 1) over the four different biflavonoid skeletons tested, amentoflavone (1) and robustaflavone (5) are the most promising ones for antidengue drug development, 2) the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and 3) the degree of oxygenation of flavonoid monomers influences their antidengue potential. Sotetsuflavone (8), with an IC50 = 0.16 µM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature.

  16. Monte Carlo-based quantitative structure-activity relationship models for toxicity of organic chemicals to Daphnia magna.

    PubMed

    Toropova, Alla P; Toropov, Andrey A; Veselinović, Aleksandar M; Veselinović, Jovana B; Leszczynska, Danuta; Leszczynski, Jerzy

    2016-11-01

    Quantitative structure-activity relationships (QSARs) for toxicity of a large set of 758 organic compounds to Daphnia magna were built up. The simplified molecular input-line entry system (SMILES) was used to represent the molecular structure. The Correlation and Logic (CORAL) software was utilized as a tool to develop the QSAR models. These models are built up using the Monte Carlo method and according to the principle "QSAR is a random event" if one checks a group of random distributions in the visible training set and the invisible validation set. Three distributions of the data into the visible training, calibration, and invisible validation sets are examined. The predictive potentials (i.e., statistical characteristics for the invisible validation set of the best model) are as follows: n = 87, r(2)  = 0.8377, root mean square error = 0.564. The mechanistic interpretations and the domain of applicability of built models are suggested and discussed. Environ Toxicol Chem 2016;35:2691-2697. © 2016 SETAC. © 2016 SETAC.

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

    PubMed

    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.

  18. Interspecies quantitative structure-activity-activity relationships (QSAARs) for prediction of acute aquatic toxicity of aromatic amines and phenols.

    PubMed

    Furuhama, A; Hasunuma, K; Aoki, Y

    2015-01-01

    We propose interspecies quantitative structure-activity-activity relationships (QSAARs), that is, QSARs with descriptors, to estimate species-specific acute aquatic toxicity. Using training datasets consisting of more than 100 aromatic amines and phenols, we found that the descriptors that predicted acute toxicities to fish (Oryzias latipes) and algae were daphnia toxicity, molecular weight (an indicator of molecular size and uptake) and selected indicator variables that discriminated between the absence or presence of various substructures. Molecular weight and the selected indicator variables improved the goodness-of-fit of the fish and algae toxicity prediction models. External validations of the QSAARs proved that algae toxicity could be predicted within 1.0 log unit and revealed structural profiles of outlier chemicals with respect to fish toxicity. In addition, applicability domains based on leverage values provided structural alerts for the predicted fish toxicity of chemicals with more than one hydroxyl or amino group attached to an aromatic ring, but not for fluoroanilines, which were not included in the training dataset. Although these simple QSAARs have limitations, their applicability is defined so clearly that they may be practical for screening chemicals with molecular weights of ≤364.9.

  19. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

    PubMed Central

    Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

    2010-01-01

    Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

  20. Comparative analysis of local and consensus quantitative structure-activity relationship approaches for the prediction of bioconcentration factor.

    PubMed

    Piir, G; Sild, S; Maran, U

    2013-01-01

    Quantitative structure-activity relationships (QSARs) are broadly classified as global or local, depending on their molecular constitution. Global models use large and diverse training sets covering a wide range of chemical space. Local models focus on smaller structurally or chemically similar subsets that are conventionally selected by human experts or alternatively using clustering analysis. The current study focuses on the comparative analysis of different clustering algorithms (expectation-maximization, K-means and hierarchical) for seven different descriptor sets as structural characteristics and two rule-based approaches to select subsets for designing local QSAR models. A total of 111 local QSAR models are developed for predicting bioconcentration factor. Predictions from local models were compared with corresponding predictions from the global model. The comparison of coefficients of determination (r(2)) and standard deviations for local models with similar subsets from the global model show improved prediction quality in 97% of cases. The descriptor content of derived QSARs is discussed and analyzed. Local QSAR models were further consolidated within the framework of consensus approach. All different consensus approaches increased performance over the global and local models. The consensus approach reduced the number of strongly deviating predictions by evening out prediction errors, which were produced by some local QSARs.

  1. The antibacterial properties of 6-tuliposide B. Synthesis of 6-tuliposide B analogues and structure-activity relationship.

    PubMed

    Shigetomi, Kengo; Shoji, Kazuaki; Mitsuhashi, Shinya; Ubukata, Makoto

    2010-02-01

    6-Tuliposide B is a secondary metabolite occurring specifically in tulip anthers. Recently, a potent antibacterial activity of 6-tuliposide B has been reported. However, its molecular target has not yet been established, nor its action mechanism. To shed light on such issues, 6-tuliposide B and tulipalin B analogues were synthesized and a structure-activity relationship (SAR) was examined using a broad panel of bacterial strains. As the results of SAR among a total of 25 compounds, only tulipalin B and the compounds having 3',4'-dihydroxy-2'-methylenebutanoate (DHMB) moieties showed any significant antibacterial activity. Moreover, the 3'R analogues of these compounds displayed essentially the same activities as 6-tuliposide B and the structure of the 3'R-DMBA moiety was the same as that of the proposed active moiety of cnicin. These results suggest that 6-tuliposide B has the same action mechanism as proposed for cnicin and bacterial MurA is one of the major molecular targets of 6-tuliposide B.

