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Sample records for structure activity relationships

  1. Ecological Structure Activity Relationships

    EPA Science Inventory

    Ecological Structure Activity Relationships, v1.00a, February 2009
    ECOSAR (Ecological Structure Activity Relationships) is a personal computer software program that is used to estimate the toxicity of chemicals used in industry and discharged into water. The program predicts...

  2. Structure-activity relationship of anthelmintic cyclooctadepsipeptides.

    PubMed

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

    2011-01-01

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

  3. 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. PMID:26265354

  4. Structural relationships and vasorelaxant activity of monoterpenes

    PubMed Central

    2012-01-01

    Background and purpose of the study The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure-activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. Methods Contractions of the vessels were induced with 10 μM of phenylephine (Phe) in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively) were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. Results The results from the present study showed that both oxygenated terpenes (rotundifolone, (+)-limonene epoxide, pulegone epoxide, carvone epoxide, and (+)-pulegone) and non-oxygenated terpene ((+)-limonene) exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. Major conclusion The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity. PMID:23351149

  5. THE PRACTICE OF STRUCTURE ACTIVITY RELATIONSHIPS (SAR) IN TOXICOLOGY

    EPA Science Inventory

    Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issue...

  6. Synthetic retinoids: structure-activity relationships.

    PubMed

    Barnard, Jonathan H; Collings, Jonathan C; Whiting, Andrew; Przyborski, Stefan A; Marder, Todd B

    2009-11-01

    Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells. PMID:19821467

  7. 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.

  8. Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.

    PubMed

    Paczal, Attila; Bálint, Balázs; Wéber, Csaba; Szabó, Zoltán B; Ondi, Levente; Theret, Isabelle; De Ceuninck, Frédéric; Bernard, Catherine; Ktorza, Alain; Perron-Sierra, Francoise; Kotschy, András

    2016-01-28

    7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds. PMID:26685731

  9. Structure-Activity Relationships in Nitro-Aromatic Compounds

    NASA Astrophysics Data System (ADS)

    Vogt, R. A.; Rahman, S.; Crespo-Hernández, C. E.

    Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure-activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure-activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure-activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure-activity relationships to predict those physicochemical properties.

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

    PubMed

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

    2015-12-01

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

  11. 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

  12. 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.

  13. Structure-cardiac activity relationship of C19-diterpenoid alkaloids.

    PubMed

    Jian, Xi-Xian; Tang, Pei; Liu, Xiu-Xiu; Chao, Ruo-Bing; Chen, Qiao-Hong; She, Xue-Ke; Chen, Dong-Lin; Wang, Feng-Peng

    2012-06-01

    Thirty three C19-diterpenoid alkaloids, twenty-two prepared from known C19-diterpenoid alkaloids and eleven isolated from Aconitum and Delphinium spp. were evaluated for their cardiac activity in the isolated bullfrog heart assay. Among them, eleven compounds exhibited cardiac activity, with average rate of amplitude increase in the range of 16-118%. Compound 7, mesaconine (17), hypaconine (25), and beiwutinine (26) exhibited strong cardiac activities relative to the reference drug. The structure-activity relationship data acquired indicated that an alpha-hydroxyl group at C-15, a hydroxyl group at C-8, an alpha-methoxyl or hydroxyl group at C-1, and a secondary amine or N-methyl group in ring A are important structure features necessary for the cardiac activities of the aconitine-type C19-diterpenoid alkaloids without any ester groups. In addition, an alpha-hydroxyl group at C-3 is also helpful for the cardiac activity of these alkaloids. PMID:22816290

  14. Antioxidant activity of taxifolin: an activity-structure relationship.

    PubMed

    Topal, Fevzi; Nar, Meryem; Gocer, Hulya; Kalin, Pınar; Kocyigit, Umit M; Gülçin, İlhami; Alwasel, Saleh H

    2016-08-01

    Taxifolin is a kind of flavanonol, whose biological ability. The objectives of this study were to investigate the antioxidants and antiradical activities of taxifolin by using different in vitro bioanalytical antioxidant methods including DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, the total antioxidant influence, reducing capabilities, and Fe(2+)-chelating activities. Taxifolin demonstrated 81.02% inhibition of linoleic acid emulsion peroxidation at 30 µg/mL concentration. At the same concentration, standard antioxidants including trolox, α-tocopherol, BHT, and BHA exhibited inhibitions of linoleic acid emulsion as 88.57, 73.88, 94.29, and 90.12%, respectively. Also, taxifolin exhibited effective DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, reducing capabilities, and Fe(2+)-chelating effects. The results obtained from this study clearly showed that taxifolin had marked antioxidant, reducing ability, radical scavenging and metal-chelating activities. Also, this study exhibits a scientific shore for the significant antioxidant activity of taxifolin and its structure-activity insight. PMID:26147349

  15. Quantitative Structure-Antifungal Activity Relationships for cinnamate derivatives.

    PubMed

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

    2015-12-01

    Quantitative Structure-Activity Relationships (QSAR) are established with the aim of analyzing the fungicidal activities of a set of 27 active cinnamate derivatives. The exploration of more than a thousand of constitutional, topological, geometrical and electronic molecular descriptors, which are calculated with Dragon software, leads to predictions of the growth inhibition on Pythium sp and Corticium rolfsii fungi species, in close agreement to the experimental values extracted from the literature. A set containing 21 new structurally related cinnamate compounds is prepared. The developed QSAR models are applied to predict the unknown fungicidal activity of this set, showing that cinnamates like 38, 28 and 42 are expected to be highly active for Pythium sp, while this is also predicted for 28 and 34 in C. rolfsii. PMID:26410195

  16. Structure-activity relationship of crustacean peptide hormones.

    PubMed

    Katayama, Hidekazu

    2016-04-01

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

  17. Penoxsulam--structure-activity relationships of triazolopyrimidine sulfonamides.

    PubMed

    Johnson, Timothy C; Martin, Timothy P; Mann, Richard K; Pobanz, Mark A

    2009-06-15

    The discovery of the sulfonamide herbicides, which inhibit the enzyme acetolactate synthase (ALS), has resulted in many investigations to exploit their herbicidal activity. One area which proved particularly productive was the N-aryltriazolo[1,5-c]pyrimidine sulfonamides, providing three commercial herbicides, cloransulam-methyl, diclosulam and florasulam. Additional structure-activity investigations by reversing the sulfonamide linkage resulted in the discovery of triazolopyrimidine sulfonamides with cereal crop selectivity and high levels of grass and broadleaf weed control. Research efforts to exploit these high levels of weed activity ultimately led to the discovery of penoxsulam, a new herbicide developed for grass, sedge and broadleaf weed control in rice. Synthetic efforts and structure-activity relationships leading to the discovery of penoxsulam will be discussed. PMID:19464188

  18. 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.

  19. 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...

  20. 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...

  1. Synthesis and Structural Activity Relationship Study of Antitubercular Carboxamides

    PubMed Central

    Ugwu, D. I.; Ezema, B. E.; Eze, F. U.; Ugwuja, D. I.

    2014-01-01

    The unusual structure and chemical composition of the mycobacterial cell wall, the tedious duration of therapy, and resistance developed by the microorganism have made the recurrence of the disease multidrug resistance and extensive or extreme drug resistance. The prevalence of tuberculosis in synergy with HIV/AIDS epidemic augments the risk of developing the disease by 100-fold. The need to synthesize new drugs that will shorten the total duration of effective treatment and/or significantly reduce the dosage taken under DOTS supervision, improve on the treatment of multidrug-resistant tuberculosis which defies the treatment with isoniazid and rifampicin, and provide effective treatment for latent TB infections which is essential for eliminating tuberculosis prompted this review. In this review, we considered the synthesis and structure activity relationship study of carboxamide derivatives with antitubercular potential. PMID:25610646

  2. Autotaxin Structure Activity Relationships Revealed through Lysophosphatidylcholine Analogs

    PubMed Central

    North, E. Jeffrey; Osborne, Daniel A.; Bridson, Peter K.; Baker, Daniel L.; Parrill, Abby L.

    2009-01-01

    Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization. PMID:19345587

  3. 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.

  4. 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

  5. Synthesis and structure-activity relationships of neuromuscular blocking agents.

    PubMed

    Tuba, Zoltan; Maho, Sandor; Vizi, E Sylvester

    2002-08-01

    The first use of neuromuscular blocking agents (muscle relaxants) in clinical practice (1942) revolutionised the practice of anaesthesia and started the modern era of surgery. Since 1942 introduction of tubocurarine (18) neuromuscular blocking agents have been used routinely to provide skeletal muscle relaxation during surgical procedures allowing access to body cavities without hindrance from voluntary or reflex muscle movement. After the introduction of tubocurarine and the depolarizing suxamethonium chloride (4) (1949) several nondepolarizing steroidal and nonsteroidal neuromuscular blocking agents with different onset time and duration of effect were introduced e.g. gallamine triethiodide (1) (1949), methocurine (2) (1949), alcuronium chloride (3) (1963), pancuronium bromide (9) (1968), vecuronium bromide (11) (1982), pipecuronium bromide (10) (1982), atracurium besylate (5) (1982), doxacurium chloride (6) (1991), mivacurium chloride (8) (1992), rocuronium bromide (12) (1994) cisatracurium besylate (7) (1996), and rapacuronium bromide (13) (2000). SZ 1677 (14) a steroid type nondepolarizing neuromuscular blocking agent under development (preclinical phase). This review article deals with a comprehensive survey of the progress in chemical, pharmacological and, in some respects, of clinical studies of neuromuscular blocking agents used in the clinical practice and under development, including the synthesis, structure elucidation, pharmacological actions, structure activity relationships studies of steroidal and nonsteroidal derivatives. PMID:12171561

  6. Structure-activity relationships of glutamate carboxypeptidase II (GCPII) inhibitors.

    PubMed

    Ferraris, D V; Shukla, K; Tsukamoto, T

    2012-01-01

    Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a zinc metallopeptidase that hydrolyzes N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate in the nervous system. Inhibition of GCPII has the potential to reduce extracellular glutamate and represents an opportune target for treating neurological disorders in which excess glutamate is considered pathogenic. Furthermore, GCPII was found to be identical to a tumor marker, prostate-specific membrane antigen (PSMA), and has drawn significant interest as a diagnostic and/or therapeutic target in oncology. Over the past 15 years, tremendous efforts have been made in the discovery of potent GCPII inhibitors, particularly those with phosphorus-, urea- and thiol-based zinc binding groups. In addition, significant progress has been made in understanding the three-dimensional structural characteristics of GCPII in complex with various ligands. The purpose of this review article is to analyze the structure-activity relationships (SAR) of GCPII inhibitors reported to date, which are classified on the basis of their zinc-binding group. SAR and crystallographic data are evaluated in detail for each of these series to highlight the future challenges and opportunities to identify clinically viable GCPII inhibitors. PMID:22304717

  7. 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.

  8. 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

  9. Synthesis, Antifungal Activity, and Structure Activity Relationships of Coruscanone A Analogs

    PubMed Central

    Babu, K. Suresh; Li, Xing-Cong; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; Ferreira, Daneel; Clark, Alice M.

    2008-01-01

    Coruscanone A, a plant derived cyclopentenedione derivative, showed potent in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, comparable to amphotericin B and fluconazole. A series of analogs have been synthesized by modification of the cyclopentenedione ring, the enolic methoxy functionality, and the side chain styryl moiety of this natural product lead. A structurally close 1,4-benzoquinone analog was also prepared. All the compounds were examined for their in vitro activity against major opportunistic fungal pathogens including C. albicans, C. neoformans and Aspergillus fumigatus, and fluconazole-resistant C. albicans strains, with several analogs demonstrating potent antifungal activity. Structure activity relationship studies indicate that the 2-methoxymethylene-cyclopent-4-ene-1,3-dione structural moiety is the pharmacophore responsible for the antifungal activity of this class of compounds, while the side chain styryl-like moiety plays an important complementary role, presumably contributing to target binding. PMID:17181171

  10. Method for the evaluation of structure-activity relationship information associated with coordinated activity cliffs.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2014-08-14

    Activity cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity cliffs focuses on compound pairs, the vast majority of cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity cliffs, which often overlap. In activity cliff networks, coordinated cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bioactive compounds and analyzed their topologies. For structure-activity relationship (SAR) analysis, activity cliff clusters are of high interest, since they contain more SAR information than cliffs that are individually considered. For medicinal chemistry applications, a key question becomes how to best extract SAR information from activity cliff clusters. This represents a challenging problem, given the complexity of many activity cliff configurations. Herein we introduce a generally applicable methodology to organize activity cliff clusters on the basis of structural relationships, prioritize clusters, and systematically extract SAR information from them. PMID:25014781

  11. Structure-antimicrobial activity relationship between pleurocidin and its enantiomer

    PubMed Central

    Lee, Juneyoung

    2008-01-01

    To develop novel antibiotic peptides useful as therapeutic drugs, the enantiomeric analogue of pleurocidin (Ple), which is a well known 25-mer antimicrobial peptide, was designed for proteolytic resistance by D-amino acids substitution. The proteolytic resistance was confirmed by using HPLC after the digestion with various proteases. To investigate the antibiotic effect of L- and D-Ple, the antibacterial activity and hemolytic effect were tested against human erythrocytes. The D-Ple showed a decreased antibacterial activity and a dramatically decreased hemolytic activity compared with L-Ple. The hemolytic effect of analogue was further confirmed by using calcein leakage measurement with liposome. To elucidate these results, the secondary structure of the peptides was investigated by using circular dichroism spectroscopy. The results revealed that D-Ple, as well as L-Ple, had typical α-helical structures which were mirror images, with a different helicity. These results suggested that the discrepancy of the structure between the two peptides made their antibacterial activity distinct. PMID:18779649

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

    PubMed

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

    2009-10-01

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

  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. COMPUTER-ASSISTED STUDIES OF MOLECULAR STRUCTURE-BIOLOGICAL ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conforma...

  15. 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. PMID:27016707

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

    PubMed

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

    2015-01-01

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents. PMID:25985362

  17. Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic δGABA(A) Receptors.

    PubMed

    Carver, Chase Matthew; Reddy, Doodipala Samba

    2016-04-01

    Synaptic GABAA receptors are primary mediators of rapid inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurologic disorders. The δ-subunit GABAA receptors are expressed extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. However, the neurosteroid structure-function relationship at δGABA(A) receptors within the native hippocampus neurons remains unclear. Here we report a structure-activity relationship for neurosteroid modulation of extrasynaptic GABAA receptor-mediated tonic inhibition in the murine dentate gyrus granule cells. We recorded neurosteroid allosteric potentiation of GABA as well as direct activation of tonic currents using a wide array of natural and synthetic neurosteroids. Our results shows that, for all neurosteroids, the C3α-OH group remains obligatory for extrasynaptic receptor functional activity, as C3β-OH epimers were inactive in activating tonic currents. Allopregnanolone and related pregnane analogs exhibited the highest potency and maximal efficacy in promoting tonic currents. Alterations at the C17 or C20 region of the neurosteroid molecule drastically altered the transduction kinetics of tonic current activation. The androstane analogs had the weakest modulatory response among the analogs tested. Neurosteroid potentiation of tonic currents was completely (approximately 95%) diminished in granule cells from δ-knockout mice, suggesting that δ-subunit receptors are essential for neurosteroid activity. The neurosteroid sensitivity of δGABA(A) receptors was confirmed at the systems level using a 6-Hz seizure test. A consensus neurosteroid pharmacophore model at extrasynaptic δGABA(A) receptors is proposed based on a structure-activity relationship for activation of tonic current and seizure protection. PMID:26857959

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

    PubMed

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

    2011-06-01

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

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

    PubMed

    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

    2010-12-01

    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

  20. 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

  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. PMID:26153539

  2. 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. PMID:26826838

  3. Probing structure-antifouling activity relationships of polyacrylamides and polyacrylates.

    PubMed

    Zhao, Chao; Zhao, Jun; Li, Xiaosi; Wu, Jiang; Chen, Shenfu; Chen, Qiang; Wang, Qiuming; Gong, Xiong; Li, Lingyan; Zheng, Jie

    2013-07-01

    We have synthesized two different polyacrylamide polymers with amide groups (polySBAA and polyHEAA) and two corresponding polyacrylate polymers without amide groups (polySBMA and polyHEA), with particular attention to the evaluation of the effect of amide group on the hydration and antifouling ability of these systems using both computational and experimental approaches. The influence of polymer architectures of brushes, hydrogels, and nanogels, prepared by different polymerization methods, on antifouling performance is also studied. SPR and ELISA data reveal that all polymers exhibit excellent antifouling ability to repel proteins from undiluted human blood serum/plasma, and such antifouling ability can be further enhanced by presenting amide groups in polySBAA and polyHEAA as compared to polySBMA and polyHEA. The antifouling performance is positively correlated with the hydration properties. Simulations confirm that four polymers indeed have different hydration characteristics, while all presenting a strong hydration overall. Integration of amide group with pendant hydroxyl or sulfobetaine group in polymer backbones is found to increase their surface hydration of polymer chains and thus to improve their antifouling ability. Importantly, we present a proof-of-concept experiment to synthesize polySBAA nanogels, which show a switchable property between antifouling and pH-responsive functions driven by acid-base conditions, while still maintaining high stability in undiluted fetal bovine serum and minimal toxicity to cultured cells. This work provides important structural insights into how very subtle structural changes in polymers can yield great improvement in biological activity, specifically the inclusion of amide group in polymer backbone/sidechain enables to obtain antifouling materials with better performance for biomedical applications. PMID:23562049

  4. 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. PMID:23657615

  5. Improving quantitative structure-activity relationships through multiobjective optimization.

    PubMed

    Nicolotti, Orazio; Giangreco, Ilenia; Miscioscia, Teresa Fabiola; Carotti, Angelo

    2009-10-01

    A multiobjective optimization algorithm was proposed for the automated integration of structure- and ligand-based molecular design. Driven by a genetic algorithm, the herein proposed approach enabled the detection of a number of trade-off QSAR models accounting simultaneously for two independent objectives. The first was biased toward best regressions among docking scores and biological affinities; the second minimized the atom displacements from a properly established crystal-based binding topology. Based on the concept of dominance, 3D QSAR equivalent models profiled the Pareto frontier and were, thus, designated as nondominated solutions of the search space. K-means clustering was, then, operated to select a representative subset of the available trade-off models. These were effectively subjected to GRID/GOLPE analyses for quantitatively featuring molecular determinants of ligand binding affinity. More specifically, it was demonstrated that a) diverse binding conformations occurred on the basis of the ligand ability to profitably contact different part of protein binding site; b) enzyme selectivity was better approached and interpreted by combining diverse equivalent models; and c) trade-off models were successful and even better than docking virtual screening, in retrieving at high sensitivity active hits from a large pool of chemically similar decoys. The approach was tested on a large series, very well-known to QSAR practitioners, of 3-amidinophenylalanine inhibitors of thrombin and trypsin, two serine proteases having rather different biological actions despite a high sequence similarity. PMID:19785453

  6. 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...

  7. 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...

  8. Isothiocyanate synthetic analogs: biological activities, structure-activity relationships and synthetic strategies.

    PubMed

    Milelli, Andrea; Fimognari, Carmela; Ticchi, Nicole; Neviani, Paolo; Minarini, Anna; Tumiatti, Vincenzo

    2014-01-01

    Sulforaphane is a natural product that is constantly under biological investigation for its unique biological properties. This naturally occurring isothiocyanate (ITC) and its analogs are the main components of cruciferous vegetables, such as cauliflower, watercress, broccoli, cabbage, Brussels sprouts, widely used as chemopreventive agents. Due to their interesting biological profiles, natural ITCs have been exploited as starting point to develop new synthetic analogs. The present mini-review briefly highlights the most important biological actions of selected new synthetic ITCs focusing on their structure-activity relationships and related synthetic strategies. PMID:25373847

  9. A quantitative structure-activity relationship model for radical scavenging activity of flavonoids.

    PubMed

    Om, A; Kim, J H

    2008-03-01

    A quantitative structure-activity relationship (QSAR) study has been carried out for a training set of 29 flavonoids to correlate and predict the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity (RSA) values obtained from published data. Genetic algorithm and multiple linear regression were employed to select the descriptors and to generate the best prediction model that relates the structural features to the RSA activities using (1) three-dimensional (3D) Dragon (TALETE srl, Milan, Italy) descriptors and (2) semi-empirical descriptor calculations. The predictivity of the models was estimated by cross-validation with the leave-one-out method. The result showed that a significant improvement of the statistical indices was obtained by deleting outliers. Based on the data for the compounds used in this study, our results suggest a QSAR model of RSA that is based on the following descriptors: 3D-Morse, WHIM, and GETAWAY. Therefore, satisfactory relationships between RSA and the semi-empirical descriptors were found, demonstrating that the energy of the highest occupied molecular orbital, total energy, and energy of heat of formation contributed more significantly than all other descriptors. PMID:18361735

  10. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    PubMed Central

    Guerrero, Ligia; Castillo, Julián; Quiñones, Mar; Garcia-Vallvé, Santiago; Arola, Lluis; Pujadas, Gerard; Muguerza, Begoña

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results. PMID:23185345

  11. ESTIMATION OF ELECTRON AFFINITY BASED ON STRUCTURE ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Electron affinity for a wide range of organic molecules was calculated from molecular structure using the chemical reactivity models developed in SPARC. hese models are based on fundamental chemical structure theory applied to the prediction of chemical reactivities for organic m...

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

    PubMed

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

    2016-01-01

    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

  13. 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

  14. Structure-reactivity relationships between fluorescent chromophores and antioxidant activity of grain and sweet sorghum seeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyphenolic structures, such as tannins, are the putative cause of a variety of seed functions including bird/insect resistance and antioxidant activity. Structure-reactivity relationships are necessary to understand the influence of polyphenolic chromophore structures on the tannin content and fr...

  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. PMID:24710340

  16. 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

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

    PubMed

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

    2015-07-01

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

  18. Synthesis and structure-activity relationship of trimebutine derivatives.

    PubMed

    Sai, H; Ozaki, Y; Hayashi, K; Onoda, Y; Yamada, K

    1996-06-01

    Trimebutine derivatives were synthesized by utilizing alkylation or acylation of isonitriles and nitrile as a key step. The colonic contractile effects of these compounds were examined, and T-1815 was found to have strong colonic propulsive activity. PMID:8814947

  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. Structure-activity relationship investigations of leishmanicidal N-benzylcytisine derivatives.