  2. Comprehensive Structure-Activity Relationship of Triantennary N-Acetylgalactosamine Conjugated Antisense Oligonucleotides for Targeted Delivery to Hepatocytes.

    PubMed

    Prakash, Thazha P; Yu, Jinghua; Migawa, Michael T; Kinberger, Garth A; Wan, W Brad; Østergaard, Michael E; Carty, Recaldo L; Vasquez, Guillermo; Low, Audrey; Chappell, Alfred; Schmidt, Karsten; Aghajan, Mariam; Crosby, Jeff; Murray, Heather M; Booten, Sheri L; Hsiao, Jill; Soriano, Armand; Machemer, Todd; Cauntay, Patrick; Burel, Sebastien A; Murray, Susan F; Gaus, Hans; Graham, Mark J; Swayze, Eric E; Seth, Punit P

    2016-03-24

    The comprehensive structure-activity relationships of triantennary GalNAc conjugated ASOs for enhancing potency via ASGR mediated delivery to hepatocytes is reported. Seventeen GalNAc clusters were assembled from six distinct scaffolds and attached to ASOs. The resulting ASO conjugates were evaluated in ASGR binding assays, in primary hepatocytes, and in mice. Five structurally distinct GalNAc clusters were chosen for more extensive evaluation using ASOs targeting SRB-1, A1AT, FXI, TTR, and ApoC III mRNAs. GalNAc-ASO conjugates exhibited excellent potencies (ED50 0.5-2 mg/kg) for reducing the targeted mRNAs and proteins. This work culminated in the identification of a simplified tris-based GalNAc cluster (THA-GN3), which can be efficiently assembled using readily available starting materials and conjugated to ASOs using a solution phase conjugation strategy. GalNAc-ASO conjugates thus represent a viable approach for enhancing potency of ASO drugs in the clinic without adding significant complexity or cost to existing protocols for manufacturing oligonucleotide drugs.

  3. Structure-activity relationship study of tetrapeptide inhibitors of the Vascular Endothelial Growth Factor A binding to Neuropilin-1.

    PubMed

    Tymecka, Dagmara; Lipiński, Piotr F J; Fedorczyk, Bartłomiej; Puszko, Anna; Wileńska, Beata; Perret, Gerard Y; Misicka, Aleksandra

    2017-08-01

    Neuropilin-1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP-1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP-1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence. Here, we present a structure-activity relationship study of the systematic optimization of amino acid residues in positions 1-3 in the above tetrapeptides. All the 13 synthesized analogs possessed C-terminal arginine that is a necessary element for interaction with NRP-1. The obtained results of the inhibitory activity and modeling by molecular dynamics indicate that simultaneous interactions of the basic amino acid residues in position 1 and 4 (Arg) with Neuropilin-1 are crucial and their cooperation strongly affects the inhibitory activity. In addition, the binding strength is modulated by the flexibility of the peptide backbone (in the central part of the peptide), and the nature of the side chain of the amino acids at the second or third position. A dramatic decrease in the activity to the receptor is observed in flexible derivatives that are missing proline residues. The results described in this paper should prove useful for future studies aimed at establishing the best pharmacophore for inhibitors of VEGF165 binding to NRP-1. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.

    PubMed

    Song, Jiho; Yoo, Jakyung; Kwon, Ara; Kim, Doran; Nguyen, Hong Khanh; Lee, Bong-Yong; Suh, Wonhee; Min, Kyung Hoon

    2015-01-01

    Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

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

    PubMed

    Costa, Eduarda C; Cassamale, Tatiana B; Carvalho, Diego B; Bosquiroli, Lauriane S S; Ojeda, Mariáh; Ximenes, Thalita V; Matos, Maria F C; Kadri, Mônica C T; Baroni, Adriano C M; Arruda, Carla C P

    2016-06-20

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

  6. Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity Relationship Analysis.

    PubMed

    Huang, Shenzhen; Song, Chunli; Wang, Xiang; Zhang, Guo; Wang, Yanlin; Jiang, Xiaojuan; Sun, Qizheng; Huang, Luyi; Xiang, Rong; Hu, Yiguo; Li, Linli; Yang, Shengyong

    2017-04-24

    SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50 value of 1.3 μM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, SR86 showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of SR86, it could serve as a promising lead compound, hence deserving further studies.

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

    PubMed

    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.

  8. Structure-activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity.

    PubMed

    Xu, Xiaoli; Wu, Yue; Hu, Mingyang; Li, Xiang; Gu, Congying; You, Qidong; Zhang, Xiaojin

    2016-10-01

    Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure-activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy. Copyright © 2016. Published by Elsevier Ltd.

  9. Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)

    PubMed Central

    Baqi, Younis; Weyler, Stefanie; Iqbal, Jamshed; Zimmermann, Herbert

    2008-01-01

    Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive. 1-Amino-2-sulfo-4-p-chloroanilinoanthraquinone (18) was identified as a nonselective competitive blocker of NTPDases1, 2, and 3 (Ki 16–18 μM), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (Ki 0.328 μM) and NTPDase3 (Ki 2.22 μM). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (Ki 1.5 μM). PMID:18528783

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

    SciTech Connect

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

    2012-05-01

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

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

    PubMed

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

    2016-02-13

    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.

    PubMed

    Deberardinis, Albert M; Madden, Daniel J; Banerjee, Upasana; Sail, Vibhavari; Raccuia, Daniel S; De Carlo, Daniel; Lemieux, Steven M; Meares, Adam; Hadden, M Kyle

    2014-05-08

    A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.

  13. Qualitative and quantitative structure-activity relationship modelling for predicting blood-brain barrier permeability of structurally diverse chemicals.

    PubMed

    Gupta, S; Basant, N; Singh, K P

    2015-01-01

    In this study, structure-activity relationship (SAR) models have been established for qualitative and quantitative prediction of the blood-brain barrier (BBB) permeability of chemicals. The structural diversity of the chemicals and nonlinear structure in the data were tested. The predictive and generalization ability of the developed SAR models were tested through internal and external validation procedures. In complete data, the QSAR models rendered ternary classification accuracy of >98.15%, while the quantitative SAR models yielded correlation (r(2)) of >0.926 between the measured and the predicted BBB permeability values with the mean squared error (MSE) <0.045. The proposed models were also applied to an external new in vitro data and yielded classification accuracy of >82.7% and r(2) > 0.905 (MSE < 0.019). The sensitivity analysis revealed that topological polar surface area (TPSA) has the highest effect in qualitative and quantitative models for predicting the BBB permeability of chemicals. Moreover, these models showed predictive performance superior to those reported earlier in the literature. This demonstrates the appropriateness of the developed SAR models to reliably predict the BBB permeability of new chemicals, which can be used for initial screening of the molecules in the drug development process.

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

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

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

  15. Analysis of positions and substituents on genotoxicity of fluoroquinolones with quantitative structure-activity relationship and 3D Pharmacophore model.

    PubMed

    Fengxian, Chen; Reti, Hai

    2017-02-01

    The genotoxicity values of 21 quinolones were studied to establish a quantitative structure-activity relationship model and 3D Pharmacophore model separately for screening essential positions and substituents that contribute to genotoxicity of fluoroquinolones (FQs). A full factor experimental design was performed to analyze the specific main effect and second-order interaction effect of different positions and substituents on genotoxicity, forming a reasonable modification scheme which was validated on typical FQ with genotoxicity and efficacy data. Four positions (1, 5, 7, 8) were screened finally to form the full factorial experimental design which contained 72 congeners in total, illustrating that: the dominant effect of 5 and 7-positions on genotoxicity of FQs is main effect; meanwhile the effect of 1 and 8-positions is a second-order interaction effect; two adjacent positions always have stronger second-order interaction effect and lower genotoxicity; the obtained modification scheme had been validated on typical FQ congeners with the modified compound has a lower genotoxicity, higher synthesis feasibilities and efficacy.

  16. Structure-activity relationship of oleanane disaccharides isolated from Akebia quinata versus cytotoxicity against cancer cells and NO inhibition.

    PubMed

    Jung, Hyun-Ju; Lee, Chong Ock; Lee, Kyung-Tae; Choi, Jongwon; Park, Hee-Juhn

    2004-05-01

    In order to further determine the nature of structure-activity relationship on the cytotoxicities of saponins with 1-->2 and 1-->3 linkages of disaccharides, we isolated guaianin N, collinsonidin, kalopanaxsaponin A and hederoside D(2) as disaccharides, and patrinia glycoside B-II as a trisaccharide, from the n-BuOH extract of Akebia quinata (Lardizabalaceae). Complete acid hydrolysis of the extract afforded oleanolic acid (1) and hederagenin (2). By sulforhodamine B (SRB) assay, kalopanaxsaponin A containing an alpha-L-rhap-(1-->2)-alpha-L-arap moiety exhibited distinctly higher cytotoxicity (IC(50) 1.8-2.7 microg/ml) against all of the tested cell lines than the other saponins (IC(50), 4-8 microg/ml). These results suggest that the alpha-L-rhap-(1-->2)-alpha-L-arap moiety has a unique structural significance in terms of its cell biochemistry, compared to those oleanane glycosides with other sugar linkages. On the other hand, kalopanaxsaponin A exhibited a significant inhibitory effect on nitric oxide production by lipopolysaccharide (LPS)-activated macrophage 264.7, whereas other saponins had weaker activities.