    PubMed

    Turabekova, Malakhat A; Vinogradova, Valentina I; Werbovetz, Karl A; Capers, Jeffrey; Rasulev, Bakhtiyor F; Levkovich, Mikhail G; Rakhimov, Shukhrat B; Abdullaev, Nasrulla D

    2011-07-01

    In vitro leishmanicidal activity of 16 N-benzylcytisine derivatives has been evaluated using Leishmania donovani axenic amastigotes. In general, halogen (bromo-, chloro-) derivatives appeared to be more toxic against parasites than their parent compounds. Quantum-chemical calculations helped to recognize certain patterns in the structure of frontier orbitals related to bioactivity of compounds. Thus, the presence of halogen atom is shown to have a significant effect on both distribution and the energy of LUMOs thereby on potent activity that was also confirmed by Quantitative-Structure Activity Relationship (QSAR) analysis. Experimentally and theoretically observed structure-cytotoxicity relationships are described. PMID:21457471

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

    PubMed

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

    2015-01-15

    To develop new rosin-based wood preservatives with good antifungal activity, 24 rosin derivatives were synthesized, bioassay tested with Trametes versicolor and Gloeophyllum trabeum, and subjected to analysis of their quantitative structure-activity relationships (QSAR). A QSAR analysis using Ampac 9.2.1 and Codessa 2.7.16 software built two QSAR models of antifungal ratio for T. versicolor and G. trabeum with values of R(2)=0.9740 and 0.9692, respectively. Based on the models, tri-N-(3-hydroabietoxy-2-hydroxy) propyl-triethyl ammonium chloride was designed and the bioassay test result proved its better inhibitory effect against the two selected fungi as expected. PMID:25466709

  2. Antipoliovirus structure-activity relationships of some aporphine alkaloids.

    PubMed

    Boustie, J; Stigliani, J L; Montanha, J; Amoros, M; Payard, M; Girre, L

    1998-04-01

    A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity. An SAR study demonstrated the importance of a methoxyl group at C-2 on the tetrahydroisoquinoline ring for the induction of antipoliovirus activity. Molecular modeling of some compounds in this series revealed the close similarities between the three-dimensional conformational features of the inactive 1,2-substituted derivatives (+)-boldine (6) and (+)-laurolitsine (5) with derivatives containing the 1,2-(methylenedioxy) moiety, which were generally found to be inactive as exemplified by (+)-cassythicine (9). PMID:9584402

  3. Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.

    PubMed

    Sahu, Pramod K

    2016-10-01

    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. PMID:27318975

  4. A quantitative structure--activity relationship model for the intrinsic activity of uncouplers of oxidative phosphorylation.

    PubMed

    Spycher, Simon; Escher, Beate I; Gasteiger, Johann

    2005-12-01

    A quantitative structure-activity relationship (QSAR) has been derived for the prediction of the activity of phenols in uncoupling oxidative and photophosphorylation. Twenty-one compounds with experimental data for uncoupling activity as well as for the acid dissociation constant, pKa, and for partitioning constants of the neutral and the charged species into model membranes were analyzed. From these measured data, the effective concentration in the membrane was derived, which allowed the study of the intrinsic activity of uncouplers within the membrane. A linear regression model for the intrinsic activity could be established using the following three descriptors: solvation free energies of the anions, an estimate for heterodimer formation describing transport processes, and pKa values describing the speciation of the phenols. In a next step, the aqueous effect concentrations were modeled by combining the model for the intrinsic uncoupling activity with descriptors accounting for the uptake into membranes. Results obtained with experimental membrane-water partitioning data were compared with the results obtained with experimental octanol-water partition coefficients, log Kow, and with calculated log Kow values. The properties of these different measures of lipophilicity were critically discussed. PMID:16359176

  5. Structure-Activity Relationship of Chlorotoxin-Like Peptides

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-02-01

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

  7. Structure-activity relationship of immunostimulatory effects of phthalates

    PubMed Central

    Larsen, Søren T; Nielsen, Gunnar D

    2008-01-01

    Background Some chemicals, including some phthalate plasticizers, have been shown to have an adjuvant effect in mice. However, an adjuvant effect, defined as an inherent ability to stimulate the humoral immune response, was only observed after exposure to a limited number of the phthalates. An adjuvant effect may be due to the structure or physicochemical characteristics of the molecule. The scope of this study was to investigate which molecular characteristics that determine the observed adjuvant effect of the most widely used phthalate plasticizer, the di-(2-ethylhexyl) phthalate (DEHP), which is documented as having a strong adjuvant effect. To do so, a series of nine lipophilic compounds with structural and physicochemical relations to DEHP were investigated. Results Adjuvant effect of phthalates and related compounds were restricted to the IgG1 antibody formation. No effect was seen on IgE. It appears that lipophilicity plays a crucial role, but lipophilicity does not per se cause an adjuvant effect. In addition to lipophilicity, a phthalate must also possess specific stereochemical characteristics in order for it to have adjuvant effect. Conclusion The adjuvant effect of phthalates are highly influenced by both stereochemical and physico-chemical properties. This knowledge may be used in the rational development of plasticizers without adjuvant effect as well as in the design of new immunological adjuvants. PMID:18976460

  8. Structure-Activity Relationships in Human Toll-like Receptor 7-Active Imidazoquinoline Analogues

    PubMed Central

    Shukla, Nikunj M.; Malladi, Subbalakshmi S.; Mutz, Cole A.; Balakrishna, Rajalakshmi; David, Sunil A.

    2010-01-01

    Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. A structure-activity study was conducted on the TLR7-agonistic imidazoquinolines, starting with 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a lead. Modifications of the secondary amine of the C2 ethylaminomethylene sidechain are poorly tolerated. The 4-amino group must be retained for activity. Replacement of the imidazole ring of the scaffold with triazole or cyclic urea led to complete loss of activity. A systematic exploration of N1-benzyl-C2-alkyl substituents showed a very distinct relationship between alkyl length and TLR7-agonistic potency with the optimal compound bearing a C2-n-butyl group. Transposition of the N1 and C2 substituents led to the identification of an extremely active TLR7-agonistic compound with an EC50 value of 8.6 nM. The relative potencies in human TLR7-based primary reporter gene assays were paralleled by interferon-α induction activities in whole human blood models. PMID:20481492

  9. 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.

  10. 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

  11. 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.

  12. STRUCTURE-ACTIVITY RELATIONSHIPS FOR SCREENING ORGANIC CHEMICALS FOR POTENTIAL ECOTOXICITY EFFECTS

    EPA Science Inventory

    The paper presents structure-activity relationships (QSAR) for estimating the bioconcentration factor and acute toxicity of some classes of industrial chemicals using only the n-octanol/water partition coefficient (Log P) which is derived from chemical structure. The bioconcentra...

  13. Structure-activity relationships of aromatic diamines in the Ames Salmonella typhimurium assay. Part II.

    PubMed

    Kalopissis, G

    1992-09-01

    Structure-activity relationships in the case of aromatic monoamines, diversely substituted on the ring, using the mutagenic activity in the Ames test were studied in part I. This part II is based on the same general principles but applied to phenylene diamines (ortho, para and meta) diversely substituted on the ring. PMID:1381475

  14. Structural Relationships between Social Activities and Longitudinal Trajectories of Depression among Older Adults

    ERIC Educational Resources Information Center

    Hong, Song-Iee; Hasche, Leslie; Bowland, Sharon

    2009-01-01

    Purpose: This study examines the structural relationships between social activities and trajectories of late-life depression. Design and Methods: Latent class analysis was used with a nationally representative sample of older adults (N = 5,294) from the Longitudinal Study on Aging II to classify patterns of social activities. A latent growth curve…

  15. Neuroprotective and Antioxidant Activities of 4-Methylcoumarins: Development of Structure-Activity Relationships.

    PubMed

    Malhotra, Shashwat; Tavakkoli, Marjan; Edraki, Najmeh; Miri, Ramin; Sharma, Sunil Kumar; Prasad, Ashok Kumar; Saso, Luciano; Len, Christophe; Parmar, Virinder Singh; Firuzi, Omidreza

    2016-01-01

    Coumarins are a major class of polyphenols that are abundantly present in many dietary plants and possess different biological activities. Neuroprotective effect of 28 variously substituted 4-methylcoumarins was evaluated in a cell model of oxidative stress-induced neurodegeneration, which measures viability in PC12 cells challenged with hydrogen peroxide by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The inhibitory activity of these compounds against intracellular reactive oxygen species (ROS) formation was also determined by 2',7'-dichlorofluorescein diacetate method in the same cells. Chemical redox-based assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) tests were employed to explore structure-antioxidant activity relationships in a cell-free environment. The results demonstrated that 4-methylcoumarins containing ortho-dihydroxy or ortho-diacetoxy substituents on the benzenoid ring possess considerable neuroprotective effects. ortho-Dihydroxy compounds inhibited cytotoxicity (44.7-62.9%) and ROS formation (41.6-71.1%) at 50 µM and showed considerable antioxidant effects. We conclude that 4-methylcoumarins are promising neuroprotective and antioxidant scaffolds potentially usefull for management of neurodegenerative diseases. PMID:27582333

  16. 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

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

    PubMed

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

    2006-06-01

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

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

    PubMed

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

    2012-02-01

    Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food. PMID:21940715

  19. 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

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

    PubMed

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

    2016-10-01

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

  1. Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.

    PubMed

    Alonso, Juan Antonio; Andrés, Miriam; Bravo, Mónica; Calbet, Marta; Eastwood, Paul R; Eichhorn, Peter; Esteve, Cristina; Ferrer, Manel; Gómez, Elena; González, Jacob; Mir, Marta; Moreno, Imma; Petit, Silvia; Roberts, Richard S; Sevilla, Sara; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere; Zanuy, Miriam

    2014-11-01

    Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles. PMID:25437505

  2. Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists.

    PubMed

    Andrés, Miriam; Buil, Maria Antonia; Calbet, Marta; Casado, Oscar; Castro, Jordi; Eastwood, Paul R; Eichhorn, Peter; Ferrer, Manel; Forns, Pilar; Moreno, Imma; Petit, Silvia; Roberts, Richard S

    2014-11-01

    Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs. PMID:25437503

  3. 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. PMID:18045063

  4. DEVELOPMENT OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR PREDICTING BIODEGRADATION KINETICS

    EPA Science Inventory

    Results have been presented on the development of a structure-activity relationship for biodegradation using a group contribution approach. sing this approach, reported results of the kinetic rate constant agree within 20% with the predicted values. dditional compound studies are...

  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. STRUCTURE-ACTIVITY RELATIONSHIPS (SARS) AMONG MUTAGENS AND CARCINOGENS: A REVIEW

    EPA Science Inventory

    The review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correla...

  7. 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

  8. STRUCTURE-ACTIVITY RELATIONSHIPS AND ESTIMATION TECHNIQUES FOR BIODEGRADATION OF XENOBIOTICS

    EPA Science Inventory

    The Current status of structure-activity relationships for the biodegradation of xenobiotics is reviewed. esults are presented of a pilot study on biodegradation Constants obtained from Computer databases. ew analyses for a relatively large number of anilines and phenols are pres...

  9. Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.

    PubMed

    Sawada, Hiromi; Onoda, Kenji; Morita, Daichi; Ishitsubo, Erika; Matsuno, Kenji; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

    2013-12-15

    We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity. PMID:24239015

  10. Indolo[3,2-b]quinolines: Synthesis, Biological Evaluation and Structure Activity-Relationships

    PubMed Central

    Kumar, Eyunni V.K. Suresh; Etukala, Jagan R.; Ablordeppey, Seth Y.

    2013-01-01

    The tetracyclic indolo[3,2-b]quinoline ring system constitutes an important structural moiety in natural products exhibiting numerous biological activities. In particular, indolo [3, 2-b]quinoline, commonly known as linear quindo-line is of particular interest, because of its rigid structure and scope of derivatization. Although the core linear quindoline skeleton shows little or no activity in several biological systems, introduction of a methyl group on the N-5 atom leading to cryptolepine induces remarkable activity against a broad spectrum of biological targets. A number of analogs of quindoline and cryptolepine have been synthesized, incorporating various functional groups on the core quindoline skeleton leading to improved biological activities. In this review, we describe various synthetic methodologies leading to the quindoline scaffold, the biological activities and the structure activity relationships (SAR) of quindoline derivatives toward different disease states to give a better picture of the importance of this moiety in medicinal chemistry. PMID:18537709

  11. 4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses▿

    PubMed Central

    Hocart, Simon J.; Liu, Huayin; Deng, Haiyan; De, Dibyendu; Krogstad, Frances M.; Krogstad, Donald J.

    2011-01-01

    Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets. PMID:21383099

  12. 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.

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

    PubMed Central

    Pu, Wenjun; Wang, Dongmei; Zhou, Dan

    2015-01-01

    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. PMID:26350974

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

    PubMed

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

    2016-09-20

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

  15. The structure-activity relationships of the antiviral chemotherapeutic activity of isatin β-thiosemicarbazone

    PubMed Central

    Bauer, D. J.; Sadler, P. W.

    1960-01-01

    As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin β-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin β-thiosemicarbazone as a standard. The overall dimensions of the isatin β-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH2 group in relation to the ring nitrogen was found to be critical, as the α-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin β-thiosemicarbazone, with an activity of 286 (isatin β-thiosemicarbazone≡100). Isatin β-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia. PMID:13797622

  16. Oxidative Dehydrogenation on Nanocarbon: Intrinsic Catalytic Activity and Structure-Function Relationships.

    PubMed

    Qi, Wei; Liu, Wei; Guo, Xiaoling; Schlögl, Robert; Su, Dangsheng

    2015-11-01

    Physical and chemical insights into the nature and quantity of the active sites and the intrinsic catalytic activity of nanocarbon materials in alkane oxidative dehydrogenation (ODH) reactions are reported using a novel in situ chemical titration process. A study on the structure-function relationship reveals that the active sites are identical both in nature and function on various nanocarbon catalysts. Additionally, the quantity of the active sites could be used as a metric to normalize the reaction rates, and thus to evaluate the intrinsic activity of nanocarbon catalysts. The morphology of the nanocarbon catalysts at the microscopic scale exhibits a minor influence on their intrinsic ODH catalytic activity. The number of active sites calculated from the titration process indicates the number of catalytic centers that are active (that is, working) under the reaction conditions. PMID:26388451

  17. Relationship between structure of phenothiazine analogues and their activity on platelet calcium fluxes.

    PubMed Central

    Enouf, J.; Lévy-Toledano, S.

    1984-01-01

    Phenothiazine analogues have been tested for their effect on calcium uptake into platelet membrane vesicles and on ionophore-induced platelet activation, both phenomena being Ca2+-dependent. Both calcium uptake into membrane vesicles and ionophore-induced platelet activation were inhibited by the drugs. Evidence for two inhibitors as potent as chlorpromazine and trifluoperazine was found. These drugs are apparently competitive inhibitors of calcium uptake. A structure-activity relationship has been established. The data suggest that the phenothiazines are able to inhibit calmodulin-insensitive calcium uptake of platelet membrane vesicles and that therefore they cannot be assumed to be selective inhibitors of calmodulin interactions under all circumstances. PMID:6697061

  18. 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. PMID:24105965

  19. 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. PMID:25935289

  20. Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.

    PubMed

    Dickson, Callum J; Hornak, Viktor; Velez-Vega, Camilo; McKay, Daniel J J; Reilly, John; Sandham, David A; Shaw, Duncan; Fairhurst, Robin A; Charlton, Steven J; Sykes, David A; Pearlstein, Robert A; Duca, Jose S

    2016-06-23

    Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions. PMID:27239696

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

    PubMed

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

    2014-01-01

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

  2. Structure-Activity Relationship for Fe(III)-Salen-Like Complexes as Potent Anticancer Agents

    PubMed Central

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

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R2train = 0.99, RMSE = 0.138, and Q2LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  3. Quantitative Structure-Cytotoxic Activity Relationship 1-(Benzoyloxy)urea and Its Derivative.

    PubMed

    Hardjono, Suko; Siswodihardjo, Siswandono; Pramono, Purwanto; Darmanto, Win

    2016-01-01

    Drug development is originally carried out on a trial and error basis and it is cost-prohibitive. To minimize the trial and error risks, drug design is needed. One of the compound development processes to get a new drug is by designing a structure modification of the mother compound whose activities are recognized. A substitution of the mother compounds alters the physicochemical properties: lipophilic, electronic and steric properties. In Indonesia, one of medical treatments to cure cancer is through chemotherapy and hydroxyurea. Some derivatives, phenylthiourea, phenylurea, benzoylurea, thiourea and benzoylphenylurea, have been found to be anticancer drug candidates. To predict the activity of the drug compound before it is synthesized, the in-silico test is required. From the test, Rerank Score which is the energy of interaction between the receptor and the ligand molecule is then obtained. Hydroxyurea derivatives were synthesized by modifying Schotten-Baumann's method by the addition of benzoyl group and its homologs resulted in the increase of lipophilic, electronic and steric properties, and cytotoxic activity. Synthesized compounds were 1-(benzoyloxy)urea and its derivatives. Structure characterization was obtained by the spectrum of UV, IR, H NMR, C NMR and Mass Spectrometer. Anticancer activity was carried out using MTT method on HeLa cells. The Quantitative Structure-Cytotoxic Activity Relationships of 1-(benzoyloxy)urea compound and its derivatives was calculated using SPSS. The chemical structure was described, namely: ClogP, π, σ, RS, CMR and Es; while, the cytotoxic activity was indicated by log (1 / IC50). The results show that the best equation of Quantitative Structure-Cytotoxic Activity Relationships (QSAR) of 1- (benzoyloxy)urea compound and its derivatives is Log 1/IC50 = - 0.205 (+ 0.068) σ - 0.051 (+ 0.022) Es - 1.911 (+ 0.020). PMID:27222144

  4. Structure-Activity Relationships of Retro-dihydrochalcones Isolated from Tacca sp

    PubMed Central

    Peng, Jiangnan; Risinger, April L.; Da, Chenxiao; Fest, Gary A.; Kellogg, Glen E.; Mooberry, Susan L.

    2014-01-01

    Several biologically active compounds have been identified from Tacca species, including glycosides, diarylheptanoids, saponins, withanolides, and the taccalonolide class of microtubule stabilizers. More recently, two cytotoxic retro-dihydrochalcones named evelynin A (7) and taccabulin A (6) were isolated and their biological activities characterized, including the finding that taccabulin has microtubule destabilizing effects. Here we describe the identification and characterization of five new retro-chalcones, named taccabulins B – E (1–4) and evelynin B (5) from Tacca sp. extracts. Their structures were determined using 1D and 2D NMR as well as mass spectroscopic data and modeled into the colchicine binding site of tubulin. The antiproliferative and microtubule effects of each compound were determined experimentally and found to be well correlated with modeling studies. The isolation and biological characterization of several retro-dihydrochalcones facilitated preliminary structure-activity relationships for this compound class concerning its antiproliferative and microtubule depolymerizing activities. PMID:24303844

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

    PubMed

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

    2014-12-15

    Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. PMID:25467149

  6. Antibacterial structure-activity relationship studies of several tricyclic sulfur-containing flavonoids.

    PubMed

    Bahrin, Lucian G; Hopf, Henning; Jones, Peter G; Sarbu, Laura G; Babii, Cornelia; Mihai, Alina C; Stefan, Marius; Birsa, Lucian M

    2016-01-01

    A structure-activity relationship study concerning the antibacterial properties of several halogen-substituted tricyclic sulfur-containing flavonoids has been performed. The compounds have been synthesized by cyclocondensation of the corresponding 3-dithiocarbamic flavanones under acidic conditions. The influence of different halogen substituents on the antibacterial properties has been tested against Staphylococcus aureus and Escherichia coli. Amongst the N,N-dialkylamino-substituted flavonoids, those having an N,N-diethylamino moiety exhibited good to excellent antimicrobial properties against both pathogens. Fluorine-substituted flavonoids were found to be less active than those bearing other halogen atoms. PMID:27340492

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  8. Use of selected toxicology information resources in assessing relationships between chemical structure and biological activity

    SciTech Connect

    Wassom, J.S.

    1985-09-01

    This paper addresses the subject of the use of the selected toxicology information resources in assessing relationships between chemical structure and specific end points. To assist the researcher in how to access the primary literature of genetic toxicology, teratogenesis, and carcinogenesis, three specific specialized information centers are discussed - Environmental Mutagen Information Center, Environmental Teratology Information Center, and Environmental Carcinogenesis Information Center. Also included are descriptions of information resources that contain evaluated (peer-reviewed) biological research results. The US Environmental Protection Agency Genetic Toxicology Program, the International Agency for Research on Cancer Monographs, and the Toxicology Data Bank are the best sources currently available to obtain peer-reviewed results for compounds tested for genotoxicity, carcinogenicity, and other toxicological end points. The value of published information lies in its use. It has become evident that most information cannot be accepted at face value for interpretation and analysis when subjected to stringent quality evaluation criteria. This deficit can be corrected by rigid editorship and the cognizance of authors. Increased interest in alternative methods to in vivo animal testing will be exemplified by use of short-term bioassays and in structure-activity relationship studies. With respect to this latter area, it must be remembered that mechanically (computer generated) derived data cannot substitute, at least at this stage, for data obtained from actual animal testing. The future of structure-activity relationship studies will rest only in their use as a predictive tool.

  9. Use of selected toxicology information resources in assessing relationships between chemical structure and biological activity.

    PubMed Central

    Wassom, J S

    1985-01-01

    This paper addresses the subject of the use of selected toxicology information resources in assessing relationships between chemical structure and specific biological end points. To assist the researcher in how to access the primary literature of genetic toxicology, teratogenesis, and carcinogenesis, three specific specialized information centers are discussed--Environmental Mutagen Information Center, Environmental Teratology Information Center, and Environmental Carcinogenesis Information Center. Also included are descriptions of information resources that contain evaluated (peer-reviewed) biological research results. The U.S. Environmental Protection Agency Genetic Toxicology Program, the International Agency for Research on Cancer Monographs, and the Toxicology Data Bank are the best sources currently available to obtain peer-reviewed results for compounds tested for genotoxicity, carcinogenicity, and other toxicological end points. The value of published information lies in its use. It has become evident that most information cannot be accepted at face value for interpretation and analysis when subjected to stringent quality evaluation criteria. This deficit can be corrected by rigid editorship and the cognizance of authors. Increased interest in alternative methods to in vivo animal testing will be exemplified by use of short-term bioassays and in structure-activity relationship studies. With respect to this latter area, it must be remembered that mechanically (computer generated) derived data cannot substitute, at least at this stage, for data obtained from actual animal testing. The future of structure-activity relationship studies will rest only in their use as a predictive tool. PMID:4065070

  10. Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides.