  17. Structure-activity relationship study on a simple cationic peptide motif for cellular delivery of antisense peptide nucleic acid.

    PubMed

    Albertshofer, Klaus; Siwkowski, Andrew M; Wancewicz, Edward V; Esau, Christine C; Watanabe, Tanya; Nishihara, Kenji C; Kinberger, Garth A; Malik, Leila; Eldrup, Anne B; Manoharan, Muthiah; Geary, Richard S; Monia, Brett P; Swayze, Eric E; Griffey, Richard H; Bennett, C Frank; Maier, Martin A

    2005-10-20

    Improving cellular uptake and biodistribution remains one of the major obstacles for a successful and broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, we reported the identification and functional characterization of an antisense PNA, which redirects splicing of murine CD40 pre-mRNA. In this context, it was discovered that a simple octa(l-lysine) peptide covalently linked to the PNA is capable of promoting free uptake of the conjugate into BCL1 cells as well as primary murine macrophages. On the basis of this peptide motif, the present study aimed at identifying the structural features, which define effective peptide carriers for cellular delivery of PNA. While the structure-activity relationship study revealed some clear correlations, only a few modifications actually led to an overall improvement as compared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution study in healthy mice, the parent conjugate exhibited relatively broad tissue distribution and only modest elimination via excretion within the time frame of the study.

  18. Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study

    PubMed Central

    Satpathy, Raghunath; Guru, R. K.; Behera, R.; Nayak, B.

    2015-01-01

    Context: Boswellic acid consists of a series of pentacyclic triterpene molecules that are produced by the plant Boswellia serrata. The potential applications of Bowsellic acid for treatment of cancer have been focused here. Aims: To predict the property of the bowsellic acid derivatives as anticancer compounds by various computational approaches. Materials and Methods: In this work, all total 65 derivatives of bowsellic acids from the PubChem database were considered for the study. After energy minimization of the ligands various types of molecular descriptors were computed and corresponding two-dimensional quantitative structure activity relationship (QSAR) models were obtained by taking Andrews coefficient as the dependent variable. Statistical Analysis Used: Different types of comparative analysis were used for QSAR study are multiple linear regression, partial least squares, support vector machines and artificial neural network. Results: From the study geometrical descriptors shows the highest correlation coefficient, which indicates the binding factor of the compound. To evaluate the anticancer property molecular docking study of six selected ligands based on Andrews affinity were performed with nuclear factor-kappa protein kinase (Protein Data Bank ID 4G3D), which is an established therapeutic target for cancers. Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. Conclusions: Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. PMID:25709332

  19. Discovery of anabaenopeptin 679 from freshwater algal bloom material: Insights into the structure-activity relationship of anabaenopeptin protease inhibitors.

    PubMed

    Harms, Henrik; Kurita, Kenji L; Pan, Li; Wahome, Paul G; He, Haiyin; Kinghorn, A Douglas; Carter, Guy T; Linington, Roger G

    2016-10-15

    Cyanobacteria possess a unique capacity for the production of structurally novel secondary metabolites compared to the biosynthetic abilities of other environmental prokaryotes such as bacteria of the genus Streptomyces. Two different strategies to explore cyanobacteria-derived natural products have been explored previously: (1) cultivation of single cyanobacterial strains, in bioreactors for example; (2) bulk collections from the environment of so called 'algal blooms' that are dominated by cyanobacteria. In this study a new environmentally friendly collection technique for obtaining large quantities of algal bloom biomass was utilized. Algal biomass derived from eight million liters of lake water was concentrated using a novel continuous countercurrent filtration system. Analysis of this freshwater algal bloom from Grand Lake-Saint Marys, Ohio led to the discovery of anabaenopeptin 679 (1), as well as the known anabaenopeptins B, F, H and 908. Anabaenopeptin 679 is unusual in that it possesses the classical anabaenopeptin-like cyclic pentapeptide core, but lacks the typical sidechain attached to the constitutive ureido group. Screening of all anabaenopeptin derivatives in an enzymatic assay for inhibitory activity toward carboxypeptidase A identified anabaenopeptin 679 as a strong inhibitor of carboxypeptidase A with an IC50 value of 4.6μg/mL. This result defines a new minimal core structure for carboxypeptidase activity among the anabaenopeptin class, and provides further insight into the structure-activity relationship of anabaenopeptin-like carboxypeptidase A inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Yost, Erin E; Stanek, John; DeWoskin, Robert S; Burgoon, Lyle D

    2016-07-19

    The United States Environmental Protection Agency (EPA) identified 1173 chemicals associated with hydraulic fracturing fluids, flowback, or produced water, of which 1026 (87%) lack chronic oral toxicity values for human health assessments. To facilitate the ranking and prioritization of chemicals that lack toxicity values, it may be useful to employ toxicity estimates from quantitative structure-activity relationship (QSAR) models. Here we describe an approach for applying the results of a QSAR model from the TOPKAT program suite, which provides estimates of the rat chronic oral lowest-observed-adverse-effect level (LOAEL). Of the 1173 chemicals, TOPKAT was able to generate LOAEL estimates for 515 (44%). To address the uncertainty associated with these estimates, we assigned qualitative confidence scores (high, medium, or low) to each TOPKAT LOAEL estimate, and found 481 to be high-confidence. For 48 chemicals that had both a high-confidence TOPKAT LOAEL estimate and a chronic oral reference dose from EPA's Integrated Risk Information System (IRIS) database, Spearman rank correlation identified 68% agreement between the two values (permutation p-value =1 × 10(-11)). These results provide support for the use of TOPKAT LOAEL estimates in identifying and prioritizing potentially hazardous chemicals. High-confidence TOPKAT LOAEL estimates were available for 389 of 1026 hydraulic fracturing-related chemicals that lack chronic oral RfVs and OSFs from EPA-identified sources, including a subset of chemicals that are frequently used in hydraulic fracturing fluids.

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

    PubMed

    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.

  2. Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.

    PubMed

    Rea, Dean; Van Elzen, Roos; De Winter, Hans; Van Goethem, Sebastiaan; Landuyt, Bart; Luyten, Walter; Schoofs, Liliane; Van Der Veken, Pieter; Augustyns, Koen; De Meester, Ingrid; Fülöp, Vilmos; Lambeir, Anne-Marie

    2017-10-20

    The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

    NASA Astrophysics Data System (ADS)

    Pu, Wenjun; Wang, Dongmei; Zhou, Dan

    2015-09-01

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

  4. Two- and Three-Dimensional Quantitative Structure-Activity Relationships Studies on a Series of Liver X Receptor Ligands

    PubMed Central

    Honório, Káthia M; Salum, Lívia B; Garratt, Richard C; Polikarpov, Igor; Andricopulo, Adriano D

    2008-01-01

    Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r2 = 0.98 and q2 = 0.69; HQSAR, r2 = 0.99 and q2 = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency. PMID:19696872

  5. Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis.

    PubMed

    Hirsch, Anna K H; Alphey, Magnus S; Lauw, Susan; Seet, Michael; Barandun, Luzi; Eisenreich, Wolfgang; Rohdich, Felix; Hunter, William N; Bacher, Adelbert; Diederich, François

    2008-08-07

    Enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are therapeutic targets for the treatment of important infectious diseases. Whereas this pathway is absent in humans, it is used by plants, many eubacteria and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis. Herein, we report on the design, preparation and biological evaluation of a new series of ligands for IspE protein, a kinase from this pathway. These inhibitors were developed for the inhibition of IspE from Escherichia coli, using structure-based design approaches. Structure-activity relationships (SARs) and a co-crystal structure of Aquifex aeolicus IspE bound to a representative inhibitor validate the proposed binding mode. The crystal structure shows that the ligand binds in the substrate-rather than the adenosine 5'-triphosphate (ATP)-binding pocket. As predicted, a cyclopropyl substituent occupies a small cavity not used by the substrate. The optimal volume occupancy of this cavity is explored in detail. In the co-crystal structure, a diphosphate anion binds to the Gly-rich loop, which normally accepts the triphosphate moiety of ATP. This structure provides useful insights for future structure-based developments of inhibitors for the parasite enzymes.

  6. Quantitative structure-activity relationship of hydroxyl-substituent Schiff bases in radical-induced hemolysis of human erythrocytes.

    PubMed

    Tang, You-Zhi; Liu, Zai-Qun

    2008-01-01

    The major objective of this work was to explore the quantitative structure-activity relationship (QSAR) of hydroxyl-substituent Schiff bases in protecting human erythrocytes against 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)- induced hemolysis, in which 10 Schiff bases including 4-phenyliminomethylphenol (PIH); 4-((4-hydroxybenzylidene) amino)phenol (PAH); 2-methoxy-4-((4-hydroxyphenylimino)methyl)phenol (PMH); 4-((furan-2-ylmethylene)amino) phenol (FAH); 4-((4-N,N-dimethylaminobenzylidene)amino)phenol (PDH); 2-((4-N,N-dimethylaminobenzylidene)amino) phenol (ODH); 2-(naphthalene-1-yliminomethyl)phenol (NAH); 2-(benzyliminomethyl)phenol (BPH); 1,4-di((2-hydroxyphenylimino) methyl)benzene (DOH); 1,4-di((4-hydroxyphenylimino)methyl)benzene DPH, were available for this in vitro experimental system. The results revealed that the radical-scavenging activity of the --OH attached to the para position of methylene in Schiff base was much lower than that attached to the ortho position of the N atom. The large conjugate system and low steric hindrance in the framework of Schiff base benefit the Schiff base to trap radicals. Meanwhile, since a Schiff base, even without any substituent, can also play an antioxidative role in this experimental system, the QSAR results suggest that hydroxyl-substituent Schiff bases are potential drugs in the treatment of radical-related diseases, and provide more information for designing novel drugs.