    PubMed Central

    Coats, J R

    1990-01-01

    The mechanisms and sites of action of organochlorine (DDT-types and chlorinated alicyclics) and synthetic pyrethroid insecticides are presented with discussion of symptoms, physiological effects, and selectivity. The structural requirements for toxicity are assessed, and structure-activity relationships are considered for each subclass. Lipophilicity is important for all the groups because it facilitates delivery of these neurotoxicants to the site of action in the nerve. Steric factors including molecular volume, shape, and isomeric configuration greatly influence toxicity. Electronic parameters also have been demonstrated to affect biological activity in some of the groups of insecticides, e.g., Hammett's sigma and Taft's sigma * as indicators of electronegativity. New synthetic pyrethroids continue to be developed, with varied structures and different physicochemical and biological properties. PMID:2176589

  11. Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis.

    PubMed

    Wu, Xiaoai; Fang, Zhen; Yang, Bo; Zhong, Lei; Yang, Qiuyuan; Zhang, Chunhui; Huang, Shenzhen; Xiang, Rong; Suzuki, Takayoshi; Li, Lin-Li; Yang, Sheng-Yong

    2016-05-01

    Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies. PMID:27020306

  12. Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy

    PubMed Central

    Bhargava, Priyanshu; Singh, Ashima; Motiani, Rajender K.; Shyam, Radhey; Sreekanth, Vedagopuram; Sengupta, Sagar; Bajaj, Avinash

    2014-01-01

    We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model. PMID:25685308

  13. Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors.

    PubMed

    Bouckaert, Charlotte; Serra, Silvia; Rondelet, Grégoire; Dolušić, Eduard; Wouters, Johan; Dogné, Jean-Michel; Frédérick, Raphaël; Pochet, Lionel

    2016-03-01

    Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds. PMID:26827162

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

    PubMed

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

    2016-05-26

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

  15. Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors

    PubMed Central

    Qiao, Lixin; Choi, Sungwoon; Case, April; Gainer, Thomas G.; Seyb, Kathleen; Glicksman, Marcie A.; Lo, Donald C.; Stein, Ross L.; Cuny, Gregory D.

    2009-01-01

    A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of two hundred and eighty eight kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor. PMID:19783434

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

    PubMed

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

    2016-02-01

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

  17. Synthesis and Structure Activity Relationship of 3-Hydroxypyridin-2-thione Based Histone Deacetylase Inhibitors

    PubMed Central

    Sodji, Quaovi H.; Patil, Vishal; Kornacki, James R.; Mrksich, Milan; Oyelere, Adegboyega K.

    2014-01-01

    We have previously identified 3-hydroxypyridin-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but are devoid of HDAC1 inhibition. To further delineate the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds 10d and 14e with potent HDAC6 and HDAC8 activities, but that are inactive against HDAC1. These new HDACi possess anti-cancer activities against various cancer cell lines including Jurkat J-γ1 against which SAHA and the previously disclosed 3HPT-derived HDACi were inactive. PMID:24304348

  18. 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. PMID:24803014

  19. STUDIES OF RELATIONSHIPS BETWEEN MOLECULAR STRUCTURE AND BIOLOGICAL ACTIVITY BY PATTERN RECOGNITION METHODS

    EPA Science Inventory

    The attempt to rationalize the connections between the molecular structures of organic compounds and their biological activities comprises the field of structure-activity relations (SAR) studies. Correlations between structure and activity are important for the understanding and ...

  20. Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure-Activity Relationship Studies

    PubMed Central

    Arungundram, Sailaja; Al-Mafraji, Kanar; Asong, Jinkeng; Leach, Franklin E.; Amster, I. Jonathan; Venot, Andre; Turnbull, Jeremy E.; Boons, Geert-Jan

    2010-01-01

    Although hundreds of heparan sulfate binding proteins have been identified, and implicated in a myriad of physiological and pathological processes, very little information is known about ligand requirements for binding and mediating biological activities by these proteins. This difficulty results from a lack of technology for establishing structure-activity-relationships, which in turn is due to the structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HS-oligosaccharides. To address this deficiency, we have developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides that utilizes a relatively small number of selectively protected disaccharide building blocks, which can easily be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of twelve oligosaccharides, which has been employed to probe structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer's disease. PMID:19904943

  1. Quantitative structure-activity relationship models with receptor-dependent descriptors for predicting peroxisome proliferator-activated receptor activities of thiazolidinedione and oxazolidinedione derivatives.

    PubMed

    Lather, Viney; Kairys, Visvaldas; Fernandes, Miguel X

    2009-04-01

    A quantitative structure-activity relationship study has been carried out, in which the relationship between the peroxisome proliferator-activated receptor alpha and the peroxisome proliferator-activated receptor gamma agonistic activities of thiazolidinedione and oxazolidinedione derivatives and quantitative descriptors, V(site) calculated in a receptor-dependent manner is modeled. These descriptors quantify the volume occupied by the optimized ligands in regions that are either common or specific to the superimposed binding sites of the targets under consideration. The quantitative structure-activity relationship models were built by forward stepwise linear regression modeling for a training set of 27 compounds and validated for a test set of seven compounds, resulting in a squared correlation coefficient value of 0.90 for peroxisome proliferator-activated receptor alpha and of 0.89 for peroxisome proliferator-activated receptor gamma. The leave-one-out cross-validation and test set predictability squared correlation coefficient values for these models were 0.85 and 0.62 for peroxisome proliferator-activated receptor alpha and 0.89 and 0.50 for peroxisome proliferator-activated receptor gamma respectively. A dual peroxisome proliferator-activated receptor model has also been developed, and it indicates the structural features required for the design of ligands with dual peroxisome proliferator-activated receptor activity. These quantitative structure-activity relationship models show the importance of the descriptors here introduced in the prediction and interpretation of the compounds affinity and selectivity. PMID:19243388

  2. 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. PMID:17077558

  3. In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase.

    PubMed

    Korotchenko, Vasiliy N; Saydmohammed, Manush; Vollmer, Laura L; Bakan, Ahmet; Sheetz, Kyle; Debiec, Karl T; Greene, Kristina A; Agliori, Christine S; Bahar, Ivet; Day, Billy W; Vogt, Andreas; Tsang, Michael

    2014-07-01

    Dual specificity phosphatase 6 (DUSP6) functions as a feedback attenuator of fibroblast growth factor signaling during development. In vitro high throughput chemical screening attempts to discover DUSP6 inhibitors have yielded limited success. However, in vivo whole-organism screens of zebrafish identified compound 1 (BCI) as an allosteric inhibitor of DUSP6. Here we designed and synthesized a panel of analogues to define the structure-activity relationship (SAR) of DUSP6 inhibition. In vivo high-content analysis in transgenic zebrafish, coupled with cell-based chemical complementation assays, identified structural features of the pharmacophore of 1 that were essential for biological activity. In vitro assays of DUSP hyperactivation corroborated the results from in vivo and cellular SAR. The results reinforce the notion that DUSPs are druggable through allosteric mechanisms and illustrate the utility of zebrafish as a model organism for in vivo SAR analyses. PMID:24909879

  4. Relationship between structure, properties, and the radical scavenging activity of morin

    NASA Astrophysics Data System (ADS)

    Mendoza-Wilson, Ana María; Santacruz-Ortega, Hisila; Balandrán-Quintana, René R.

    2011-05-01

    The relationship between structure, kinetic, thermochemical and electronic properties of the morin flavonoid was researched in order to establish the molecular characteristics related to its maximum radical scavenging activity. The reaction of morin with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH rad ) was carried out in ethanol, through the hydrogen-atom transfer (HAT) mechanism. Morin showed the highest radical scavenging activity under conditions of excess of free radical. It was found, by means of experimental and computational methods, that 3-OH, 2'-OH and 4'-OH are the main reactive sites, as well as that the 3-O-2'-O quinone is the first product of the reaction, tending to prevail in the enol form through a tautomerism effect, whose observed structural arrangement corresponds to the 3-O semiquinone.

  5. 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

  6. 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. PMID:26568113

  7. 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

  8. Substrate Structure-Activity Relationships Guide Rational Engineering of Modular Polyketide Synthase Ketoreductases

    PubMed Central

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

    2015-01-01

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

  9. 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. PMID:26264839

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

    PubMed

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

    1999-01-01

    Quantitative structure-activity relationships (QSARs) for 35 cinnamamides were studied. By using a genetic algorithm (GA), a group of multiple regression models with high fitness scores was generated. From the statistical analyses of the descriptors used in the evolution procedure, the principal features affecting the anticonvulsant activity were found. The significant descriptors include the partition coefficient, the molar refraction, the Hammet sigma constant of the substituents on the benzene ring, and the formation energy of the molecules. It could be found that the steric complementarity and the hydrophobic interaction between the inhibitors and the receptor were very important to the biological activity, while the contribution of the electronic effect was not so obvious. Moreover, by construction of the spline models for these four principal descriptors, the effective range for each descriptor was identified. PMID:10529984

  11. Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase.

    PubMed

    Sosič, Izidor; Anderluh, Marko; Sova, Matej; Gobec, Martina; Mlinarič Raščan, Irena; Derouaux, Adeline; Amoroso, Ana; Terrak, Mohammed; Breukink, Eefjan; Gobec, Stanislav

    2015-12-24

    Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions. PMID:26588190

  12. A structure-activity relationship for induction of meningeal inflammation by muramyl peptides.

    PubMed Central

    Burroughs, M; Rozdzinski, E; Geelen, S; Tuomanen, E

    1993-01-01

    Components of bacterial peptidoglycans have potent biological activities, including adjuvant effects, cytotoxicity, and induction of sleep. Mixtures of peptidoglycan components also induce inflammation in the lung, subarachnoid space, and joint, but the structural requirements for activity are unknown. Using a rabbit model for meningitis, we determined the biological activities of 14 individual muramyl peptides constituting > 90% of the peptidoglycan of the gram-negative pediatric pathogen Haemophilus influenzae. Upon intracisternal inoculation, most of the muropeptides induced leukocytosis in cerebrospinal fluid (CSF), influx of protein into CSF, or brain edema, alone or in combination. The disaccharide-tetrapeptide, the major component of all gram-negative peptidoglycans, induced CSF leukocytosis and protein influx at doses as low as 0.4 microgram (0.42 nM). Modification of the N-acetyl muramic acid or substitution of the alanine at position four in the peptide side chain decreased leukocytosis but enhanced brain edema. As the size of the muropeptide increased, the inflammatory activity decreased. Muropeptide carrying the diaminopimelyl-diaminopimelic acid cross-link specifically induced cytotoxic brain edema. These findings significantly expand the spectrum of biological activities of natural muramyl peptides and provide the basis for a structure-activity relationship for the inflammatory properties of bacterial muropeptides. PMID:8325996

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

    PubMed

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

    2012-11-01

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

  14. 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

    2013-10-01

    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. PMID:24083323

  15. 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

    2013-11-01

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

  16. 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

  17. Isolation of lignans from Schisandra chinensis with anti-proliferative activity in human colorectal carcinoma: Structure-activity relationships.

    PubMed

    Gnabre, John; Unlu, Irem; Chang, Tso-Cheng; Lisseck, Paul; Bourne, Bryan; Scolnik, Ryan; Jacobsen, Neil E; Bates, Robert; Huang, Ru Chih

    2010-10-15

    Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures. PMID:20810329

  18. The structure-AChE inhibitory activity relationships study in a series of pyridazine analogues.

    PubMed

    Saracoglu, M; Kandemirli, F

    2009-07-01

    The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC(50) units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction. PMID:19689389

  19. 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

  20. 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

  1. 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

  2. Structure-Activity Relationships in Toll-like Receptor-2 agonistic Diacylthioglycerol Lipopeptides

    PubMed Central

    Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; Kimbrell, Matthew R.; Amolins, Michael W.; Ukani, Rehman; Datta, Apurba; David, Sunil A.

    2010-01-01

    The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity. PMID:20302301

  3. Further Studies on Structure-Cardiac Activity Relationships of Diterpenoid Alkaloids.

    PubMed

    Zhang, Zhong-Tang; Jian, Xi-Xian; Ding, Jia-Yu; Deng, Hong-Ying; Chao, Ruo-Bing; Chen, Qiao-Hong; Chen, Dong-Lin; Wang, Feng-Peng

    2015-12-01

    The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom. PMID:26882669

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

    PubMed

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

    2016-01-01

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

  5. Novel 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes to investigate structure/activity relationships.

    PubMed

    Rangel, Maria; Amorim, M João; Nunes, Ana; Leite, Andreia; Pereira, Eulália; de Castro, Baltazar; Sousa, Carla; Yoshikawa, Yutaka; Sakurai, Hiromu

    2009-04-01

    A previous evaluation of the insulin-like activity of three 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes raised questions about structure/activity relationships, namely the influence of the hydrophilic/lipophilic balance of the complex and the capacity of the ligand to stabilize the +4 oxidation state of vanadium ion, on achieving an positive effect. To address these questions, we synthesized six new oxidovanadium(IV) complexes with variable hydrophilic/lipophilic balance, obtained by introducing different substituents on the nitrogen atom, and used two 3-hydroxy-4-pyrones as starting reagents to provide methyl and ethyl groups in the ortho position of the ring. For the new and previously reported complexes, we studied the oxidation-reduction properties and insulin-like activity in terms of inhibitory effect on Free fatty acid (FFA) release in isolated rat adipocytes. The results obtained show that only one of the complexes, Bis(3-hydroxy-1(H)-2-methyl-4-pyridonato)oxidovanadium(IV), VO(mpp)(2), exhibits a significantly greater capacity to inhibit FFA release than VOSO(4) and consequently is worthy to be considered for further studies. The establishment of structure activity relationships was not attainable but this study brings new information about the influence of some properties of the compounds on the achievement of an insulin-like effect. The results reveal that: (i) the oxidation-reduction cycles of the complexes are identical; (ii) the presence of more lipophilic substituents on the nitrogen atom does not enhance insulin-like properties; (iii) a high solubility in water proved to be not sufficient for a positive activity in inhibiting FFA release; (iv) a small molecular size may be an important property for reaching the right targets. PMID:19195710

  6. Orthogonal chemistry for the synthesis of thiocoraline-triostin hybrids. Exploring their structure-activity relationship.

    PubMed

    Tulla-Puche, Judit; Auriemma, Sara; Falciani, Chiara; Albericio, Fernando

    2013-07-11

    The natural compounds triostin and thiocoraline are potent antitumor agents that act as DNA bisintercalators. From a pharmaceutical point of view, these compounds are highly attractive although they present a low pharmacokinetic profile, in part due to their low solubility. Synthetically, they represent a tour de force because no robust strategies have been developed to access a broad range of these bicyclic (depsi)peptides in a straightforward manner. Here we describe solid-phase strategies to synthesize new bisintercalators, such as thiocoraline-triostin hybrids, as well as analogues bearing soluble tags. Orthogonal protection schemes (up to five from: Fmoc, Boc Alloc, pNZ, o-NBS, and Troc), together with the right concourse of the coupling reagents (HOSu, HOBt, HOAt, Oxyma, EDC, DIPCDI, PyAOP, PyBOP, HATU, COMU), were crucial to establish the synthetic plan. In vitro studies and structure-activity relationships have been shown trends in the structure-activity relationship that will facilitate the design of new bisintercalators. PMID:23746132

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

    PubMed Central

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

    2016-01-01

    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. PMID:25401513

  8. 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...

  9. FISH ACUTE TOXICITY SYNDROMES: APPLICATION TO THE DEVELOPMENT OF MECHANISM-SPECIFIC QSARS (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS)

    EPA Science Inventory

    Predictive models based on quantitative structure activity relationships (QSARs), are used as rapid screening tools to identify potentially hazardous chemicals. Several QSARs are now available that predict the acute toxicity of narcotic-industrial chemicals. Predictions for compo...

  10. 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...

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

    PubMed

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

    2016-08-10

    The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified. PMID:27452503

  12. Development of quantitative structure activity relationships for the binding affinity of methoxypyridinium cations for human acetylcholinesterase.

    PubMed

    Morrill, Jason A; Topczewski, Joseph J; Lodge, Alexander M; Yasapala, Nilanthi; Quinn, Daniel M

    2015-11-01

    Among the most toxic substances known are the organophosphorus (OP) compounds used as pesticides and chemical warfare agents. Owing to their high toxicity there is a number of efforts underway to develop effective therapies for OP agent exposure. To date all therapies in use treat inhibited acetylcholinesterase (AChE), but are ineffective for the treatment of inhibited AChE, which has undergone a subsequent hydrolysis process, referred to as aging. Toward developing a therapy for treating victims of OP intoxication in the aged state we have developed Quantitative Structure-Activity Relationships (QSARs) based on the AM1 semiempirical quantum mechanical method using the program, CODESSA (COmprehensive Descriptors for Structural and Statistical Analysis). Using this methodology we obtained a multiple correlation QSAR equation which gave R(2)=0.9359 for a random training set of 38 ligands and R(2)=0.9236 for prediction on a random test set of 9 ligands. PMID:26454505

  13. 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. PMID:22422530

  14. Bioisosterism of urea-based GCPII inhibitors. Synthesis and structure activity relationship studies

    SciTech Connect

    Wang, Haofan; Byun, Youngjoo; Barinka, Cyril; Pullambhatla, Mrudula; Bhang, Hyo-eun C; Fox, James J; Lubkowski, Jacek; Mease, Ronnie C; Pomper, Martin G

    2010-10-28

    We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1prime site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with Ki values below 20 nM. Among them, compound 32d (Ki = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1prime pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.

  15. Monitoring the Progression of Structure-Activity Relationship Information during Lead Optimization.

    PubMed

    Shanmugasundaram, Veerabahu; Zhang, Liying; Kayastha, Shilva; de la Vega de León, Antonio; Dimova, Dilyana; Bajorath, Jürgen

    2016-05-12

    Lead optimization (LO) in medicinal chemistry is largely driven by hypotheses and depends on the ingenuity, experience, and intuition of medicinal chemists, focusing on the key question of which compound should be made next. It is essentially impossible to predict whether an LO project might ultimately be successful, and it is also very difficult to estimate when a sufficient number of compounds has been evaluated to judge the odds of a project. Given the subjective nature of LO decisions and the inherent optimism of project teams, very few attempts have been made to systematically evaluate project progression. Herein, we introduce a computational framework to follow the evolution of structure-activity relationship (SAR) information over a time course. The approach is based on the use of SAR matrix data structures as a diagnostic tool and enables graphical analysis of SAR redundancy and project progression. This framework should help the process of making decisions in close-in analogue work. PMID:26569348

  16. 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. PMID:26776000

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

    PubMed

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

    2012-07-14

    We report on new insights into the relationships between structure and activity of glassy carbon (GC), as a model material for electrocatalyst support, during its anodization in acid solution. Our investigation strongly confirms the role of CFGs in promotion of Pt activity by the "spill-over" effect related to CO(ads) for methanol electrooxidation (MEO) on a carbon-supported Pt catalyst. Combined analysis of voltammetric and impedance behaviour as well as changes in GC surface morphology induced by intensification of anodizing conditions reveal an intrinsic influence of the carbon functionalization and the structure of a graphene oxide (GO) layer on the electrical and electrocatalytic properties of activated GC. Although GO continuously grows during anodization, it structurally changes from being a graphite inter-layer within graphite ribbons toward a continuous GO surface layer that deteriorates the native structure of GC. As a consequence of the increased distance between GO-spaced graphite layers, the GC conductivity decreases until the case of profound GO exfoliation under drastic anodizing conditions. This exposes the native, yet abundantly functionalized, GC texture. While GC capacitance continuously increases with intensification of anodizing conditions, the surface nano-roughness and GO resistance reach the highest values at modest anodizing conditions, and then decrease upon drastic anodization due to the onset of GO exfoliation. We found for the first time that the activity of a GC-supported Pt catalyst in MEO, as one of the promising half-reactions in polymer electrolyte fuel cells, strictly follows the changes in GC nano-roughness and GO-induced GC resistance. The highest GC/Pt MEO activity is reached when optimal distance between graphite layers and optimal degree of GC functionalization bring the highest amount of CFGs into intimate contact with the Pt surface. This confirms the promoting role of CFGs in MEO catalysis. PMID:22648036

  18. Crystal Structures and Structure–Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors

    PubMed Central

    2014-01-01

    Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure–activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors. PMID:25313323

  19. Pyrazole derivatives as photosynthetic electron transport inhibitors: new leads and structure-activity relationship.

    PubMed

    Vicentini, Chiara B; Guccione, Salvatore; Giurato, Laura; Ciaccio, Rebecca; Mares, Donatella; Forlani, Giuseppe

    2005-05-18

    Four series of new pyrazoles, namely, 5 4-carboxypyrazolo-3-tert-butylcarboxamide and 6 4-carboxypyrazolo-3-cyclopropylcarboxamide derivatives and 10 pyrazolo[3,4-d][1,3]thiazine-4-one and 9 pyrazolo[3,4-d][1,3]thiazine-4-thione derivatives, were synthesized and screened as potential inhibitors of photosynthetic electron transport. The structures were confirmed by 1H NMR, elemental, and IR analyses. Their biological activity was evaluated in vitro as the ability to interfere with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Only a few compounds exhibited excellent inhibitory properties in the micromolar range, comparable to those of commercial herbicides sharing the same target, such as diuron, lenacil, and hexazinone. Nevertheless, most of the remaining molecules exerted a remarkable inhibition in the millimolar range. Combined with previous results on 6 pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and 4 pyrazolo[1,5-c][1,3,5]thiadiazine-2-one derivatives, these data allowed a comprehensive analysis of structure-activity relationship. Molecular modeling studies were undertaken to rationalize the structural determinants of activity in terms of shape, size, and molecular fields. Results suggested that the inhibitory potential of these compounds is associated mainly with their electrostatic properties. PMID:15884806

  20. 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. PMID:26119501

  1. Structure-activity relationships and in silico models of P-glycoprotein (ABCB1) inhibitors.

    PubMed

    Liu, Hongming; Ma, Zhiguo; Wu, Baojian

    2013-11-01

    1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs. 2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity. 3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure-activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein. 4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities. PMID:23617855

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

    PubMed Central

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

    2015-01-01

    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. PMID:26266415

  3. 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

    2015-08-01

    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. PMID:26266415

  4. Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships.

    PubMed

    Al Shukor, Nadin; Van Camp, John; Gonzales, Gerard Bryan; Staljanssens, Dorien; Struijs, Karin; Zotti, Moises J; Raes, Katleen; Smagghe, Guy

    2013-12-01

    In this study, 22 phenolic compounds were investigated to inhibit the angiotensin-converting enzyme (ACE). Tannic acid showed the highest activity (IC50 = 230 μM). The IC50 values obtained for phenolic acids and flavonoids ranged between 0.41 and 9.3 mM. QSAR analysis confirmed that the numbers of hydroxyl groups on the benzene ring play an important role for activity of phenolic compounds and that substitution of hydroxyl groups by methoxy groups decreased activity. Docking studies indicated that phenolic acids and flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. Other compounds, such as resveratrol and pyrogallol, may inhibit ACE via interactions with amino acids at the active site, thereby blocking the catalytic activity of ACE. These structure-function relationships are useful for designing new ACE inhibitors and potential blood-pressure-lowering compounds based on phenolic compounds. PMID:24219111

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

    PubMed

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

    2015-04-15

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

  6. 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

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

    PubMed

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

    2013-05-01

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

  8. 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.

  9. The Effect of Nano Confinement on the C–H Activation and its Corresponding Structure-Activity Relationship

    PubMed Central

    Shao, Jing; Yuan, Linghua; Hu, Xingbang; Wu, Youting; Zhang, Zhibing

    2014-01-01

    The C–H activation of methane, ethane, and t-butane on inner and outer surfaces of nitrogen-doped carbon nanotube (NCNTs) are investigated using density functional theory. It includes NCNTs with different diameters, different N and O concentrations, and different types (armchair and zigzag). A universal structure-reactivity relationship is proposed to characterize the C–H activation occurring both on the inner and outer surfaces of the nano channel. The C–O bond distance, spin density and charge carried by active oxygen are found to be highly related to the C–H activation barriers. Based on these theoretical results, some useful strategies are suggested to guide the rational design of more effective catalysts by nano channel confinement. PMID:25428459

  10. The Effect of Nano Confinement on the C-H Activation and its Corresponding Structure-Activity Relationship

    NASA Astrophysics Data System (ADS)

    Shao, Jing; Yuan, Linghua; Hu, Xingbang; Wu, Youting; Zhang, Zhibing

    2014-11-01

    The C-H activation of methane, ethane, and t-butane on inner and outer surfaces of nitrogen-doped carbon nanotube (NCNTs) are investigated using density functional theory. It includes NCNTs with different diameters, different N and O concentrations, and different types (armchair and zigzag). A universal structure-reactivity relationship is proposed to characterize the C-H activation occurring both on the inner and outer surfaces of the nano channel. The C-O bond distance, spin density and charge carried by active oxygen are found to be highly related to the C-H activation barriers. Based on these theoretical results, some useful strategies are suggested to guide the rational design of more effective catalysts by nano channel confinement.

  11. Structure-composition-activity relationships in transition-metal oxide and oxyhydroxide oxygen-evolution electrocatalysts

    NASA Astrophysics Data System (ADS)

    Trotochaud, Lena

    Solar water-splitting is a potentially transformative renewable energy technology. Slow kinetics of the oxygen evolution reaction (OER) limit the efficiency of solar-watersplitting devices, thus constituting a hurdle to widespread implementation of this technology. Catalysts must be stable under highly oxidizing conditions in aqueous electrolyte and minimally absorb light. A grand goal of OER catalysis research is the design of new materials with higher efficiencies enabled by comprehensive understanding of the fundamental chemistry behind catalyst activity. However, little progress has been made towards this goal to date. This dissertation details work addressing major challenges in the field of OER catalysis. Chapter I introduces the current state-of-the-art and challenges in the field. Chapter II highlights work using ultra-thin films as a platform for fundamental study and comparison of catalyst activity. Key results of this work are (1) the identification of a Ni0.9Fe0.1OOH catalyst displaying the highest OER activity in base to date and (2) that in base, many transition-metal oxides transform to layered oxyhydroxide materials which are the active catalysts. The latter result is critical in the context of understanding structure-activity relationships in OER catalysts. Chapter III explores the optical properties of these catalysts, using in situ spectroelectrochemistry to quantify their optical absorption. A new figure-of-merit for catalyst performance is developed which considers both optical and kinetic losses due to the catalyst and describes how these factors together affect the efficiency of composite semiconductor/catalyst photoanodes. In Chapter IV, the fundamental structure-composition-activity relationships in Ni1--xFexOOH catalysts are systematically investigated. This work shows that nearly all previous studies of Ni-based catalysts were likely affected by the presence of Fe impurities, a realization which holds significant weight for future study

  12. 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.

  13. 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. PMID:7570659

  14. 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.

  15. 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. PMID:24081608

  16. 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

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

    PubMed Central

    Żydek, 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 60F254 plates (silanized) impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids) and their mixtures (denoted as S1–S7 biochromatographic models) were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program) and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R2 = 0.78–0.84) obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. “Leave-one-out” (LOO) and “leave-N-out” (LNO) cross-validation methods were used to judge the predictive power of final regression equations. PMID:22619602

  18. Structure-property relationship of quinuclidinium surfactants--Towards multifunctional biologically active molecules.

    PubMed

    Skočibušić, Mirjana; Odžak, Renata; Štefanić, Zoran; Križić, Ivana; Krišto, Lucija; Jović, Ozren; Hrenar, Tomica; Primožič, Ines; Jurašin, Darija

    2016-04-01

    Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH; n=12, 14 and 16). The incorporation of non conventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic-hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure-property relationship i.e., way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical

  19. Structure-activity relationship studies of microbiologically active thiosemicarbazides derived from hydroxybenzoic acid hydrazides.

    PubMed

    Plech, Tomasz; Paneth, Agata; Kaproń, Barbara; Kosikowska, Urszula; Malm, Anna; Strzelczyk, Aleksandra; Stączek, Paweł

    2015-03-01

    Forty-five derivatives of thiosemicarbazide were synthesized, and their antibacterial activity against Gram-positive and Gram-negative bacteria was evaluated. Some of the described compounds exhibited interesting activity against reference strains of Gram-positive bacteria, whereas only two derivatives had the ability to inhibit the growth of Gram-negative species (Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Proteus mirabilis ATCC 12453). The most potent antimicrobial activity was observed in the cases of salicylic acid hydrazide derivatives. The differences in activity inspired us to conduct conformational analysis using molecular mechanics level. The obtained results suggest that the molecule geometry, especially at the N4-terminus of thiosemicarbazide skeleton, determines the antibacterial activity. Unfortunately, in opposition to what we expected, only one of the tested compounds inhibited the activity of the topoIV enzyme, and none of them was active against DNA gyrase. PMID:25043121

  20. Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents.

    PubMed

    Ng, Pearly Shuyi; Manjunatha, Ujjini H; Rao, Srinivasa P S; Camacho, Luis R; Ma, Ngai Ling; Herve, Maxime; Noble, Christian G; Goh, Anne; Peukert, Stefan; Diagana, Thierry T; Smith, Paul W; Kondreddi, Ravinder Reddy

    2015-12-01

    Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB. PMID:26544629

  1. A quantitative structure-activity relationship approach for assessing toxicity of mixture of organic compounds.

    PubMed

    Chang, C M; Ou, Y H; Liu, T-C; Lu, S-Y; Wang, M-K

    2016-06-01

    Four types of reactivity indices were employed to construct quantitative structure-activity relationships for the assessment of toxicity of organic chemical mixtures. Results of analysis indicated that the maximum positive charge of the hydrogen atom and the inverse of the apolar surface area are the most important descriptors for the toxicity of mixture of benzene and its derivatives to Vibrio fischeri. The toxicity of mixture of aromatic compounds to green alga Scenedesmus obliquus is mainly affected by the electron flow and electrostatic interactions. The electron-acceptance chemical potential and the maximum positive charge of the hydrogen atom are found to be the most important descriptors for the joint toxicity of aromatic compounds. PMID:27426856

  2. Amyloid-β probes: Review of structure-activity and brain-kinetics relationships.

    PubMed

    Eckroat, Todd J; Mayhoub, Abdelrahman S; Garneau-Tsodikova, Sylvie

    2013-01-01

    The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-β plaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure-activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD. PMID:23766818

  3. Quantitative structure-activity relationships for cellular uptake of surface-modified nanoparticles.

    PubMed

    Liu, Rong; Rallo, Robert; Bilal, Muhammad; Cohen, Yoram

    2015-01-01

    Quantitative structure-activity relationships (QSARs) were developed, for cellular uptake of nanoparticles (NPs) of the same iron oxide core but with different surface-modifying organic molecules, based on linear and non-linear (epsilon support vector regression (ε-SVR)). A linear QSAR provided high prediction accuracy of R2=0.751 (coefficient of determination) using 11 descriptors selected from an initial pool of 184 descriptors calculated for the NP surfacemodifying molecules, while a ε-SVR based QSAR with only 6 descriptors improved prediction accuracy to R2=0.806. The linear and ε-SVR based QSARs both demonstrated good robustness and well spanned applicability domains. It is suggested that the approach of evaluating pertinent descriptors and their significance, via QSAR analysis, to cellular NP uptake could support planning and interpretation of toxicity studies as well as provide guidance for the tailor-design NPs with respect to targeted cellular uptake for various applications. PMID:25747434

  4. New structure-activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO.

    PubMed

    Li, Jun; Schulte, Michael L; Nickels, Michael L; Manning, H Charles

    2016-08-01

    Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine. PMID:27353534

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

    PubMed

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

    2015-12-01

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

  6. Structure-activity relationships for substrate-based inhibitors of human complement factor B.

    PubMed

    Ruiz-Gómez, Gloria; Lim, Junxian; Halili, Maria A; Le, Giang T; Madala, Praveen K; Abbenante, Giovanni; Fairlie, David P

    2009-10-01

    Human complement is a cascading network of plasma proteins important in immune defense, cooperatively effecting recognition, opsonization, destruction, and removal of pathogens and infected/damaged cells. Overstimulated or unregulated complement activation can result in immunoinflammatory diseases. Key serine proteases in this cascade are difficult to study due to their multiprotein composition, short lifetimes, formation on membranes, or serum circulation as inactive zymogens. Factor B is inactive at pH 7, but a catalytically active serine protease under alkaline conditions, enabling structure-activity relationship studies for 63 substrate-based peptide inhibitors with 4-7 residues and a C-terminal aldehyde. A potent factor B inhibitor was hexpeptide Ac-RLTbaLAR-H (IC(50) 250 nM, pH 9.5), which at pH 7 also blocked formation of membrane attack complex via the "alternative pathway" of complement activation and inhibited human complement mediated lysis of rabbit erythrocytes. Inhibitors of factor B may be valuable probes and drug leads for complement mediated immunity and disease. PMID:19743866

  7. 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

  8. 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. PMID:24621664

  9. Oxidative Conversion Mediates Antiproliferative Effects of tert-Butylhydroquinone: Structure and Activity Relationship Study.

    PubMed

    Sanidad, Katherine Z; Sukamtoh, Elvira; Wang, Weicang; Du, Zheyuan; Florio, Ellie; He, Lili; Xiao, Hang; Decker, Eric A; Zhang, Guodong

    2016-05-18

    Previous studies have shown that tert-butylhydroquinone (TBHQ), a widely used food antioxidant, has cytotoxic effects at high doses; however, the underlying mechanisms are not well understood. Here, we found that the effects of TBHQ on cell proliferation, cell cycle progression, and apoptosis are mainly mediated by its oxidative conversion to a quinone metabolite tert-butylquinone (TBQ). Co-addition of cupric ion (Cu(2+)) caused accelerated oxidative conversion of TBHQ to TBQ and enhanced the biological activities of TBHQ on cell proliferation, cell cycle progression, and apoptosis in MC38 colon cancer cells. In contrast, co-addition of ethylenediaminetetraacetic acid (EDTA) suppressed TBHQ oxidation and inhibited the biological activities of TBHQ in MC38 cells. For example, after 24 h of treatment in basal medium, low-dose TBHQ (1.88-7.5 μM) had little effect on MC38 cell proliferation, while co-addition of 50 μM Cu(2+) caused 30-70% inhibition of cell proliferation; in contrast, treatment with high-dose TBHQ (15 μM) inhibited 50 ± 4% MC38 proliferation, which was abolished by co-addition of 50 μM EDTA. We further showed that TBQ had more potent actions on cell proliferation and associated cellular responses than TBHQ, supporting a critical role of TBQ formation in the biological activities of TBHQ. Finally, a structure and activity relationship study showed that the fast-oxidized para-hydroquinones had potent antiproliferative effects in MC38 cells, while the slow-oxidized para-hydroquinones had weak or little biological activities. Together, these results suggest that the biological activities of TBHQ and other para-hydroquinones are mainly mediated by their oxidative metabolism to generate more biologically active quinone metabolites. PMID:27111399

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

    PubMed

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

    2014-12-01

    Several gold(I) complexes containing a thiolate ligand functionalised with several amino acid or peptide moieties of the type [Au(SPyCOR)(PPh2R')] (where R = OH, amino acid or dipeptide and R' = Ph or Py) were prepared. These thiolate gold complexes bearing biological molecules possess potential use as antitumor agents. Cytotoxicity assays in different tumour cell lines such as A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma) revealed that the complexes exhibit good antiproliferative activity, with IC50 values in the low micromolar range. Several structural modifications such as in the type of phosphine, number of metal atoms and amino acid (type, stereochemistry and functionalisation) were carried out in order to establish the structure-activity relationship in this family of complexes, which has led to the design of new and more potent cytotoxic complexes. Observations of different cellular events after addition of the complexes indicated the possible mechanism of action or the biological targets of this type of new gold(I) drug. PMID:25302929

  11. Quantitative structure-activity relationships and the prediction of MHC supermotifs.

    PubMed

    Doytchinova, Irini A; Guan, Pingping; Flower, Darren R

    2004-12-01

    The underlying assumption in quantitative structure-activity relationship (QSAR) methodology is that related chemical structures exhibit related biological activities. We review here two QSAR methods in terms of their applicability for human MHC supermotif definition. Supermotifs are motifs that characterise binding to more than one allele. Supermotif definition is the initial in silico step of epitope-based vaccine design. The first QSAR method we review here--the additive method--is based on the assumption that the binding affinity of a peptide depends on contributions from both amino acids and the interactions between them. The second method is a 3D-QSAR method: comparative molecular similarity indices analysis (CoMSIA). Both methods were applied to 771 peptides binding to 9 HLA alleles. Five of the alleles (A*0201, A*0202, A*0203, A*0206 and A*6802) belong to the HLA-A2 superfamily and the other four (A*0301, A*1101, A*3101 and A*6801) to the HLA-A3 superfamily. For each superfamily, supermotifs defined by the two QSAR methods agree closely and are supported by many experimental data. PMID:15542370

  12. Structure-activity relationships for in vitro diuretic activity of CAP2b in the housefly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A series of truncated and Ala-replacement analogs of the peptide Manse-CAP2b (pELYAFPRV-NH2) were assayed for diuretic activity on Malpighian tubules of the housefly Musca domestica. The C-terminal hexapeptide proved to be the active core, the minimum sequence required to retain significant diureti...

  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. PMID:16053097

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

    PubMed

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

    2008-11-01

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

  15. The expert system for toxicity prediction of chemicals based on structure-activity relationship.

    PubMed Central

    Nakadate, M; Hayashi, M; Sofuni, T; Kamata, E; Aida, Y; Osada, T; Ishibe, T; Sakamura, Y; Ishidate, M

    1991-01-01

    The prediction systems of chemical toxicity has been developed by means of structure-activity relationship based on the computerized fact database (BL-DB). Numbers and ratio of elements, side chains, bonding, position, and microenvironment of side chains were used as structural factors of the chemical for the prediction. Such information was obtained from the BL-DB database by Wiswesser line-formula chemical notation. In the present study, the Salmonella/microsome assay was chosen as indicative of the target toxicity of chemicals. A set of chemicals specified with mutagenicity data was retrieved, and necessary information was extracted and transferred to the working file. Rules of the relations between characteristics of chemical structure and the assay result are extracted as parameters for rules by experts on the rearranged data set. These were analyzed statistically by the discriminant analysis and the prediction with the rules were evaluated by the elimination method. Eight kinds of rules to predict Salmonella/microsome assay were constructed, and currently results of the assay on aliphatic and heterocyclic compounds can be predicted as accurately as +90%. PMID:1820282

  16. Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

    PubMed Central

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-01-01

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. PMID:24619221

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

    PubMed

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

    2015-10-16

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

  18. Molecular-orbital analysis of the electronic structure and determination of quantitative structure-activity and structure-toxicity relationships for water-soluble ionol derivatives

    SciTech Connect

    Bushelev, S.N.

    1985-08-01

    In this paper the authors attempt to establish a quantitative relationship between experimental data on antitumor activity and the toxicity of ionol and its derivatives on the one hand, and on the other hand the electronic structure parameters of the compounds obtained as a result of the quantum chemical calculation.

  19. Peptidomimetics Based On Dehydroepiandrosterone Scaffold: Synthesis, Antiproliferation Activity, Structure-Activity Relationship, and Mechanisms.

    PubMed

    Wang, Xiaohui; Su, Haihuan; Wang, Wenda; Chen, Changshui; Cao, Xiufang

    2016-01-01

    A series of novel peptidomimetics bearing dehydroepiandrosterone moiety were designed, synthesized, and evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on inhibitory activities, some of the newly prepared compounds indicated significantly inhibition activities against human hepatoma cancer (HepG2), human lung cancer (A549), human melanoma (A875) cell lines compared with the control 5-fluorouracil. Especially, compounds Ii (IC50 < 14 μM) and Ik (IC50 < 13 μM) exhibited obvious inhibition activities against all tested cell lines. The highly potential compound Ik induced apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compound Ik were further evaluated using Annexin V-FITC/propidium iodide dual staining assay, which revealed these highly potential compounds induced cell death in HepG2 cells at least partly by apoptosis. PMID:27585479

  20. Peptidomimetics Based On Dehydroepiandrosterone Scaffold: Synthesis, Antiproliferation Activity, Structure-Activity Relationship, and Mechanisms

    PubMed Central

    Wang, Xiaohui; Su, Haihuan; Wang, Wenda; Chen, Changshui; Cao, Xiufang

    2016-01-01

    A series of novel peptidomimetics bearing dehydroepiandrosterone moiety were designed, synthesized, and evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on inhibitory activities, some of the newly prepared compounds indicated significantly inhibition activities against human hepatoma cancer (HepG2), human lung cancer (A549), human melanoma (A875) cell lines compared with the control 5-fluorouracil. Especially, compounds Ii (IC50 < 14 μM) and Ik (IC50 < 13 μM) exhibited obvious inhibition activities against all tested cell lines. The highly potential compound Ik induced apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compound Ik were further evaluated using Annexin V-FITC/propidium iodide dual staining assay, which revealed these highly potential compounds induced cell death in HepG2 cells at least partly by apoptosis. PMID:27585479

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

    PubMed

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

    2015-11-25

    The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]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 analogues to explore the structure-activity relationships of this peptide. The synthesis of selected analogues 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 N-cyclopropylmethyl substitutions resulted in analogues with the highest KOR affinities. Pharmacological results for the alanine-substituted analogues indicated that Phe(4) and Arg(6), but interestingly not the Tyr(1) phenol, are important for zyklophin's KOR affinity and that Arg(7) was important for KOR antagonist activity. In the GTPγS assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N-cyclopropylmethyl-Tyr(1) and N-benzyl-Phe(1) analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin. PMID:26491810

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

    PubMed

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

    2016-02-17

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

  3. 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. PMID:26463658

  4. Structure and hypotensive activity relationships of tetrandrine derivatives in stroke-prone spontaneously hypertensive rats.

    PubMed

    Kawashima, K; Hayakawa, T; Miwa, Y; Oohata, H; Suzuki, T; Fujimoto, K; Ogino, T; Chen, Z X

    1990-01-01

    1. Structure and hypotensive activity relationships of tetrandrine (TD), an alkaloid isolated from the Chinese herb Radix stephaniae tetrandrae and its derivatives were investigated in conscious stroke-prone spontaneously hypertensive rats (SHRSP). 2. Derivatives substituted at the 7-O position with various types of alkyl group produced varying degrees of hypotensive effect. 3. While the demethylated derivative, fangchinoline (FC), and its acetylated compound had no effect on blood pressure, 7-O-methyl FC (TD), and 7-O-ethyl and 7-O-isopropyl FC at oral doses of 25 and 50 mg/kg produced a gradual and sustained hypotensive effect without any significant effects on heart rate and plasma renin concentration. 4. Substitution at the 7-O position with longer side chains such as n-propyl, n-butyl and n-pentyl groups reduced both the degree and duration of hypotensive activity. 5. Substitution of N-methyl groups at the 2 and 2' positions with quaternary ammonium or N-oxide attenuated the hypotensive activity. 6. The results of this study suggest a possibility that 7-O-ethyl and 7-O-isopropyl derivatives as well as TD can be considered as potential antihypertensive drugs because of the gradual onset and long duration of their hypotensive action in SHRSP. PMID:2187737

  5. Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.