  7. Comprehensive Analysis of Structure Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors

    PubMed Central

    Janssen, Freek J.; Baggelaar, Marc P.; Hummel, Jessica J. A.; Overkleeft, Herman S.; Cravatt, Benjamin F.; Boger, Dale L.; van der Stelt, Mario

    2015-01-01

    Diacylglycerol lipase α (DAGLα) is responsible for the formation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLα inhibitors are required to study the physiological role of 2-AG. Previously, we identified the α-ketoheterocycles as potent and highly selective DAGLα inhibitors. Here, we present the first comprehensive structure-activity relationship study of α-ketoheterocycles as DAGLα inhibitors. Our findings indicate that the active site of DAGLα is remarkably sensitive to the type of heterocyclic scaffold with oxazolo-4N-pyridines as the most active framework. We uncovered a fundamental substituent effect in which electron-withdrawing meta-oxazole substituents increased inhibitor potency. (C6-C9)-acyl chains with a distal phenyl group proved to be the most potent inhibitors. The integrated SAR data was consistent with the proposed binding pose in a DAGLα homology model. Altogether our results may guide the design of future DAGLα inhibitors as leads for molecular therapies to treat neuroinflammation, obesity and related metabolic disorders. PMID:26584396

  8. Novel N-2-(Furyl)-2-(chlorobenzyloxyimino) Ethyl Piperazinyl Quinolones: Synthesis, Cytotoxic Evaluation and Structure-Activity Relationship

    PubMed Central

    Mohammadhosseini, Negar; Pordeli, Mahboobeh; Safavi, Maliheh; Firoozpour, Loghman; Amin, Fatame; Kabudanian Ardestani, Sussan; Edraki, Najmeh; Shafiee, Abbas; Foroumadi, Alireza

    2015-01-01

    Quinolone antibacterials are one of the most important classes of pharmacological agents known as potent inhibitors of bacterial DNA gyrase and topoisomerase IV that efficiently inhibit DNA replication and transcription by generating several double-stranded DNA break. Some quinolone derivatives demonstrated inhibitory potential against eukaryote topoismarase II and substantial dose-dependent cytotoxic potential against some cancerous cells. In present study, synthesis and cytotoxic activity evaluation of new series of N-pipearzinyl quinolones containing N-2-(furyl-2 or 3-yl)-2-(chlorobenzyloxyimino) ethyl moiety 7a-i have been studied. Reaction of quinolone, with 2-bromo-1-(furan-2 or 3-yl)ethanone-O-substituted chlorobenzyloxime in DMF in presence of NaHCO3 at room temperature, gave the title compounds N-2-(furan-2 or 3-yl)-2-(chlorobenzyloxyiminoethyl) quinolone 7a-i. Synthesized compounds were further evaluated in-vitro against three human breast tumor cell lines. Preliminary screening indicated that compound 7 g demonstrated significant growth inhibitory potential against all evaluated cell lines. The results of structure-activity relationship study exhibited that quinolone derivatives are superior in cytotoxic potential compared to 1, 8-naphthyridone series. Furthermore, ethyl quinolone derivatives were more potent cytotoxic agents comparing with cyclopropyl quinolones. PMID:26664376

  9. Structure-activity relationships of seco-prezizaane terpenoids in gamma-aminobutyric acid receptors of houseflies and rats.

    PubMed

    Kuriyama, Tadahiko; Schmidt, Thomas J; Okuyama, Emi; Ozoe, Yoshihisa

    2002-06-01

    Thirteen seco-prezizaane terpenoids isolated from star anise species (Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC(50)(fly) of 78.5 nM and an IC(50)(rat) of 271 nM, followed by anisatin (IC(50)(fly)=123 nM; IC(50)(rat)=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC(50)(fly)=376 nM; IC(50)(rat) >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.

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

    PubMed

    Gupta, Ashish; Aparoy, Polamarasetty

    2016-07-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane protein which plays crucial role in arachidonic acid metabolism, in the catalysis of PGH2 to PGE2. It is a potential drug target involved in variety of human cancers and inflammatory disorders. In the present study we made an attempt to identify crucial amino acid residues involved in the effective binding of its inhibitors at the active site. Molecular docking and Structure Activity Relationship (SAR) studies were performed. In the present study 127 inhibitors having significant variability in parent scaffold were considered. The results clearly indicated that in the GSH and PGH2 binding site Arg70, Arg73, Asn74, Glu77, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 consistently form crucial interactions with inhibitors of different classes/scaffolds. These findings are consistent with that of existing reports on the active site residues pivotal at mPGES-1 active site. Further analysis suggested that out of all important amino acid residues identified; Arg73, Asn74, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 play a crucial role in hydrogen and π-π interactions. The identified amino acid residues can act as target sites for the design and development of drug candidates against mPGES-1. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Quantitative structure-activity relationship modelling of oral acute toxicity and cytotoxic activity of fragrance materials in rodents.