    PubMed

    Beck, Daniel E; Reddy, P V Narasimha; Lv, Wei; Abdelmalak, Monica; Tender, Gabrielle S; Lopez, Sophia; Agama, Keli; Marchand, Christophe; Pommier, Yves; Cushman, Mark

    2016-04-28

    Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3'-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64. PMID:27070999

  6. Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

    PubMed

    Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T

    2013-01-01

    Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA. PMID:24020757

  7. Strong Nonadditivity as a Key Structure–Activity Relationship Feature: Distinguishing Structural Changes from Assay Artifacts

    PubMed Central

    2015-01-01

    Nonadditivity in protein–ligand affinity data represents highly instructive structure–activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. We find that all cases of strong nonadditivity (ΔΔpKi and ΔΔpIC50 > 2.0 log units) with sufficient structural information to generate reasonable hypothesis involve changes in binding mode. With the appropriate statistical basis, nonadditivity analysis offers a variety of new attempts for various areas in computer-aided drug design, including the validation of scoring functions and free energy perturbation approaches, binding pocket classification, and novel features in SAR analysis tools. PMID:25760829

  8. Synthesis, biological activities and structure-activity relationships for new avermectin analogues.

    PubMed

    Zhang, Jian; Nan, Xiang; Yu, Hai-Tao; Cheng, Pi-Le; Zhang, Yan; Liu, Ying-Qian; Zhang, Shao-Yong; Hu, Guan-Fang; Liu, Huanxiang; Chen, An-Liang

    2016-10-01

    In an effort to discover new molecules with good insecticidal activities, more than 40 new avermectin derivatives were synthesized and evaluated for their biological activities against three species of arachnids, insects and nematodes, namely, Tetranychus Cinnabarinus, Aphis craccivora and Bursaphelenchus xylophilus. All the tested compounds showed potent inhibitory activities against three insect species. Notably, the majority of compounds exhibited high selectivity against T. cinnabarinus, some of which were much better in comparison with avermectin. Especially compounds 9j (LC50: 0.005 μM) and 16d (LC50: 0.002 μM) were 2.5- and 4.7-fold more active than avermectin (LC50: 0.013 μM), respectively, against T. cinnabarinus. Moreover, compounds 9b, 9d-f, 9h, 9j, 9l, 9n, 9p, 9r, 9v and 17d showed superior activities with LC50 values of 2.959-5.013 μM compared to that of 1 (LC50: 6.746 μM) against B. xylophilus. Meanwhile, the insecticidal activities of compounds 9f, 9g, 9h, and 9m against A. craccivora were 7-8 times better than that of avermectin, with LC50 values of 7.744, 5.634, 6.809, 7.939 and 52.234 μM, respectively. Furthermore, QSAR analysis showed that the molecular shape, size, connectivity degree and electronic distribution of avermectin analogues had substantial effects on insecticidal potency. These preliminary results provided useful insight in guiding further modifications of avermectin in the development of potential new insecticides. PMID:27318119

  9. Structure-activity relationship analysis of N-benzoylpyrazoles for elastase inhibitory activity: a simplified approach using atom pair descriptors.

    PubMed

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

    2008-03-15

    Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure-activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimensional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets. PMID:18234502

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

    PubMed

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

    2016-05-01

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

  11. Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies.

    PubMed

    Lourenço, André Luiz; Saito, Max Seidy; Dorneles, Luís Eduardo Gomes; Viana, Gil Mendes; Sathler, Plínio Cunha; Aguiar, Lúcia Cruz de Sequeira; de Pádula, Marcelo; Domingos, Thaisa Francielle Souza; Fraga, Aline Guerra Manssour; Rodrigues, Carlos Rangel; de Sousa, Valeria Pereira; Castro, Helena Carla; Cabral, Lucio Mendes

    2015-01-01

    The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations. PMID:25903367

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

    PubMed Central

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

    2009-01-01

    The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action. PMID:20111734

  13. Structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein.

    PubMed

    Perugino, Giuseppe; Miggiano, Riccardo; Serpe, Mario; Vettone, Antonella; Valenti, Anna; Lahiri, Samarpita; Rossi, Franca; Rossi, Mosè; Rizzi, Menico; Ciaramella, Maria

    2015-10-15

    Alkylated DNA-protein alkyltransferases repair alkylated DNA bases, which are among the most common DNA lesions, and are evolutionary conserved, from prokaryotes to higher eukaryotes. The human ortholog, hAGT, is involved in resistance to alkylating chemotherapy drugs. We report here on the alkylated DNA-protein alkyltransferase, SsOGT, from an archaeal species living at high temperature, a condition that enhances the harmful effect of DNA alkylation. The exceptionally high stability of SsOGT gave us the unique opportunity to perform structural and biochemical analysis of a protein of this class in its post-reaction form. This analysis, along with those performed on SsOGT in its ligand-free and DNA-bound forms, provides insights in the structure-function relationships of the protein before, during and after DNA repair, suggesting a molecular basis for DNA recognition, catalytic activity and protein post-reaction fate, and giving hints on the mechanism of alkylation-induced inactivation of this class of proteins. PMID:26227971

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

    PubMed

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

    2012-01-01

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

  15. Structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein

    PubMed Central

    Perugino, Giuseppe; Miggiano, Riccardo; Serpe, Mario; Vettone, Antonella; Valenti, Anna; Lahiri, Samarpita; Rossi, Franca; Rossi, Mosè; Rizzi, Menico; Ciaramella, Maria

    2015-01-01

    Alkylated DNA-protein alkyltransferases repair alkylated DNA bases, which are among the most common DNA lesions, and are evolutionary conserved, from prokaryotes to higher eukaryotes. The human ortholog, hAGT, is involved in resistance to alkylating chemotherapy drugs. We report here on the alkylated DNA-protein alkyltransferase, SsOGT, from an archaeal species living at high temperature, a condition that enhances the harmful effect of DNA alkylation. The exceptionally high stability of SsOGT gave us the unique opportunity to perform structural and biochemical analysis of a protein of this class in its post-reaction form. This analysis, along with those performed on SsOGT in its ligand-free and DNA-bound forms, provides insights in the structure-function relationships of the protein before, during and after DNA repair, suggesting a molecular basis for DNA recognition, catalytic activity and protein post-reaction fate, and giving hints on the mechanism of alkylation-induced inactivation of this class of proteins. PMID:26227971

  16. 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). PMID:27095514

  17. Structural and molecular characteristics of lichenysin and its relationship with surface activity.

    PubMed

    Nerurkar, Anuradha S

    2010-01-01

    Lichenysins are most potent anionic cyclic lipoheptapeptide biosurfactants produced by Bacillus licheniformis on hydrocarbonless medium with mainly glucose as carbon source. They have the capacity to lower the surface tension of water from 72 to 27 mN/m. Based on species specific variations they are named lichenysin A, B, C, D, G and surfactant BL86. The lowest ever interfacial tension against decane of 0.006 mN/m is obtained with acid precipitated lichenysin B. Surfactant BL86 and lichenysin B have recorded lowest ever CMC of 10 mg/L by any surfactant under optimal conditions. Surface and interfacial tension lowering ability bears significance in the context of oil recovery from oil reservoir. Similarity exists between structure and biosynthesis of surfactin and lichenysin. Surfactin being the most studied of the two, understanding its structure and biosynthesis gives an insight into the structure and biosynthesis of lichenysin. Lichenysin is synthesized by a multienzyme complex, lichenysin synthetase (LchA/Lic) encoded by 32.4 (26.6 kb) lichenysin operon lchA (lic). The structure of lichenysin and its operon indicate the nonribosomal biosynthesis with the same multifunctional modular arrangement as seen in surfactin synthetase SrfA. The lchA operon consists of lchAA-AC (lic A-C) and lchA TE (licTE) genes encoding the proteins LchAA, LchAB, LchAC and thioesterase LchA-TE. The licA (lchAA) gene is 10,746 bp and codes for a 3,582 amino acids protein, licB (lchAB) gene is 10,764 bp and codes for a similar sized protein, while licC (lchAC) gene is 3,864 bp and codes for protein containing 1,288 amino acid. The biotechnological potential of lichenysin in MEOR has triggered research on structure-activity relationship. Both the nature of peptide and fatty acid dictate the activity of the biosurfactant. Tailormade biosurfactant with desired attributes can be obtained from engineered synthetases. Basic studies are lacking on mechanism of biosynthesis by lichenysin

  18. The nematocidal activity and the structure-activity relationships of stilbenes.

    PubMed

    Kohno, Tukasa; Togashi, Katsumi; Fukamiya, Narihiko

    2007-06-01

    The pinewood nematode, Bursaphelenchus xylophilus (Steiner et Buhrer) Nickle, is the causative agent of the pine wilt disease which has been devastating forests of Pinus densiflora Sieb.et Zucc. and P. thunbergii Parl. in Japan. To prevent the pine wilt disease, the development of nematocidal compound is required. Twenty-one synthesized stilbenes (1)-(20), (23), salicylic acid (21), and phenylsalicilate (22) were examined for their nematocidal activity against an isolate of B. xylophilus (T-4). Among the tested compounds, two fluorinated stilbenes (15) and (13), were found to be most potent compounds against T-4, demonstrating 99% and 98% lethality at 10 ppm concentration. The LD50 values of compounds 15 and 13 were 3 ppm, respectively. PMID:17613818

  19. Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity.

    PubMed

    Liu, Zhen; Yao, Yuan; Kogiso, Mari; Zheng, Baisong; Deng, Lisheng; Qiu, Jihui J; Dong, Shuo; Lv, Hua; Gallo, James M; Li, Xiao-Nan; Song, Yongcheng

    2014-10-23

    Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure-activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R(2) of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood-brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26-1.8 μM) against glioma cells with the IDH1 R132H mutation. PMID:25271760

  20. 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

    2016-01-01

    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. PMID:27331807

  1. Computational insight into the structure-activity relationship of novel N-substituted phthalimides with gibberellin-like activity.

    PubMed

    Li, Dongling; Du, Shaoqing; Tan, Weiming; Duan, Hongxia

    2015-10-01

    N-substituted phthalimides (NSPs) that show multiple gibberellin (GA)-like effects on the growth and development of higher plants have been reported. These NSPs may represent a potential alternative to commercial GAs. Therefore, in this work, molecular docking and molecular dynamics simulations were used to explore the mode of interaction between some NSPs and the GA receptor GID1A in order to clarify the relationship between structure and GA-like activity in the NSPs. The results obtained demonstrate that both a multiple-hydrogen-bond network and a "hat-shaped" hydrophobic interaction play important roles in the binding of the NSPs to GID1A. The carbonyl group of a phthalimide fragment in the NSPs acted in a similar manner to the pharmacophore group 6-COOH in GAs, forming multiple-hydrogen-bond interactions with residues Ser191 and Tyr322 in the binding domain of GID1A. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to further study the 3D quantitative structure-activity relationship (3D-QSAR) of the NSPs. It was confirmed that the GA-like activity of these NSPs is strongly linked to a few H-bond donor and acceptor field contributions of the NSPs to the H-bond interactions with GID1A. Five new NSP molecules D1-D5 were designed using the binding domain of GID1A and then docked into the receptor. D1 and D4 were shown to have good docking scores due to enhanced hydrophobic contact. We hope that these results will provide useful guidance in the rational design of new NSPs. PMID:26412055

  2. Structure-activity Relationship Analysis of N-Benzoylpyrazoles for Elastase Inhibitory Activity: A Simplified Approach Using Atom Pair Descriptors

    PubMed Central

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

    2008-01-01

    Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure–activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimentional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets. PMID:18234502

  3. Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors

    PubMed Central

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper L.; Gloriam, David E.

    2013-01-01

    Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands. PMID:24244317

  4. Structure-activity Relationships of Peptidomimetics that Inhibit PPI of HER2-HER3

    PubMed Central

    Kanthala, Shanthi; Gauthier, Ted; Satyanarayanajois, Seetharama

    2014-01-01

    Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase family protein receptor that is known to undergo heterodimerization with other members of the family of epidermal growth factor receptors (EGFR) for cell signaling. Overexpression of HER2 and deregulation of signaling has implications in breast, ovarian, and lung cancers. We have designed several peptidomimetics to block the HER2-mediated dimerization, resulting in antiproliferative activity for cancer cells. In the present work we have investigated the structure-activity relationships of peptidomimetic analogs of compound 5. Compound 5 was conformationally constrained by N- and C-terminal modification and cyclization as well as by substitution with D-amino acids at the N-and C-termini. Among the compounds studied in this work, a peptidomimetic compound 21 with D-amino acid substitution and its N- and C-termini capped with acetyl and amide functional groups and a reversed sequence compared to that of compound 5 exhibited better antiproliferative activity in HER2-overexpressed breast, ovarian, and lung cancer cell lines. Compound 21 was further evaluated for its protein-protein interaction (PPI) inhibition ability using enzyme fragment complementation (EFC) assay, proximity ligation assay (PLA), and Western blot analysis. Results suggested that compound 21 is able to block HER2:HER3 interaction and inhibit phosphorylation of the kinase domain of HER2. The mode of binding of compound 21 to HER2 protein was modeled using a docking method. Compound 21 seems to bind to domain IV of HER2 near the PPI site of EGFR:HER2 and HER:HER3 and inhibit PPI. PMID:24222531

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

    PubMed

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

    2015-01-01

    Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media. PMID:25803685

  6. Structure-Thermodynamics-Antioxidant Activity Relationships of Selected Natural Phenolic Acids and Derivatives: An Experimental and Theoretical Evaluation

    PubMed Central

    Zheng, Jie; Liang, Guizhao

    2015-01-01

    Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media. PMID:25803685

  7. Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.

    PubMed

    Gombar, Vijay K; Hall, Stephen D

    2013-04-22

    Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To

  8. 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. PMID:26773437

  9. COMPUTER-ASSISTED STRUCTURE ACTIVITY RELATIONSHIPS OF NITROGENOUS CYCLIC COMPOUNDS TESTED IN SALMONELLA ASSAYS FOR MUTAGENICITY

    EPA Science Inventory

    Study of the relationship between mutagenicity and molecular structure for a data set of nitrogenous cyclic compounds is reported. A computerized SAR system (ADAPT) was utilized to classify a data set of 114 nitrogenous cyclic compounds with 19 molecular descriptors. All of the d...

  10. 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.

  11. Quantitative structure-activity relationships for the mutagenicity of propylene oxides with Salmonella.

    PubMed

    Hooberman, B H; Chakraborty, P K; Sinsheimer, J E

    1993-04-01

    A quantitative structure-activity relationship approach was used to investigate the mutagenicity of a series of seventeen-monosubstituted propylene oxides in Salmonella typhimurium strains TA100 and TA1535. Mutagenicity in strain TA100, using a liquid suspension assay, was found to correlate with chemical reactivity, as measured by the rates of reaction with two model bionucleophiles, nicotinamide and 4-(4-nitrobenzyl)pyridine. However, since the reactivity of three of the epoxides did not correlate to their Taft sigma * values, as a measure of the electronic effects of substituent groups, neither was their mutagenicity predicted by this substituent constant. The relative mutagenicity for the propylene oxides was different in the liquid suspension assay than that determined by the standard plate incorporation assay and also differed between the two bacterial strains. The assay differences were attributed to epoxide stability. The differences between strains was observed to be due to the response of the error-prone repair system, found only in TA100, to the stronger alkylating agents. PMID:7680427

  12. 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.

  13. Structure-activity relationship study at C9 position of kaitocephalin.

    PubMed

    Yasuno, Yoko; Hamada, Makoto; Yoshida, Yuya; Shimamoto, Keiko; Shigeri, Yasushi; Akizawa, Toshifumi; Konishi, Motomi; Ohfune, Yasufumi; Shinada, Tetsuro

    2016-08-01

    Kaitocephalin (KCP) isolated from Eupenicillium shearii PF1191 is an unusual amino acid natural product in which serine, proline, and alanine moieties are liked with carbon-carbon bonds. KCP exhibits potent and selective binding affinity for one of the ionotropic glutamate receptor subtypes, NMDA receptors (Ki=7.8nM). In this study, new structure-activity relationship studies at C9 of KCP were implemented. Eleven new KCP analogs with different substituents at C9 were prepared and employed for binding affinity tests using native ionotropic glutamate receptors. Replacement of the 3,5-dichloro-4-hydroxybenzoyl group of KCP with a 3-phenylpropionyl group resulted in significant loss of binding affinity for NMDARs (Ki=1300nM), indicating an indispensable role of the aromatic ring of KCP in the potent and selective binding to NMDARs. Other analogs showed potent binding affinity in a range of 11-270nM. These findings would directly link to develop useful chemical tools toward imaging and labeling of NMDARs. PMID:27329796

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

    PubMed

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

    2016-05-17

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

  15. Trainable structure-activity relationship model for virtual screening of CYP3A4 inhibition.

    PubMed

    Didziapetris, Remigijus; Dapkunas, Justas; Sazonovas, Andrius; Japertas, Pranas

    2010-11-01

    A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC₅₀ threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis. PMID:20814717

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

    PubMed

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

    2015-02-23

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

  17. 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. PMID:25961528

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

    PubMed

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

    2002-01-01

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

  19. [Application of the rough sets theory to the analysis of structure-activity relationships of pyridinium antifungal compounds].

    PubMed

    Krysiński, J

    1994-04-01

    Relationships between chemical structure and antifungal activity of 72 quaternary pyridinium chlorides were analysed using the method of rough sets. In the information system the compounds are described by eight condition attributes and divided into three classes of activity. Using the rough sets approach a smallest set of four condition attributes significant for a high quality of classification and accuracy of classes has been found. The resulting decision algorithm describes relations between structure and antifungal activity in terms of significant condition attributes. It may be helpful in predicting structures of new antifungal compounds to be synthesized. PMID:8204024

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

    PubMed

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

    2015-11-17

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

  1. Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals.

    PubMed

    Seth, Punit P; Jazayeri, Ali; Yu, Jeff; Allerson, Charles R; Bhat, Balkrishen; Swayze, Eric E

    2012-01-01

    We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with α-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-α-L-LNA but not R-6'-Me- or 3'-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012. PMID:23344239

  2. Structure-function relationships affecting the insecticidal and miticidal activity of sugar esters.

    PubMed

    Puterka, Gary J; Farone, William; Palmer, Tracy; Barrington, Anthony

    2003-06-01

    Synthetic sugar esters are a relatively new class of insecticidal compounds that are produced by reacting sugars with fatty acids. The objective of this research was to determine how systematic alterations in sugar or fatty acid components of sugar ester compounds influenced their insecticidal properties. Sucrose octanoate, sorbitol octanoate, sorbitol decanoate, sorbitol caproate, xylitol octanoate, xylitol decanoate and xylitol dodecanoate were synthesized and evaluated against a range of arthropod pests. Dosage-mortality studies were conducted on pear psylla (Cacopsylla pyricola Foerster) on pear, tobacco aphid (Myzus nicotianae) Blackman and tobacco hornworm (Manduca sexta [Johannson]) on tobacco, and twospotted spider mite (Tetranychus urticae Koch) on apple in laboratory bioassays. These sugar esters were compared with insecticidal soap (M-Pede, Dow AgroSciences L.L.C., San Diego, CA), to determine how toxicologically similar these materials were against the arthropod pests. Substitutions in either the sugar or fatty acid component led to significant changes in the physical properties and insecticidal activity of these compounds. The sugar esters varied in their solubility in water and in emulsion stability, yet, droplet spread upon pear leaves occurred at low concentrations of 80-160 ppm and was strongly correlated with psylla mortalities (R2 = 0.73). Sequentially altering the sugar or fatty acid components from lower to higher numbers of carbon chains, or whether the sugar was a monosaccharide or disaccharide did not follow a predictable relationship to insecticidal activity. Intuitively, changing the hydrophile from sorbitol (C6) to xylitol (C5) would require a decrease in lipophile chain length to maintain hydrophilic-lipophilic balance (HLB) relationships, yet an increase in lipophile chain length was unexpectedly needed for increasing insecticidal activity. Thus, the HLB of these materials did not correlate with pear psylla mortalities. Initial insect

  3. Toward a class-independent quantitative structure--activity relationship model for uncouplers of oxidative phosphorylation.

    PubMed

    Spycher, Simon; Smejtek, Pavel; Netzeva, Tatiana I; Escher, Beate I

    2008-04-01

    A mechanistically based quantitative structure-activity relationship (QSAR) for the uncoupling activity of weak organic acids has been derived. The analysis of earlier experimental studies suggested that the limiting step in the uncoupling process is the rate with which anions can cross the membrane and that this rate is determined by the height of the energy barrier encountered in the hydrophobic membrane core. We use this mechanistic understanding to develop a predictive model for uncoupling. The translocation rate constants of anions correlate well with the free energy difference between the energy well and the energy barrier, Delta G well-barrier,A (-) , in the membrane calculated by a novel approach to describe internal partitioning in the membrane. An existing data set of 21 phenols measured in an in vitro test system specific for uncouplers was extended by 14 highly diverse compounds. A simple regression model based on the experimental membrane-water partition coefficient and Delta G well-barrier,A (-) showed good predictive power and had meaningful regression coefficients. To establish uncoupler QSARs independent of chemical class, it is necessary to calculate the descriptors for the charged species, as the analogous descriptors of the neutral species showed almost no correlation with the translocation rate constants of anions. The substitution of experimental with calculated partition coefficients resulted in a decrease of the model fit. A particular strength of the current model is the accurate calculation of excess toxicity, which makes it a suitable tool for database screening. The applicability domain, limitations of the model, and ideas for future research are critically discussed. PMID:18358007

  4. Aquatic toxicity of acrylates and methacrylates: quantitative structure-activity relationships based on Kow and LC50

    SciTech Connect

    Reinert, K.H.

    1987-12-01

    Recent EPA scrutiny of acrylate and methacrylate monomers has resulted in restrictive consent orders and Significant New Use Rules under the Toxic Substances Control Act, based on structure-activity relationships using mouse skin painting studies. The concern is centered on human health issues regarding worker and consumer exposure. Environmental issues, such as aquatic toxicity, are still of concern. Understanding the relationships and environmental risks to aquatic organisms may improve the understanding of the potential risks to human health. This study evaluates the quantitative structure-activity relationships from measured log Kow's and log LC50's for Pimephales promelas (fathead minnow) and Carassius auratus (goldfish). Scientific support of the current regulations is also addressed. Two monomer classes were designated: acrylates and methacrylates. Spearman rank correlation and linear regression were run. Based on this study, an ecotoxicological difference exists between acrylates and methacrylates. Regulatory activities and scientific study should reflect this difference.

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

    PubMed

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

    2008-03-01

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

  6. Structural Elucidation and Structure-Anti-inflammatory Activity Relationships of Cembranoids from Cultured Soft Corals Sinularia sandensis and Sinularia flexibilis.

    PubMed

    Tsai, Tsung-Chang; Chen, Hsueh-Yu; Sheu, Jyh-Horng; Chiang, Michael Y; Wen, Zhi-Hong; Dai, Chang-Feng; Su, Jui-Hsin

    2015-08-19

    New cembranoids 4-carbomethoxyl-10-epigyrosanoldie E (1), 7-acetylsinumaximol B (2), diepoxycembrene B (6), dihydromanaarenolide I (8), and isosinulaflexiolide K (9), along with 11 known related metabolites, were isolated from cultured soft corals Sinularia sandensis and Sinularia flexibilis. The structures were elucidated by means of infrared, mass spectrometry, and nuclear magnetic resonance techniques, and the absolute configurations of 1, 4, 9, and 15 were further confirmed by single-crystal X-ray diffraction analysis. The absolute configurations of these coral metabolites and comparison with known analogues showed that one hypothesis (that cembrane diterpenes possessing an absolute configuration of an isopropyl group at C1 obtained from Alcyonacean soft corals belong to the α series, whereas analogues isolated from Gorgonacean corals belong to the β series) is not applicable for a small number of cembranoids. An in vitro anti-inflammatory study using LPS-stimulated macrophage-like cell line RAW 264.7 revealed that compounds 9-14 significantly suppressed the accumulation of pro-inflammatory proteins, iNOS and COX-2. Structure-activity relationship analysis indicated that cembrane-type compounds with one seven-membered lactone moiety at C-1 are potential anti-inflammatory agents. This is the first culture system in the world that has successfully been used to farm S. sandensis. PMID:26260702

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2015-01-28

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

  9. Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents.

    PubMed

    Li, Wen-Shan; More, Shivaji V; Wang, Chie-Hong; Jen, Ya Ching; Yao, Ching-Fa; Wang, Tein-Fu; Hung, Chin-Chun; Jao, Shu-Chuan

    2010-02-01

    This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. PMID:20022505

  10. Three dimensional quantitative structure-activity relationships of sulfonamides binding monoclonal antibody by comparative molecular field analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs, binding a monoclonal antibody (MabSMR) produced against sulfamerazine was carried out by comparative molecular field analysis (CoMFA). The affinities of MabSMR, expressed as Log10IC50, for 17 ...

  11. The relationship between molecular structure and biological activity of alkali metal salts of vanillic acid: Spectroscopic, theoretical and microbiological studies

    NASA Astrophysics Data System (ADS)

    Świsłocka, Renata; Piekut, Jolanta; Lewandowski, Włodzimierz

    In this paper we investigate the relationship between molecular structure of alkali metal vanillate molecules and their antimicrobial activity. To this end FT-IR, FT-Raman, UV absorption and 1H, 13C NMR spectra for lithium, sodium, potassium, rubidium and caesium vanillates in solid state were registered, assigned and analyzed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis and Candida albicans. In order to evaluate the dependence between chemical structure and biological activity of alkali metal vanillates the statistical analysis was performed for selected wavenumbers from FT-IR spectra and parameters describing microbial activity of vanillates. The geometrical structures of the compounds studied were optimized and the structural characteristics were determined by density functional theory (DFT) using at B3LYP method with 6-311++G** as basis set. The obtained statistical equations show the existence of correlation between molecular structure of vanillates and their biological properties.

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

    PubMed

    Hamada, Yoshitomo; Takano, Syota; Ayano, Yoshihiro; Tokunaga, Masahiro; Koashi, Takahiro; Okamoto, Syuhei; Doi, Syoma; Ishida, Masahiko; Kawasaki, Takashi; Hamada, Masahiro; Nakajima, Noriyuki; Saito, Akiko

    2015-01-01

    Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4-8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (-)-epigallocatechin-[4,8]-(+)-catechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-(-)-epigallocatechin and performed structure-activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity. PMID:26501251

  13. Structure-Property-Function Relationship in Humic Substances to Explain the Biological Activity in Plants

    PubMed Central

    García, Andrés Calderín; de Souza, Luiz Gilberto Ambrosio; Pereira, Marcos Gervasio; Castro, Rosane Nora; García-Mina, José María; Zonta, Everaldo; Lisboa, Francy Junior Gonçalves; Berbara, Ricardo Luis Louro

    2016-01-01

    Knowledge of the structure-property-function relationship of humic substances (HSs) is key for understanding their role in soil. Despite progress, studies on this topic are still under discussion. We analyzed 37 humic fractions with respect to their isotopic composition, structural characteristics, and properties responsible for stimulating plant root parameters. We showed that regardless of the source of origin of the carbon (C3 or C4), soil-extracted HSs and humic acids (HAs) are structurally similar to each other. The more labile and functionalized HS fraction is responsible for root emission, whereas the more recalcitrant and less functionalized HA fraction is related to root growth. Labile structures promote root stimulation at lower concentrations, while recalcitrant structures require higher concentrations to promote a similar stimulus. These findings show that lability and recalcitrance, which are derived properties of humic fractions, are related to the type and intensity of their bioactivity. In summary, the comparison of humic fractions allowed a better understanding of the relationship between the source of origin of plant carbon and the structure, properties, and type and intensity of the bioactivity of HSs in plants. In this study, scientific concepts are unified and the basis for the agronomic use of HSs is established. PMID:26862010

  14. Structure-Property-Function Relationship in Humic Substances to Explain the Biological Activity in Plants.

    PubMed

    García, Andrés Calderín; de Souza, Luiz Gilberto Ambrosio; Pereira, Marcos Gervasio; Castro, Rosane Nora; García-Mina, José María; Zonta, Everaldo; Lisboa, Francy Junior Gonçalves; Berbara, Ricardo Luis Louro

    2016-01-01

    Knowledge of the structure-property-function relationship of humic substances (HSs) is key for understanding their role in soil. Despite progress, studies on this topic are still under discussion. We analyzed 37 humic fractions with respect to their isotopic composition, structural characteristics, and properties responsible for stimulating plant root parameters. We showed that regardless of the source of origin of the carbon (C3 or C4), soil-extracted HSs and humic acids (HAs) are structurally similar to each other. The more labile and functionalized HS fraction is responsible for root emission, whereas the more recalcitrant and less functionalized HA fraction is related to root growth. Labile structures promote root stimulation at lower concentrations, while recalcitrant structures require higher concentrations to promote a similar stimulus. These findings show that lability and recalcitrance, which are derived properties of humic fractions, are related to the type and intensity of their bioactivity. In summary, the comparison of humic fractions allowed a better understanding of the relationship between the source of origin of plant carbon and the structure, properties, and type and intensity of the bioactivity of HSs in plants. In this study, scientific concepts are unified and the basis for the agronomic use of HSs is established. PMID:26862010

  15. Structure-Property-Function Relationship in Humic Substances to Explain the Biological Activity in Plants

    NASA Astrophysics Data System (ADS)

    García, Andrés Calderín; de Souza, Luiz Gilberto Ambrosio; Pereira, Marcos Gervasio; Castro, Rosane Nora; García-Mina, José María; Zonta, Everaldo; Lisboa, Francy Junior Gonçalves; Berbara, Ricardo Luis Louro

    2016-02-01

    Knowledge of the structure-property-function relationship of humic substances (HSs) is key for understanding their role in soil. Despite progress, studies on this topic are still under discussion. We analyzed 37 humic fractions with respect to their isotopic composition, structural characteristics, and properties responsible for stimulating plant root parameters. We showed that regardless of the source of origin of the carbon (C3 or C4), soil-extracted HSs and humic acids (HAs) are structurally similar to each other. The more labile and functionalized HS fraction is responsible for root emission, whereas the more recalcitrant and less functionalized HA fraction is related to root growth. Labile structures promote root stimulation at lower concentrations, while recalcitrant structures require higher concentrations to promote a similar stimulus. These findings show that lability and recalcitrance, which are derived properties of humic fractions, are related to the type and intensity of their bioactivity. In summary, the comparison of humic fractions allowed a better understanding of the relationship between the source of origin of plant carbon and the structure, properties, and type and intensity of the bioactivity of HSs in plants. In this study, scientific concepts are unified and the basis for the agronomic use of HSs is established.

  16. Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin▿

    PubMed Central

    Vanderlinden, Evelien; Göktaş, Fusun; Cesur, Zafer; Froeyen, Matheus; Reed, Mark L.; Russell, Charles J.; Cesur, Nesrin; Naesens, Lieve

    2010-01-01

    A new class of N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide inhibitors of influenza virus hemagglutinin (HA)-mediated membrane fusion that has a narrow and defined structure-activity relationship was identified. In Madin-Darby canine kidney (MDCK) cells infected with different strains of human influenza virus A/H3N2, the lead compound, 4c, displayed a 50% effective concentration of 3 to 23 μM and an antiviral selectivity index of 10. No activity was observed for A/H1N1, A/H5N1, A/H7N2, and B viruses. The activity of 4c was reduced considerably when added 30 min or later postinfection, indicating that 4c inhibits an early step in virus replication. 4c and its congeners inhibited influenza A/H3N2 virus-induced erythrocyte hemolysis at low pH. 4c-resistant virus mutants, selected in MDCK cells, contained either a single D112N change in the HA2 subunit of the viral HA or a combination of three substitutions, i.e., R220S (in HA1) and E57K (in HA2) and an A-T substitution at position 43 or 96 of HA2. The mutants showed efficiency for receptor binding and replication similar to that of wild-type virus yet displayed an increased pH of erythrocyte hemolysis. In polykaryon assays with cells expressing single-mutant HA proteins, the E57K, A96T, and D112N mutations resulted in 4c resistance, and the HA proteins containing R220S, A96T, and D112N mutations displayed an increased fusion pH. Molecular modeling identified a binding cavity for 4c involving arginine-54 and glutamic acid-57 in the HA2 subunit. Our studies with the new fusion inhibitor 4c confirm the importance of this HA region in the development of influenza virus fusion inhibitors. PMID:20181685

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

    PubMed

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

    2011-01-01

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

  18. 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. PMID:22939392

  19. Quantitative structure-activity relationships (QSARs) using the novel marine algal toxicity data of phenols.

    PubMed

    Ertürk, M Doğa; Saçan, Melek Türker; Novic, Marjana; Minovski, Nikola

    2012-09-01

    The present study reports for the first time in its entirety the toxicity of 30 phenolic compounds to marine alga Dunaliella tertiolecta. Toxicity of polar narcotics and respiratory uncouplers was strongly correlated to hydrophobicity as described by the logarithm of the octanol/water partition coefficient (Log P). Compounds expected to act by more reactive mechanisms, particularly hydroquinones, were shown to have toxicity in excess of that predicted by Log P. A quality quantitative structure-activity relationship (QSAR) was obtained with Log P and a 2D autocorrelation descriptor weighted by atomic polarizability (MATS3p) only after the removal of hydroquinones from the data set. In an attempt to model the whole data set including hydroquinones, 3D descriptors were included in the modeling process and three quality QSARs were developed using multiple linear regression (MLR). One of the most significant results of the present study was the superior performance of the consensus MLR model, obtained by averaging the predictions from each individual linear model, which provided excellent prediction accuracy for the test set (Q(test)²=0.94). The four-parameter Counter Propagation Artificial Neural Network (CP ANN) model, which was constructed using four out of six descriptors that appeared in the linear models, also provided an excellent external predictivity (Q(test)²=0.93). The proposed algal QSARs were further tested in their predictivity using an external set comprising toxicity data of 44 chemicals on freshwater alga Pseudokirchneriella subcapitata. The two-parameter global model employing a 3D descriptor (Mor24m) and a charge-related descriptor (C(ortho)) not only had high external predictivity (Q(ext)²=0.74), but it also had excellent external data set coverage (%97). PMID:23085159

  20. 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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

    2013-01-01

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

  3. 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

    2002-11-01

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

  4. N4-amino-acid derivatives of 6-azacytidine: structure-activity relationship.

    PubMed

    Alexeeva, I; Palchikovskaya, L; Shalamay, A; Nosach, L; Zhovnovataya, V; Povnitsa, O; Dyachenko, N

    2000-01-01

    Several N4-derivatives of 6-azacytidine were synthesized using of Vorbrüggen's condensation method. Their antiviral activity with respect to the adenovirus serotypes 2 and 5 in Hep-2 cells culture was studied and primary specific activity was determined. Correlation between chemical structure of new 6-azacytidine derivatives and their biological properties is discussed. PMID:10961682

  5. 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.

  6. Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I.

    PubMed

    Alonso, Juan Antonio; Andrés, Miriam; Bravo, Mónica; Buil, Maria Antonia; Calbet, Marta; Castro, Jordi; Eastwood, Paul R; Eichhorn, Peter; Esteve, Cristina; Gómez, Elena; González, Jacob; Mir, Marta; Petit, Silvia; Roberts, Richard S; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere; Zanuy, Miriam

    2014-11-01

    A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times. PMID:25437504

  7. 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. PMID:27586364

  8. The pheromone biosynthesis activating neuropeptide (PBAN) receptor of Heliothis virescens: Identification, functional expression, and structure-activity relationships of ligand analogs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pheromone biosynthesis activating neuropeptide (PBAN) promotes synthesis and release of sex pheromones in moths. We have identified and functionally expressed a PBAN receptor from Heliothis virescens (HevPBANR) and elucidated structure-activity relationships of PBAN analogs. Screening of a larval C...

  9. Structure-activity relationships of oligo-beta-glucoside elicitors of phytoalexin accumulation in soybean.

    PubMed Central

    Cheong, J J; Birberg, W; Fügedi, P; Pilotti, A; Garegg, P J; Hong, N; Ogawa, T; Hahn, M G

    1991-01-01

    The abilities of a family of chemically synthesized oligo-beta-glucosides, ranging in size from hexamer to decamer, to induce phytoalexin accumulation in soybean cotyledons were investigated to determine which structural elements of the oligoglucosides are important for their biological activity. The results of the biological assays established that the following structural motif is necessary for the oligo-beta-glucosides to have high elicitor activity: [formula; see text] The branched trisaccharide at the nonreducing end of the oligoglucosides was found to be essential for maximum elicitor activity. Substitution of either the nonreducing terminal backbone glucosyl residue or the side-chain glucosyl residue closest to the nonreducing end with glucosaminyl or N-acetylglucosaminyl residues reduced the elicitor activity of the oligoglucosides between 10-fold and 10,000-fold. Elicitor activity was also reduced 1000-fold if the two side-chain glucosyl residues were attached to adjacent backbone glucosyl residues rather than to glucosyl residues separated by an unbranched residue. In contrast, modifications of the reducing terminal glucosyl residue of an elicitor-active hepta-beta-glucoside by conjugation with tyramine and subsequent iodination had no significant effect on the elicitor activity of the hepta-beta-glucoside. These results demonstrate that oligo-beta-glucosides must have a specific structure to trigger the signal transduction pathway, which ultimately leads to the de novo synthesis of phytoalexins in soybean. PMID:1840904

  10. Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

    PubMed Central

    Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J.; Kuca, Kamil

    2013-01-01

    Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

  11. A Binding Site Model and Structure-Activity Relationships for the Rat A3 Adenosine Receptor

    PubMed Central

    VAN GALEN, PHILIP J. M.; VAN BERGEN, ANDREW H.; GALLO-RODRIGUEZ, CAROLA; MELMAN, NELI; OLAH, MARK E.; IJZERMAN, AD P.; STILES, GARY L.; JACOBSON, KENNETH A.

    2012-01-01

    SUMMARY A novel adenosine receptor, the A3 receptor, has recently been cloned. We have systematically investigated the hitherto largely unexplored structure-activity relationships (SARs) for binding at A3 receptors, using 125I-N6-2-(4-aminophenyl)ethyladenosine as a radioligand and membranes from Chinese hamster ovary cells stably transfected with the rat A3-cDNA. As is the case for A1 and A2a, receptors, substitutions at the N6 and 5′ positions of adenosine, the prototypic agonist ligand, may yield fairly potent compounds. However, the highest affinity and A3 selectivity is found for N6,5′-disubstituted compounds, in contrast to A1 and A2a receptors. Thus, N6-benzyladenosine-5′-N-ethylcarboxamide is highly potent (Ki, 6.8 nM) and moderately selective (13- and 14-fold versus A1 and A2a). The N6 region of the A3 receptor also appears to tolerate hydrophilic substitutions, in sharp contrast to the other subtypes. Potencies of N6,5′-disubstituted compounds in inhibition of adenylate cyclase via A3 receptors parallel their high affinity in the binding assay. None of the typical xanthine or nonxanthine (A1/A2) antagonists tested show any appreciable affinity for rat A3 receptors. 1,3-Dialkylxanthines did not antagonize the A3 agonist-induced inhibition of adenylate cyclase. A His residue in helix 6 that is absent in A3 receptors but present in A1/A2 receptors may be causal in this respect. In a molecular model for the rat A3 receptor, this mutation, together with an increased bulkiness of residues surrounding the ligand, make antagonist binding unfavorable when compared with a previously developed A1 receptor model. Second, this A3 receptor model predicted similarities with A1 and A2 receptors in the binding requirements for the ribose moiety and that xanthine-7-ribosides would bind to rat A3 receptors. This hypothesis was supported experimentally by the moderate affinity (Ki 6 μM) of 7-riboside of 1,3-dibutylxanthine, which appears to be a partial agonist at

  12. Antimicrobial peptides with potential for biofilm eradication: synthesis and structure activity relationship studies of battacin peptides.

    PubMed

    De Zoysa, Gayan Heruka; Cameron, Alan James; Hegde, Veena V; Raghothama, Srinivasarao; Sarojini, Vijayalekshmi

    2015-01-22

    We report on the first chemical syntheses and structure-activity analyses of the cyclic lipopeptide battacin which revealed that conjugation of a shorter fatty acid, 4-methyl-hexanoic acid, and linearization of the peptide sequence improves antibacterial activity and reduces hemolysis of mouse blood cells. This surprising finding of higher potency in linear lipopeptides than their cyclic counterparts is economically beneficial. This novel lipopeptide was membrane lytic and exhibited antibiofilm activity against Pseudomonas aeruginosa, Staphylococcus aureus, and, for the first time, Pseudomonas syringe pv. actinidiae. The peptide was unstructured in aqueous buffer and dimyristoylphosphatidylcholine-polymerized diacetylene vesicles, with 12% helicity induced in 50% v/v of trifluoroethanol. Our results indicate that a well-defined secondary structure is not essential for the observed antibacterial activity of this novel lipopeptide. A truncated pentapeptide conjugated to 4-methyl hexanoic acid, having similar potency against Gram negative and Gram positive pathogens was identified through alanine scanning. PMID:25495219

  13. Design, Synthesis, and Structure-Activity Relationship of Substrate Competitive, Selective, and in Vivo Active Triazole and Thiadiazole inhibitors of the c-Jun N-Terminal Kinase

    PubMed Central

    De, Surya K.; Stebbins, John L.; Chen, Li-Hsing; Riel-Mehan, Megan; Machleidt, Thomas; Dahl, Russell; Yuan, Hongbin; Emdadi, Aras; Barile, Elisa; Chen, Vida; Murphy, Ria; Pellecchia, Maurizio

    2009-01-01

    We report comprehensive structure activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that displays promising in vivo activity in mouse models of insulin insensitivity. PMID:19271755

  14. Quantitative Structure-Activity Relationship (QSAR) of indoloacetamides as inhibitors of human isoprenylcysteine carboxyl methyltransferase

    PubMed Central

    Leow, Jo-Lene; Baron, Rudi; Casey, Patrick C; Go, Mei-Lin

    2007-01-01

    A QSAR is developed for the isoprenylcysteine carboxyl methyltransferase (ICMT) inhibitory activities of a series of indoloacetamides (n = 71) that are structurally related to cysmethynil, a selective ICMT inhibitor. Multivariate analytical tools (principal component analysis and projection to latent structures), multi-linear regression and comparative molecular field analysis (CoMFA) are used to develop a suitably predictive model for the purpose of optimizing and identifying members with more potent inhibitory activity. The resulting model shows that good activity is determined largely by the characteristics of the substituent attached to the indole nitrogen, which should be a lipophilic residue with fairly wide dimensions. In contrast, the substituted phenyl ring attached to the indole ring must be of limited dimensions and lipophilicity. PMID:17157012

  15. Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety.

    PubMed

    Obata, R; Sunazuka, T; Tian, Z; Tomoda, H; Harigaya, Y; Omura, S

    1997-03-01

    Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition. PMID:9127194

  16. Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety

    PubMed

    Obata; Sunazuka; Tian; Tomoda; Harigaya; Omura

    1997-03-01

    Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition. PMID:9439694

  17. 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

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

    PubMed

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

    2016-04-01

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

  19. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    PubMed

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

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

    PubMed

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

    2012-01-01

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

  1. Structure-Activity Relationship Studies and Biological Characterization of Human NAD+-dependent 15-Hydroxyprostaglandin Dehydrogenase Inhibitors

    PubMed Central

    Duveau, Damien Y.; Yasgar, Adam; Wang, Yuhong; Hu, Xin; Kouznetsova, Jennifer; Brimacombe, Kyle R.; Jadhav, Ajit; Simeonov, Anton; Thomas, Craig J.; Maloney, David J.

    2014-01-01

    The structure-activity relationship (SAR) study of two chemotypes identified as inhibitors of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15-PGDH) was conducted. Top compounds from both series displayed potent inhibition (IC50 <50 nM), demonstrate excellent selectivity towards HPGD and potently induce PGE2 production in A549 lung cancer and LNCaP prostate cancer cells. PMID:24360556

  2. Folate-vinca alkaloid conjugates for cancer therapy: a structure-activity relationship.

    PubMed

    Leamon, Christopher P; Vlahov, Iontcho R; Reddy, Joseph A; Vetzel, Marilynn; Santhapuram, Hari Krishna R; You, Fei; Bloomfield, Alicia; Dorton, Ryan; Nelson, Melissa; Kleindl, Paul; Vaughn, Jeremy F; Westrick, Elaine

    2014-03-19

    Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted. PMID:24564229

  3. Structure-activity relationships of the plasminogen modulator SMTP with respect to the inhibition of soluble epoxide hydrolase.