    PubMed

    Papa, E; Luini, M; Gramatica, P

    2009-10-01

    Fragrance materials are used as ingredients in many consumer and personal care products. The wide and daily use of these substances, as well as their mainly uncontrolled discharge through domestic sewage, make fragrance materials both potential indoor and outdoor air pollutants which are also connected to possible toxic effects on humans (asthma, allergies, headaches). Unfortunately, little is known about the environmental fate and toxicity of these substances. However, the use of alternative, predictive approaches, such as quantitative structure-activity relationships (QSARs), can help in filling the data gap and in the characterization of the environmental and toxicological profile of these substances. In the proposed study, ordinary least squares regression-based QSAR models were developed for three toxicological endpoints: mouse oral LD(50), inhibition of NADH-oxidase (EC(50) NADH-Ox) and the effect on mitochondrial membrane potential (EC(50) DeltaPsim). Theoretical molecular descriptors were calculated by using DRAGON software, and the best QSAR models were developed according to the principles defined by the Organization for Economic Co-operation and Development.

  12. Biologically relevant chemical space navigator: from patent and structure-activity relationship analysis to library acquisition and design.

    PubMed

    Rabal, Obdulia; Oyarzabal, Julen

    2012-12-21

    A new and versatile visualization tool, based on a descriptor accounting for ligand-receptor interactions (LiRIf), is introduced for guiding medicinal chemists in analyzing the R-groups from a congeneric series. Analysis is performed in a reference-independent scenario where the whole biologically relevant chemical space (BRCS) is represented. Using a real project-based data set, we show the impact of this tool on four key navigation strategies for the drug discovery process. First, this navigator analyzes competitors' patents, including a comparison of patents coverage and the identification of the most frequent fragments. Second, the tool analyzes the structure-activity relationship (SAR) leading to the representation of reference-independent activity landscapes that enable the identification not only of critical ligand-receptor interactions (LRI) and substructural features but also of activity cliffs. Third, this navigator enables comparison of libraries, thus selecting commercially available molecules that complement unexplored spaces or areas of interest. Finally, this tool also enables the design of new analogues, which is based on reaction types and the exploration purpose (focused or diverse), selecting the most appropriate reagents.

  13. Structure-activity relationship of a recombinant hybrid Manganese superoxide dismutase of Staphylococcus saprophyticus/S. equorum.

    PubMed

    Retnoningrum, Debbie S; Arumsari, Sekar; Artarini, Anita; Ismaya, Wangsa T

    2017-05-01

    Recombinant hybrid Manganese superoxide dismutase from Staphyloccus saphropyticus/S. equorum (rMnSODSeq) exhibits stability at high temperatures. The enzyme occurs as a dimer that dissociates around 52°C prior to unfolding of the monomer around 64°C, demonstrating contribution of the dimeric form to stability. Here, structure - activity relationship of rMnSODSeq was evaluated on the basis of its activity and stability in the presence of inhibitors, NaCl, denaturants, detergents, reducing agents, and at different pH values. The activity was evaluated at both 37°C and 52°C, which the latter is the temperature for dissociation of the dimer. Dimer to monomer transition coincided with significant decrease in residual activity at 52°C. However, the activity assay results at 52°C and 37°C suggest spontaneous re-association of the monomer into dimer. Intriguingly, various new species with melting temperature (TM) values other than those of the dimer or monomer were observed. These species displayed medium to comparable level of residual activities to the native at 37°C. This report suggests that dimer to monomer transition may be not the only explanation for activity loss or decrease.

  14. Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi.

    PubMed

    Guido, Rafael V C; Trossini, Gustavo H G; Castilho, Marcelo S; Oliva, Glaucius; Ferreira, Elizabeth I; Andricopulo, Adriano D

    2008-12-01

    Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q(2) = 0.75 and r(2) = 0.96; classical QSAR, q(2) = 0.72 and r(2) = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.95; classical QSAR, r(2)(pred) = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.

  15. Approach on quantitative structure-activity relationship for design of a pH neutral carrier containing tertiary amino group.

    PubMed

    Cao, Zhong; Gong, Fu-Chun; Li, He-Ping; Xiao, Zhong-Liang; Long, Shu; Zhang, Ling; Peng, San-Jun

    2007-01-02

    The quantitative structure-activity relationship (QSAR) for neutral carriers used to prepare hydrogen ion sensors has been studied. A series of synthesized carrier compounds were taken as the training set. Five molecular structure parameters of the compounds were calculated by using CNDO/2 algorithm and used as feature variables in constructing QSAR model. The lower and upper limits of the linear pH response range were taken as the activity measure. The corresponding model equations were derived from the stepwise regression procedure. With the established QSAR model, a new pH carrier, (4-hydroxybenzyl) didodecylamine (XIII) was proposed and synthesized. The PVC membrane pH electrode based on carrier XIII with a wide pH linear response range of 2.0-12.5 was prepared. Having a theoretical Nernstian response slope of 57.2+/-0.3 mV/pH (n=5 at 25 degrees C) without a super-Nernstian phenomenon, the sensor had low resistance, short response time, high selectivity and good reproducibility. Moreover, the sensor was successfully applied to detecting the pH value of serum samples.