    PubMed

    Matsumoto, Naoki; Suzuki, Eriko; Tsujihara, Kota; Nishimura, Yuuichi; Hasumi, Keiji

    2015-11-01

    A family of fungal metabolites, SMTP, is a small-molecule plasminogen modulator that enhances plasminogen activation, leading to thrombolysis. We recently demonstrated that SMTP-7 effectively treats ischemic stroke due to its thrombolytic activity as well as anti-inflammatory action, which is attributable to soluble epoxide hydrolase (sEH) inhibition. In this paper, we studied detailed structure-activity relationships of plasminogen modulation and sEH inhibition using 25 SMTP congeners including six newly synthesized ones. The results clearly demonstrate that the structure of the N-linked side chain of SMTP congeners markedly affect their activities toward plasminogen modulation and inhibitions of the two activities of sEH (C-terminal epoxide hydrolase and N-terminal phosphatase). A slight change in the N-linked side chain results in affording selectivity of SMTP congeners. Many congeners, which lacked plasminogen modulation activity, differently inhibited the two sEH activities depending on the structures of the N-linked side chain. Some congeners were active in plasminogen modulation and inhibition of both activities of sEH. These results help comprehensive understanding of ideal design of a drug useful for ischemic diseases that are associated with inflammation, such as stroke. PMID:25966853

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

    PubMed

    Brahma, Biswajit; Patra, Mahesh Chandra; Karri, Satyanagalakshmi; Chopra, Meenu; Mishra, Purusottam; De, Bidhan Chandra; Kumar, Sushil; Mahanty, Sourav; Thakur, Kiran; Poluri, Krishna Mohan; Datta, Tirtha Kumar; De, Sachinandan

    2015-01-01

    Cathelicidins are an ancient class of antimicrobial peptides (AMPs) with broad spectrum bactericidal activities. In this study, we investigated the diversity and biological activity of cathelicidins of buffalo, a species known for its disease resistance. A series of new homologs of cathelicidin4 (CATHL4), which were structurally diverse in their antimicrobial domain, was identified in buffalo. AMPs of newly identified buffalo CATHL4s (buCATHL4s) displayed potent antimicrobial activity against selected Gram positive (G+) and Gram negative (G-) bacteria. These peptides were prompt to disrupt the membrane integrity of bacteria and induced specific changes such as blebing, budding, and pore like structure formation on bacterial membrane. The peptides assumed different secondary structure conformations in aqueous and membrane-mimicking environments. Simulation studies suggested that the amphipathic design of buCATHL4 was crucial for water permeation following membrane disruption. A great diversity, broad-spectrum antimicrobial action, and ability to induce an inflammatory response indicated the pleiotropic role of cathelicidins in innate immunity of buffalo. This study suggests short buffalo cathelicidin peptides with potent bactericidal properties and low cytotoxicity have potential translational applications for the development of novel antibiotics and antimicrobial peptidomimetics. PMID:26675301

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

    PubMed Central

    Brahma, Biswajit; Patra, Mahesh Chandra; Karri, Satyanagalakshmi; Chopra, Meenu; Mishra, Purusottam; De, Bidhan Chandra; Kumar, Sushil; Mahanty, Sourav; Thakur, Kiran; Poluri, Krishna Mohan; Datta, Tirtha Kumar; De, Sachinandan

    2015-01-01

    Cathelicidins are an ancient class of antimicrobial peptides (AMPs) with broad spectrum bactericidal activities. In this study, we investigated the diversity and biological activity of cathelicidins of buffalo, a species known for its disease resistance. A series of new homologs of cathelicidin4 (CATHL4), which were structurally diverse in their antimicrobial domain, was identified in buffalo. AMPs of newly identified buffalo CATHL4s (buCATHL4s) displayed potent antimicrobial activity against selected Gram positive (G+) and Gram negative (G-) bacteria. These peptides were prompt to disrupt the membrane integrity of bacteria and induced specific changes such as blebing, budding, and pore like structure formation on bacterial membrane. The peptides assumed different secondary structure conformations in aqueous and membrane-mimicking environments. Simulation studies suggested that the amphipathic design of buCATHL4 was crucial for water permeation following membrane disruption. A great diversity, broad-spectrum antimicrobial action, and ability to induce an inflammatory response indicated the pleiotropic role of cathelicidins in innate immunity of buffalo. This study suggests short buffalo cathelicidin peptides with potent bactericidal properties and low cytotoxicity have potential translational applications for the development of novel antibiotics and antimicrobial peptidomimetics. PMID:26675301

  6. Relationship between observed upper mantle structures and recent tectonic activity across the Southeastern United States

    NASA Astrophysics Data System (ADS)

    Biryol, C. Berk; Wagner, Lara S.; Fischer, Karen M.; Hawman, Robert B.

    2016-05-01

    The lithospheric structure of the Southeastern United States is a product of earlier episodes of continental collision and breakup. The region is located in the interior of the North American Plate, away from active plate margins. However, there is ongoing tectonism in the region with multiple zones of seismicity, uplifting arches, and Cenozoic intraplate volcanism. The mechanisms controlling this activity and the state of stress remain enigmatic. Two important factors are plate strength and preexisting, inherited structures. Here we present new tomographic images of the upper mantle beneath the Southeastern United States, revealing large-scale structural variations in the upper mantle. Examples include the relatively thick lithospheric mantle of stable North America that abruptly thins beneath the Paleozoic Appalachian orogeny, and the slow upper mantle of the Proterozoic Reelfoot rift. Our results also indicate fast seismic velocity patterns that can be interpreted as ongoing lithospheric foundering. This provides a viable explanation for seismicity, uplifting, and young intraplate volcanism. We postulate that not only tectonic inheritance but also continuing lithospheric foundering may control the ongoing activity of the region long after it became a passive margin. Based on distinct variations in the geometry and thickness of the lithospheric mantle and foundered lithosphere, we propose that piecemeal delamination has occurred beneath the region throughout the Cenozoic, removing a significant amount of reworked/deformed mantle lithosphere. Ongoing lithospheric foundering beneath the eastern margin of stable North America explains significant variations in thickness of lithospheric mantle across the former Grenville deformation front.

  7. Active structural growth in central Taiwan in relationship to large earthquakes and pore-fluid pressures

    NASA Astrophysics Data System (ADS)

    Yue, Li-Fan

    Central Taiwan is subject to a substantial long-term earthquake risk with a population of five million and two disastrous earthquakes in the last century, the 1935 ML=7.1 Tuntzuchiao and 1999 Mw=7.6 Chi-Chi earthquakes. Rich data from these earthquakes combined with substantial surface and subsurface data accumulated from petroleum exploration form the basis for these studies of the growth of structures in successive large earthquakes and their relationships to pore-fluid pressures. Chapter 1 documents the structural context of the bedding-parallel Chelungpu thrust that slipped in the Chi-Chi earthquake by showing for this richly instrumented earthquake the close geometric relationships between the complex 3D fault shape and the heterogeneous coseismic displacements constrained by geodesy and seismology. Chapter 2 studies the accumulation of deformation by successive large earthquakes by studying the deformation of flights of fluvial terraces deposited over the Chelungpu and adjacent Changhua thrusts, showing the deformation on a timescale of tens of thousands of years. Furthermore these two structures, involving the same stratigraphic sequence, show fundamentally different kinematics of deformation with associated contrasting hanging-wall structural geometries. The heights and shapes of deformed terraces allowed testing of existing theories of fault-related folding. Furthermore terrace dating constrains a combined shortening rate of 37 mm/yr, which is 45% of the total Taiwan plate-tectonic rate, and indicates a substantial earthquake risk for the Changhua thrust. Chapter 3 addresses the long-standing problem of the mechanics of long-thing thrust sheets, such as the Chelungpu and Changhua thrusts in western Taiwan, by presenting a natural test for the classic Hubbert-Rubey hypothesis, which argues that ambient excess pore-fluid pressure substantially reduces the effective fault friction allowing the thrusts to move. Pore-fluid pressure data obtained from 76 wells

  8. Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

    PubMed

    Zhao, Qingjie; Vargas, Mireille; Dong, Yuxiang; Zhou, Lin; Wang, Xiaofang; Sriraghavan, Kamaraj; Keiser, Jennifer; Vennerstrom, Jonathan L

    2010-05-27

    In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatica. PMID:20423101

  9. 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. PMID:27116029

  10. Cucurbitane glycosides derived from mogroside IIE: structure-taste relationships, antioxidant activity, and acute toxicity.

    PubMed

    Wang, Lei; Yang, Ziming; Lu, Fenglai; Liu, Jinglei; Song, Yunfei; Li, Dianpeng

    2014-01-01

    Mogroside IIE is a bitter triterpenoid saponin which is the main component of unripe Luo Han Guo fruit and a precursor of the commercially available sweetener mogroside V. In this study, we developed an enzymatic glycosyl transfer method, by which bitter mogroside IIE could be converted into a sweet triterpenoid saponin mixture. The reactant concentration, temperature, pH and buffer system were studied. New saponins with the α-glucose group were isolated from the resulting mixtures, and the structures of three components of the extract were determined. The structure-taste relationships of these derivatives were also studied together with those of the natural mogrosides. The number and stereoconfiguration of glucose groups present in the mogroside molecules were found to be the main factor to determine the sweet or bitter taste of a compound. The antioxidant and food safety properties were initially evaluated by their radical scavenging ability and via 7 day mice survival tests, respectively. The results showed that the sweet triterpenoid saponin mixture has the same favorable physiological and safety characteristics as the natural mogrosides. PMID:25140446

  11. Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists.

    PubMed

    Zheng, Guo Zhu; Bhatia, Pramila; Daanen, Jerome; Kolasa, Teodozyj; Patel, Meena; Latshaw, Steven; El Kouhen, Odile F; Chang, Renjie; Uchic, Marie E; Miller, Loan; Nakane, Masaki; Lehto, Sonya G; Honore, Marie P; Moreland, Robert B; Brioni, Jorge D; Stewart, Andrew O

    2005-11-17

    SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models. PMID:16279797

  12. Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline

    PubMed Central

    Honeyman, Laura; Ismail, Mohamed; Nelson, Mark L.; Bhatia, Beena; Bowser, Todd E.; Chen, Jackson; Mechiche, Rachid; Ohemeng, Kwasi; Verma, Atul K.; Cannon, E. Pat; Macone, Ann; Levy, Stuart

    2015-01-01

    A series of novel tetracycline derivatives were synthesized with the goal of creating new antibiotics that would be unaffected by the known tetracycline resistance mechanisms. New C-9-position derivatives of minocycline (the aminomethylcyclines [AMCs]) were tested for in vitro activity against Gram-positive strains containing known tetracycline resistance mechanisms of ribosomal protection (Tet M in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) and efflux (Tet K in S. aureus and Tet L in E. faecalis). A number of aminomethylcyclines with potent in vitro activity (MIC range of ≤0.06 to 2.0 μg/ml) were identified. These novel tetracyclines were more active against one or more of the resistant strains than the reference antibiotics tested (MIC range, 16 to 64 μg/ml). The AMC derivatives were active against bacteria resistant to tetracycline by both efflux and ribosomal protection mechanisms. This study identified the AMCs as a novel class of antibiotics evolved from tetracycline that exhibit potent activity in vitro against tetracycline-resistant Gram-positive bacteria, including pathogenic strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). One derivative, 9-neopentylaminomethylminocycline (generic name omadacycline), was identified and is currently in human trials for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). PMID:26349824

  13. Riccardin C derivatives as anti-MRSA agents: structure-activity relationship of a series of hydroxylated bis(bibenzyl)s.

    PubMed

    Sawada, Hiromi; Okazaki, Miki; Morita, Daichi; Kuroda, Teruo; Matsuno, Kenji; Hashimoto, Yuichi; Miyachi, Hiroyuki

    2012-12-15

    Members of a series of macrocyclic bis(bibenzyl) riccardin-class derivatives were found to exhibit antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship (SAR) studies were conducted, focusing on the number and position of the hydroxyl groups. The minimum essential structure for anti-MRSA activity was also investigated. PMID:23122868

  14. Structure-activity relationship of lipid core peptide-based Group A Streptococcus vaccine candidates.

    PubMed

    Chan, Amy; Hussein, Waleed M; Ghaffar, Khairunnisa Abdul; Marasini, Nirmal; Mostafa, Ahmed; Eskandari, Sharareh; Batzloff, Michael R; Good, Michael F; Skwarczynski, Mariusz; Toth, Istvan

    2016-07-15

    Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure-activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure. PMID:27246859

  15. 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.

  16. 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

  17. Study of structure-activity relationship of enantiomeric, protonated and deprotonated forms of warfarin via vibrational spectroscopy and DFT calculations

    NASA Astrophysics Data System (ADS)

    Mishra, Alok; Srivastava, Sunil Kumar; Swati, D.

    2013-09-01

    The structure-activity relationship of the anticoagulant drug warfarin were studied by studying two enantiomeric forms (S-form and R-form) of warfarin and its protonated as well as deprotonated structures in aqueous media using density functional theory (DFT). Theoretically computed Raman and IR spectra of all the computed structures were compared and their specific vibrational spectroscopic signatures were discussed. The percentage contributions of individual normal modes of warfarin, which provides direct evidence of the different molecular activity due to change in relative atomic position of atoms in molecule, were investigated through potential energy distribution (PED). The optimized energy and molecular electrostatic potential (MEP) maps show that the S-form of the drug molecules warfarin is energetically more stable than R-form and provides higher docking opportunity for the molecular binding with the receptors in the bio-systems.

  18. Synthesis and structure activity relationship study of N-substituted 3,5-diarylidenepiperidin- 4-ones as potential antitumor agents.

    PubMed

    El-Nassan, Hala Bakr

    2014-02-01

    A new series of N-substituted diarylidenepiperidin-4-ones was synthesized and screened for their possible anticancer activity at the NCI Developmental Therapeutic Program. Almost all the synthesized compounds showed more potent antiproliferative activity than curcumin. The most active compound in this study was 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (8a) with MG-MID GI50, TGI, and LC50 values of 0.35, 1.62 and 9.12 µM, respectively. Compound 8a displayed broad spectrum antiproliferative activity with GI50 values below 1 µM in 81% of the tested cell lines and was found to be two folds more potent than EF-24. A detailed study of the structure activity relationship of the N-substitution was also described. PMID:24102314

  19. Structure-activity relationships of alpha-conotoxins targeting neuronal nicotinic acetylcholine receptors.

    PubMed

    Millard, Emma L; Daly, Norelle L; Craik, David J

    2004-06-01

    alpha-Conotoxins that target the neuronal nicotinic acetylcholine receptor have a range of potential therapeutic applications and are valuable probes for examining receptor subtype selectivity. The three-dimensional structures of about half of the known neuronal specific alpha-conotoxins have now been determined and have a consensus fold containing a helical region braced by two conserved disulfide bonds. These disulfide bonds define the two-loop framework characteristic for alpha-conotoxins, CCX(m)CX(n)C, where loop 1 comprises four residues (m = 4) and loop 2 between three and seven residues (n = 3, 6 or 7). Structural studies, particularly using NMR spectroscopy have provided an insight into the role and spatial location of residues implicated in receptor binding and biological activity. PMID:15182347

  20. Leishmania lipophosphoglycan: how to establish structure-activity relationships for this highly complex and multifunctional glycoconjugate?

    PubMed Central

    Forestier, Claire-Lise; Gao, Qi; Boons, Geert-Jan

    2015-01-01

    A key feature of many pathogenic microorganisms is the presence of a dense glycocalyx at their surface, composed of lipid-anchored glycoproteins and non-protein-bound polysaccharides. These surface glycolipids are important virulence factors for bacterial, fungal and protozoan pathogens. The highly complex glycoconjugate lipophosphoglycan (LPG) is one of the dominant surface macromolecules of the promastigote stage of all Leishmania parasitic species. LPG plays critical pleiotropic roles in parasite survival and infectivity in both the sandfly vector and the mammalian host. Here, we review the composition of the Leishmania glycocalyx, the chemical structure of LPG and what is currently known about its effects in the mammalian host, specifically. We will then discuss the current approaches employed to elucidate LPG functions. Finally, we will provide a viewpoint on future directions that this area of investigation could take to unravel in detail the biological activity of the specific molecular elements composing the structurally complex LPG. PMID:25653924

  1. Structure-Activity Relationship in Nanostructured Copper-Ceria-Based Preferential CO Oxidation Catalysts

    SciTech Connect

    Gamarra,D.; Munuera, G.; Hungria, A.; Fernandez-Garcia, M.; Conesa, J.; Midgley, P.; Wang, X.; Hanson, J.; Rodriguez, J.; Martinez-Arias, A.

    2007-01-01

    Two series of nanostructured oxidized copper-cerium catalysts with varying copper loadings, and prepared, respectively, by impregnation of ceria and by coprecipitation of the two components within reverse microemulsions, have been characterized in detail at structural and electronic levels by X-ray diffraction (XRD), Raman spectroscopy, high-resolution electron microscopy (HREM), X-ray energy dispersive spectroscopy (XEDS), X-ray photoelectron spectroscopy (XPS) (including Ar{sup +}-sputtering), and X-ray absorption fine structure (XAFS). These results have been correlated with analysis of their catalytic properties for preferential oxidation of CO in a H{sub 2}-rich stream (CO-PROX), complemented by Operando-DRIFTS. A relevant difference between the two series of catalysts concerns the nature of the support for the surface-dispersed copper oxide entities, which is essentially ceria for the samples prepared by impregnation and a Ce-Cu mixed oxide for those prepared by microemulsion-coprecipitation. The existence of copper segregation in the form of copper oxide or copper-enriched Cu-Ce mixed oxides for the latter type of samples is uniquely revealed by nanoprobe XEDS and XPS Ar{sup +}-sputtering experiments. The CO oxidation activity under CO-PROX conditions is correlated to the degree of support-promoted reduction achieved by the dispersed copper oxide particles under reaction conditions. Nevertheless, catalysts which display higher CO oxidation activity are generally more efficient also for the undesired H{sub 2} oxidation reaction. The balance between both reactions results in differences in the CO-PROX activity between the two series of catalysts which are examined on the basis of the structural differences found.

  2. Calophyllum inophyllum and Calophyllum soulattri source of anti-proliferative xanthones and their structure-activity relationships.

    PubMed

    Mah, Siau Hui; Ee, Gwendoline Cheng Lian; Teh, Soek Sin; Sukari, Mohd Aspollah

    2015-01-01

    Extensive chromatographic isolation and purification of the extracts of the stem bark of Calophyllum inophyllum and Calophyllum soulattri have resulted in 11 xanthones. C. inophyllum gave inophinnin (1), inophinone (2), pyranojacareubin (5), rheediaxanthone A (6), macluraxanthone (7) and 4-hydroxyxanthone (8), while C. soulattri afforded soulattrin (3), phylattrin (4), caloxanthone C (9), brasixanthone B (10) and trapezifolixanthone (11). The structures of these compounds were determined on the basis of spectroscopic analyses such as 1D and 2D NMR, GC-MS, IR and UV. Cytotoxicity screening (MTT assay) carried out in vitro on all the xanthones using five human cancer cell lines indicated good activities for some of these xanthones. The structure-activity relationship study revealed that the inhibitory activities exhibited by these xanthone derivatives to be closely related to the existence and nature of the pyrano and the prenyl substituent groups on their skeleton. PMID:25229947

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

    PubMed

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

    2016-06-01

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

  4. Macrobenthos community structure and trophic relationships within active and inactive Pacific hydrothermal sediments

    NASA Astrophysics Data System (ADS)

    Levin, Lisa A.; Mendoza, Guillermo F.; Konotchick, Talina; Lee, Raymond

    2009-09-01

    Hydrothermal fluids passing through sediments create a habitat hypothesized to influence the community structure of infaunal macrobenthos. Here we characterize the density, biomass, species composition, diversity, distributions, lifestyle, and nutritional sources of macroinfauna in hydrothermal sediments in NE and SW Pacific settings, and draw comparisons in search of faunal attributes characteristic of this habitat. There is increasing likelihood that seafloor massive sulfide deposits, associated with active and inactive hydrothermal venting, will be mined commercially. This creates a growing imperative for a more thorough understanding of the structure, dynamics, and resilience of the associated sediment faunas, and has stimulated the research presented here. Macrobenthic assemblages were studied at Manus Basin (1430-1634 m, Papua New Guinea [PNG]) as a function of location (South Su vs. Solwara 1), and hydrothermal activity (active vs. inactive), and at Middle Valley (2406-2411 m, near Juan de Fuca Ridge) as a function of habitat (active clam bed, microbial mat, hot mud, inactive background sediment). The studies conducted in PNG formed part of the environmental impact assessment work for the Solwara 1 Project of Nautilus Minerals Niugini Limited. We hypothesized that hydrothermally active sites should support (a) higher densities and biomass, (b) greater dominance and lower diversity, (c) a higher fraction of deposit feeders, and (d) greater isotopic evidence for chemosynthetic food sources than inactive sites. Manus Basin macrofauna generally had low density (<1000 ind. m -2) and low biomass (0.1-1.07 g m -2), except for the South Su active site, which had higher density (3494 ind. m -2) and biomass (11.94 g m -2), greater dominance (R1D=76%), lower diversity and more spatial (between-core) homogeneity than the Solwara 1 and South Su inactive sites. Dominant taxa at Manus Basin were Spionidae ( Prionospio sp.) in active sediments, and tanaids and deposit

  5. Benzoic acid derivatives with improved antifungal activity: Design, synthesis, structure-activity relationship (SAR) and CYP53 docking studies.