  16. Stability to gastrointestinal enzymes and structure-activity relationship of beta-casein-peptides with antihypertensive properties.

    PubMed

    Quirós, Ana; del Mar Contreras, María; Ramos, Mercedes; Amigo, Lourdes; Recio, Isidra

    2009-10-01

    Physiological digestion plays a key role in the formation and degradation of angiotensin-converting enzyme (ACE)-inhibitory peptides. In this study, we evaluated the impact of a simulated gastrointestinal digestion on the stability of eight peptides previously identified in fermented milk with antihypertensive activity. Two of these identified peptides with sequences LHLPLP and LVYPFPGPIPNSLPQNIPP, possess ACE-inhibitory activity in vitro and antihypertensive activity in vivo. The results showed that LHLPLP was resistant to digestive enzymes. In contrast, LVYPFPGPIPNSLPQNIPP was totally hydrolyzed and its activity decreased after incubation with pepsin and a pancreatic extract. The peptide LHLPLP was incubated with ACE and was found to be a true inhibitor of the enzyme and to exhibit a competitive inhibitor pattern. A structure-activity relationship study of this peptide was carried out by synthesizing several modified peptides related to the sequence LHLPLP. The substitution of amino acid Leu in the penultimate position by Gly improved the ACE-inhibitory activity twofold and the substitution of Pro at C-terminal position by Arg increased the activity twofold, with an IC50 of LHLPLR as low as 1.8 microM.

  17. Risk assessment of high-energy chemicals by in vitro toxicity screening and quantitative structure-activity relationships.

    PubMed

    Trohalaki, Steven; Zellmer, Robert J; Pachter, Ruth; Hussain, Saber M; Frazier, John M

    2002-08-01

    Hydrazine propellants pose a substantial operational concern to the U.S. Air Force and to the aerospace industry because of their toxicity. In our continuing efforts to develop methods for the prediction of the toxicological response to such materials, we have measured in vitro toxicity endpoints for a series of high-energy chemicals (HECs) that were recently proposed as propellants. The HECs considered are structurally diverse and can be classified into four chemical types (hydrazine-based, amino-based, triazoles, and a quaternary ammonium salt), although most are hydrazine derivatives. We measured the following endpoints in primary cultures of isolated rat hepatocytes: mitochondrial function (MTT), lactate dehydrogenase leakage (LDH), generation of reactive oxygen species (ROS), and total glutathione content (GSH). In several instances, effective concentrations (EC) were indeterminate, and only lower limits to the measured endpoints could be ascertained. Using molecular descriptors calculated with a semiempirical molecular orbital method, quantitative structure-activity relationships (QSARs) were derived for MTT (EC25) and for GSH (EC50). Correlation coefficients for 2- and 3-parameter QSARs of about 0.9 enable us to predict the toxicity for similar compounds. Furthermore, except in one case, predicted EC values for the uncertain endpoints were consistent with experiment. Descriptors comprising the QSARs for MTT were consistent with the biophysical mechanism of toxic response found experimentally for hydrazine derivatives. Application of our derived QSARs will assist in predicting toxicity for newly proposed propellants.

  18. Quantitative structure-activity relationships and comparative molecular field analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors

    NASA Astrophysics Data System (ADS)

    Hannongbua, Supa; Pungpo, Pornpan; Limtrakul, Jumras; Wolschann, Peter

    1999-11-01

    Quantitative structure-activity relationships (QSAR) and Comparative Molecular Field Analysis (CoMFA) have been applied in order to explain the structural requirements of HIV-1 reverse transcriptase (HIV-1 RT) inhibitory activity of TIBO derivatives on the MT-4 cells. The best QSAR model is satisfactory in both statistical significance and predictive ability. The derived structural descriptors indicate the importance of electronic contributions toward the HIV-1 RT inhibition of this class of compounds. However, it could not reveal any hydrophobic influence because of high collinearity between C2 and log P variables. In order to cope with steric interaction in the correlation, 3D-QSAR was performed using CoMFA. The obtained CoMFA model shows high predictive ability, r2 cv=0.771, and clearly demonstrates its potential in the steric feature of the molecules through contour maps, explaining a majority (81.8%) of the variance in the data. Consequently, these results can be useful in identifying the structural requirements of TIBO derivatives and helpful for better understanding the HIV-1 RT inhibition. Eventually, they provide a beneficial basis to design new and more potent inhibitors of HIV-1 RT.

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

    PubMed

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

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substa