    PubMed

    Berne, Sabina; Kovačič, Lidija; Sova, Matej; Kraševec, Nada; Gobec, Stanislav; Križaj, Igor; Komel, Radovan

    2015-08-01

    Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53-ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi. PMID:26154240

  6. 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. PMID:25110971

  7. Structural investigations of T854A mutation in EGFR and identification of novel inhibitors using structure activity relationships

    PubMed Central

    2015-01-01

    Background The epidermal growth factor receptor (EGFR) is a member of the ErbB family that is involved in a number of processes responsible for cancer development and progression such as angiogenesis, apoptosis, cell proliferation and metastatic spread. Malfunction in activation of protein tyrosine kinases has been shown to result in uncontrolled cell growth. The EGFR TK domain has been identified as suitable target in cancer therapy and tyrosine kinase inhibitors such as erlotinib have been used for treatment of cancer. Mutations in the region of the EGFR gene encoding the tyrosine kinase (TK) domain causes altered responses to EGFR TK inhibitors (TKI). In this paper we perform molecular dynamics simulations and PCA analysis on wild-type and mutant (T854A) structures to gain insight into the structural changes observed in the target protein upon mutation. We also report two novel inhibitors identified by combined approach of QSAR model development. Results The wild-type and mutant structure was observed to be stable for 26 ns and 24 ns respectively. In PCA analysis, the mutant structure proved to be more flexible than wild-type. We developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds which was later used for prediction of inhibitory activity of natural compounds of ZINC library. The 3D-QSAR model was proved to be robust by the statistical parameters such as r2 (0.9751), q2(0.9491) and pred_r2(0.9525). Conclusion Analysis of molecular dynamics simulations results indicate stability loss and increased flexibility in the mutant structure. This flexibility results in structural changes which render the mutant protein drug resistant against erlotinib. We report two novel compounds having high predicted inhibitory activity to EGFR TK domain with both wild-type and mutant structure. PMID:26041145

  8. Hepatoprotection of sesquiterpenoids: a quantitative structure-activity relationship (QSAR) approach.

    PubMed

    Vinholes, Juliana; Rudnitskaya, Alisa; Gonçalves, Pedro; Martel, Fátima; Coimbra, Manuel A; Rocha, Sílvia M

    2014-03-01

    The relative hepatoprotection effect of fifteen sesquiterpenoids, commonly found in plants and plant-derived foods and beverages was assessed. Endogenous lipid peroxidation (assay A) and induced lipid peroxidation (assay B) were evaluated in liver homogenates from Wistar rats by the thiobarbituric acid reactive species test. Sesquiterpenoids with different chemical structures were tested: trans,trans-farnesol, cis-nerolidol, (-)-α-bisabolol, trans-β-farnesene, germacrene D, α-humulene, β-caryophyllene, isocaryophyllene, (+)-valencene, guaiazulene, (-)-α-cedrene, (+)-aromadendrene, (-)-α-neoclovene, (-)-α-copaene, and (+)-cyclosativene. Ascorbic acid was used as a positive antioxidant control. With the exception of α-humulene, all the sesquiterpenoids under study (1mM) were effective in reducing the malonaldehyde levels in both endogenous and induced lipid peroxidation up to 35% and 70%, respectively. The 3D-QSAR models developed, relating the hepatoprotection activity with molecular properties, showed good fit (Radj(2) 0.819 and 0.972 for the assays A and B, respectively) with good prediction power (Q(2)>0.950 and SDEP<2%, for both models A and B). A network of effects associated with structural and chemical features of sesquiterpenoids such as shape, branching, symmetry, and presence of electronegative fragments, can modulate the hepatoprotective activity observed for these compounds. PMID:24176316

  9. Quantitative structure retention/activity relationships of biologically relevant 4-amino-7-chloroquinoline based compounds.

    PubMed

    Šegan, Sandra; Opsenica, Igor; Zlatović, Mario; Milojković-Opsenica, Dušanka; Šolaja, Bogdan

    2016-02-15

    The chromatographic behaviour of series of 4-amino-7-chloroquinoline (4,7-ACQ) based compounds was studied by reversed-phase thin-layer chromatography (RPTLC) with binary mobile phases containing water and the organic modifiers, DMSO or acetone. The lipophilicity of the studied compounds was determined by extrapolation of retention parameters RM to pure water content in mobile phase. In order to obtain some basic insight into the chromatographic behaviour and structural features of investigated compounds, PCA was performed on both chromatographic data (RM values) and calculated 2D and 3D structural descriptors. Both QSRR and QSAR models were built by means of the partial least squares (PLS) statistical method. It was found that descriptors which encode hydrophobic (dispersive) interactions have positive influence on retention, while influence of descriptors encoding polar interactions was negative. According to the obtained PLS model for inhibition of botulinum neurotoxin serotype A light chain, hydrophobic interactions influence positively on the mechanism of action of the investigated 4,7-ACQ, while polar interactions are less favoured. Contrary, the results of PLS modelling of activity against Plasmodium falciparum strains (W2, D6 and TM91C235) indicate that higher polarity of 4,7-ACQ contribute to their higher antimalarial activity. PMID:26827282

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

    PubMed

    Harju, Mikael; Hamers, Timo; Kamstra, Jorke H; Sonneveld, Edwin; Boon, Jan P; Tysklind, Mats; Andersson, Patrik L

    2007-04-01

    In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure-activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecularproperties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200-320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure-activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist. PMID:17447568

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

    PubMed

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

    2009-04-01

    Callicarpenal (=13,14,15,16-tetranorclerod-3-en-12-al=[(1S,2R,4aR,8aR)-1,2,3,4,4a,7,8,8a-octahydro-1,2,4a,5-tetramethylnaphthalen-1-yl]acetaldehyde; 1) has previously demonstrated significant mosquito bite-deterring activity against Aedes aegypti and Anopheles stephensi in addition to repellent activity against host-seeking nymphs of the blacklegged tick, Ixodes scapularis. In the present study, structural modifications were performed on callicarpenal (1) in an effort to understand the functional groups necessary for maintaining and/or increasing its activity and to possibly lead to more effective insect control agents. All modifications in this study targeted the C(12) aldehyde or the C(3) alkene functionalities or combinations thereof. Mosquito biting deterrency appeared to be influenced most by C(3) alkene modification as evidenced by catalytic hydrogenation that resulted in a compound having significantly less effectiveness than 1 at a test amount of 25 nmol/cm2. Oxidation and/or reduction of the C(12) aldehyde did not diminish mosquito biting deterrency, but, at the same time, none of the modifications were more effective than 1 in deterring mosquito biting. Toxicities of synthesized compounds towards Ae. aegypti ranged from an LD50 value of 2.36 to 40.11 microg per mosquito. Similarly, LD95 values ranged from a low of 5.59 to a high of 104.9 microg. PMID:19353538

  12. Phenylpropiophenone derivatives as potential anticancer agents: synthesis, biological evaluation and quantitative structure-activity relationship study.

    PubMed

    Ivković, Branka M; Nikolic, Katarina; Ilić, Bojana B; Žižak, Željko S; Novaković, Radmila B; Čudina, Olivera A; Vladimirov, Sote M

    2013-05-01

    Series of twelve chalcone and propafenone derivatives has been synthesized and evaluated for anticancer activities against HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cell lines. The 2D-QSAR and 3D-QSAR studies were performed for all compounds with cytotoxic activities against each cancer cell line. Partial least squares (PLS) regression has been applied for selection of the most relevant molecular descriptors and QSAR models building. Predictive potentials of the created 2D-QSAR and 3D-QSAR models for each cell line were compared, by use of leave-one-out cross-validation and external validation, and optimal QSAR models for each cancer cell line were selected. The QSAR studies have selected the most significant molecular descriptors and pharmacophores of the chalcone and propafenone derivatives and proposed structures of novel chalcone and propafenone derivatives with enhanced anticancer activity on the HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cells. PMID:23501110

  13. Structure-analgesic activity relationship studies on the C(18)- and C(19)-diterpenoid alkaloids.

    PubMed

    Wang, Jian-Li; Shen, Xiang-Li; Chen, Qiao-Hong; Qi, Gong; Wang, Wei; Wang, Feng-Peng

    2009-08-01

    For evaluation of C(18)- and C(19)-diterpenoid alkaloids as analgesics, three C(19)-diterpenoid alkaloids were isolated from the roots of Aconitum hemsleyanum var. circinatum and A. transsecutum; and twenty-five semisynthetic C(18)- or C(19)-diterpenoid alkaloids were prepared from lappaconitine, crassicauline A or yunaconitine. In a mice acetic acid-induced abdominal constriction assay, four crassicauline A analogs and three yunaconitine analogs exhibited good analgesic activities with 77.8-94.1% inhibition range in 0.1-10 mg/kg subcutaneous (s.c.) dose range at the point of 20 min after drug administration. Among them, 8-O-deacetyl-8-O-ethylcrassicauline A (ED(50)=0.0972 mg/kg) and 8-O-ethylyunaconitine (ED(50)=0.0591 mg/kg) were the most potent analgesics relative to the reference drugs lappaconitine (ED(50)=3.50 mg/kg) and crassicauline A (ED(50)=0.0480 mg/kg). Analgesic activity data of these C(18)- and C(19)-diterpenoid alkaloids indicate that a tertiary amine in ring A, an acetoxyl or an ethoxyl group at C-8, an aromatic ester at C-14, and the saturation state of the ring D are important structural features necessary to the analgesic activity of the C(19)-diterpenoid alkaloids. PMID:19652403

  14. Structure-Activity Relationship and Signaling of New Chimeric CXCR4 Agonists.

    PubMed

    Mona, Christine E; Besserer-Offroy, Élie; Cabana, Jérôme; Lefrançois, Marilou; Boulais, Philip E; Lefebvre, Marie-Reine; Leduc, Richard; Lavigne, Pierre; Heveker, Nikolaus; Marsault, Éric; Escher, Emanuel

    2016-08-25

    The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gαi full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor-ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series. PMID:27434274

  15. 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. PMID:23891182

  16. Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis.

    PubMed

    Flatman, Ruth H; Eustaquio, Alessandra; Li, Shu-Ming; Heide, Lutz; Maxwell, Anthony

    2006-04-01

    Novobiocin and clorobiocin are gyrase inhibitors produced by Streptomyces strains. Structurally, the two compounds differ only by substitution at two positions: CH3 versus Cl at position 8' of the aminocoumarin ring and carbamoyl versus 5-methyl-pyrrol-2-carbonyl (MePC) at the 3"-OH of noviose. Using genetic engineering, we generated a series of analogs carrying H, CH3, or Cl at 8' and H, carbamoyl, or MePC at 3"-OH. Comparison of the gyrase inhibitory activities of all nine structural permutations confirmed that acylation of 3"-OH is essential for activity, with MePC being more effective than carbamoyl. Substitution at 8' further enhanced activity, but the effect of CH3 or Cl depended on the nature of the acyl group at 3": in the presence of carbamoyl at 3", CH3 resulted in higher activity; in the presence of MePC at 3", Cl resulted in higher activity. This suggests that the structures of both natural compounds are highly evolved for optimal interaction with gyrase. In a second series of experiments, clorobiocin derivatives with and without the methyl group at 4"-OH of noviose, and with different positions of the MePC group of noviose, were tested. Again clorobiocin was superior to all of its analogs. The activities of all compounds were also tested against topoisomerase IV (topo IV). Clorobiocin stood out as a remarkably effective topo IV inhibitor. The relative activities of the different compounds toward topo IV showed a pattern similar to that of the relative gyrase-inhibitory activities. This is the first report of a systematic evaluation of a series of aminocoumarins against both gyrase and topo IV. The results give further insight into the structure-activity relationships of aminocoumarin antibiotics. PMID:16569821

  17. Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120.

    PubMed

    Wang, Jingsong; Le, Nhut; Heredia, Alonso; Song, Haijing; Redfield, Robert; Wang, Lai-Xi

    2005-05-01

    This paper describes selected modification and structure-activity relationship of the small molecule HIV-1 inhibitor, 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806). The results revealed: i) that both the presence and configuration (R vs. S) of the 3-methyl group on the piperazine moiety are important for the antiviral activity, with the 3-(R)-methyl derivatives showing the highest activity; ii) that the electronegativity of the C-4 substituent on the indole or azaindole ring seems to be important for the activity, with a small, electron-donating group such as a fluoro or a methoxy group showing enhanced activity, while a nitro group diminishes the activity; iii) that the N-1 position of the indole ring is not eligible for modification without losing activity; and iv) that bulky groups around the C-4 position of the indole or azaindole ring diminish the activity, probably due to steric hindrance in the binding. We found that a synthetic bivalent compound with two BMS-378806 moieties being tethered by a spacer demonstrated about 5-fold enhanced activity in an nM range against HIV-1 infection than the corresponding monomeric inhibitor. But the polyacrylamide-based polyvalent compounds did not show inhibitory activity at up to 200 nM. PMID:15858664

  18. Antipodal crambescin A2 homologues from the marine sponge Pseudaxinella reticulata. Antifungal structure-activity relationships.

    PubMed

    Jamison, Matthew T; Molinski, Tadeusz F

    2015-03-27

    Investigation of antifungal natural products from the marine sponge Pseudaxinella reticulata from the Bahamas led to the discovery of new crambescin homologues (1, 2) and enantiomers (3, 4) of known natural products. The cyclic-guanidine structures were solved through analysis of 2D NMR, MS-MS, and CD data. The absolute configurations of 1-4 were established as 13R-opposite of known homologues reported from Crambe crambe obtained from the Mediterranean Sea-by comparison of their CD spectra with predicted Cotton effects obtained from DFT calculations. Antifungal activities of 1-4 against the pathogenic strains Candida albicans and Cryptococcus sp. were observed to correlate potency (MIC50 and MIC90) with the length of the alkyl side chain. PMID:25738226

  19. Structure-activity relationships of mineral dusts as heterogeneous nuclei for ammonium sulfate crystallization from supersaturated aqueous solutions.

    PubMed

    Martin, S T; Schlenker, J; Chelf, J H; Duckworth, O W

    2001-04-15

    Mineral inclusions, present in aqueous atmospheric salt droplets, regulate crystallization when relative humidity decreases by providing a surface for heterogeneous nucleation and thus reducing the critical supersaturation. Although laboratory studies have quantified these processes to some extent, the diverse atmospheric mineralogy presents more chemical systems than practically feasible for direct study. Structure--activity relationships are necessary. To that end, in the present work the interactions of ammonium sulfate with corundum, hematite, mullite, rutile, anatase, and baddeleyite were studied by diffuse reflectance fourier transform infrared spectroscopy (DRIFTS) and by epitaxial modeling. The spectroscopic results show that shifts in sulfate peak positions due to chemisorption are not a correlative indicator of the efficacy of heterogeneous nucleation. In contrast, epitaxial modeling results of unreconstructed surfaces explain the sequence of critical supersaturations for constant particle size. If validated by further work, this computer modeling method would provide an important structure--activity tool for the estimation of heterogeneous nucleation properties of the atmospheric mineralogy. PMID:11329712

  20. 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

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

    PubMed

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

    2010-07-01

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

  2. Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships.

    PubMed

    Seyberth, Tobias; Voss, Söhnke; Brock, Roland; Wiesmüller, Karl-Heinz; Jung, Günther

    2006-03-01

    Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or covalently linked. The lanthionine scaffold has structural similarity with the S-(2,3-dihydroxypropyl)cysteine core structure of the lipopeptides. Therefore, lanthionine-based lipopeptide amides were synthesized and probed for activity as potential TLR2 agonists or antagonists. A collection of analytically defined lipolanthionine peptide amides exhibited an inhibitory effect of the TLR2-mediated IL-8 secretion when applied in high molar excess to the agonistic synthetic lipopeptide Pam3Cys-Ser-(Lys)4-OH. Structure-activity relationships revealed the influence of the chirality of the two alpha-carbon atoms, the chain lengths of the attached fatty acids and fatty amines, and the oxidation level of the sulfur atom on the inhibitory activity of the lipolanthionine peptide amides. PMID:16509590

  3. Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors.

    PubMed

    Cadelis, Melissa M; Bourguet-Kondracki, Marie-Lise; Dubois, Joëlle; Valentin, Alexis; Barker, David; Copp, Brent R

    2016-07-15

    Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. PMID:27240468

  4. Dendrotoxins: structure-activity relationships and effects on potassium ion channels.

    PubMed

    Harvey, A L; Robertson, B

    2004-12-01

    Dendrotoxins are small proteins isolated from mamba (Dendroaspis) snakes. The original dendrotoxin was found in venom of the Eastern green mamba, Dendroaspis angusticeps, and related proteins were subsequently found in other mamba venoms. The dendrotoxins contain 57-60 amino acid residues cross-linked by three disulphide bridges, and they are homologous to Kunitz-type serine protease inhibitors, such as aprotinin (BPTI). The dendrotoxins have little or no anti-protease activity, but they block particular subtypes of voltage-dependent potassium channels of the Kv1 subfamily in neurones. Alpha-dendrotoxin from green mamba Dendroaspis angusticeps and toxin I from the black mamba Dendroaspis polylepis block cloned Kv1.1, Kv1.2 and Kv1.6 channels in the low nanomolar range; toxin K, also from the black mamba Dendroaspis polylepis, preferentially blocks Kv1.1 channels and is active at picomolar concentrations. Structural modifications and mutations to dendrotoxins have helped to define the molecular recognition properties of different types of K+ channels, although more work is needed to characterise the chemical features of the toxins that underlie their selectivity and potency at particular subtypes of channels. Dendrotoxins have been useful markers of subtypes of K+ channels in vivo, and dendrotoxins have become widely used as probes for studying the function of K+ channels in physiology and pathophysiology. With some pathological conditions being associated with voltage-gated K+ channels, analogues of dendrotoxins might have therapeutic potential. PMID:15579000

  5. Computer-aided study of the relationship between structure and antituberculosis activity of a series of isoniazid derivatives

    NASA Astrophysics Data System (ADS)

    Klopman, Gilles; Fercu, Dan; Jacob, Jason

    1996-04-01

    The Multiple Computer Automated Structure Evaluation (MultiCASE) program was used to analyze the relationship between the structure and antituberculous activity of a series of 136 hydrazides, most of them isoniazid related. The structural features revealed by this analysis are discussed. The most significant one seemed to be the distance between the pyridinic nitrogen and the terminal nitrogen of the hydrazido group. Given the affiliation of these two heteroatoms with a planar conjugated system, we suggest that Schiff base chemistry similar to that of vitamin B 6 may be involved in the mode of action of isoniazid and its related compounds. A mechanism of action of isoniazid is proposed and suggestions for the design of new isoniazid-type drugs are made.

  6. Design, Synthesis and Structure-Activity Relationship Studies of Novel 4 (1-adamantyl) Phenyl Analogues as HIF-1α Inhibitors.

    PubMed

    Xia, Yan; Duan, Qiong; Zhao, Bao-Hua; Li, Dong-Feng; Hou, Rui-Bin

    2016-01-01

    Hypoxia inducible factor-1 (HIF-1) is a key mediator during cancer cells to adapt tumor hypoxic condition. In this study, a series of adamantane-based compounds were synthesized and evaluated as potential inhibitors of HIF-1α. Examination of their structure-activity relationship (SAR) identified the adamantane-containing indole derivative 20a as a potent inhibitor of HIF-1α in Hep3B cell lines under tumor hypoxia (IC50 = 0.02 µM). The study herein may provide valuable information for the development of novel therapeutics against cancer and tumor angiogenesis. PMID:26548744

  7. 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

    2015-01-01

    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. PMID:26703557

  8. 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). PMID:18539035

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

    PubMed

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

    2016-05-01

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

  10. Structure-activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells.

    PubMed

    Yokoi, Taiyo; Minami, Saki; Nakagawa, Yoshiaki; Miyagawa, Hisashi

    2015-05-01

    Diacylhydrazines are the first non-steroidal ecdysone agonists, and five compounds are used as insecticides in agriculture. After the discovery of diacylhydrazine-type compounds, numerous non-steroidal structures were reported as ecdysone agonists. Among various ecdysone agonists, imidazothiadiazoles are reported to be very potent in vitro; however, the experimental detail for the structure identification and bioassays are not stated in the paper (Holmwood and Schindler, Bioorg. Med. Chem. 17, 4064-4070, 2009). In our present study, we synthesized 18 imidazothiadiazole-type compounds and confirmed the chemical structures by spectrometric analyses. The binding activity of the synthesized compounds to the ecdysone receptor was evaluated in terms of the concentration required for 50% inhibition of [(3)H]ponasterone A incorporation [IC50 (M)] into lepidopteran (Sf-9), coleopteran (BCRL-Lepd-SL1), and dipteran (NIAS-AeAl2) cells. 6-(2-Chlorophenyl)-2-(trifluoromethyl)imidazo[2,1-b] [1,3,4]-thiadiazol-5-yl)acrylamide analogs with CONHR (secondary amide) were very potent against Sf-9 cells, but further alkylation (tertiary amide: CONR2) decreased the activity dramatically. Additionally, a primary amide analog (CONH2) was inactive. The activity also decreased 150-fold by the saturation of olefin region of the acrylamide moiety. In addition, various substituents were introduced at the 2-position of the imidazothiadiazole ring to disclose the physicochemical properties of the substituents which are important for receptor binding. The activity increased by 7500-fold with the introduction of the CF2CF2CF3 group compared to the unsubstituted compound against Sf-9 cells. Quantitative structure-activity relationship analysis for these substituents indicated that hydrophobic and electron-withdrawing groups were favorable for binding. Some of the compounds with strong receptor binding activity showed good larvicidal activity against Spodoptera litura. In contrast, the binding

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

    PubMed

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

    2016-04-01

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

  12. New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis.

    PubMed

    Grosse, Sandrine; Mathieu, Véronique; Pillard, Christelle; Massip, Stéphane; Marchivie, Mathieu; Jarry, Christian; Bernard, Philippe; Kiss, Robert; Guillaumet, Gérald

    2014-09-12

    Synthesis and functionalization strategies of the imidazo[1,2-b]pyrazole core were developed giving a rapid access to three series of novel imidazo[1,2-b]pyrazole type derivatives: C-2/C-6/C-7 trisubstituted, C-2/C-3/C-6 tri(hetero)arylated and C-2/C-3/C-6/C-7 tetrasubstituted imidazo[1,2-b]pyrazoles. 39 of the synthetized products were evaluated for in vitro anticancer activity using the MTT colorimetric assay against 5 human and 1 murine cancer cell lines. Promising in vitro growth inhibitory activities were exhibited by some of the target compounds. Of the 39 evaluated products, 4 displayed an IC50 ≤ 10 μM in the 6 cell lines analyzed (compounds 4d, 4g, 9a, 11a). A structure activity relationship analysis is also reported in this paper. PMID:25064349

  13. Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)

    PubMed Central

    Steffen, Jamin D.; Coyle, Donna L.; Damodaran, Komath; Beroza, Paul; Jacobson, Myron K.

    2011-01-01

    The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials due to their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, Target-related Affinity Profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of drug-like compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogs of one of the most active chemotypes were synthesized to explore structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1, and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development. PMID:21692479

  14. Uniform 2 nm gold nanoparticles supported on iron oxides as active catalysts for CO oxidation reaction: Structure-activity relationship

    DOE PAGESBeta

    Guo, Yu; Senanayake, Sanjaya; Gu, Dong; Jin, Zhao; Du, Pei -Pei; Si, Rui; Xu, Wen -Qian; Huang, Yu -Ying; Tao, Jing; Song, Qi -Sheng; et al

    2015-01-12

    Uniform Au nanoparticles (~2 nm) with narrow size-distribution (standard deviation: 0.5–0.6 nm) supported on both hydroxylated (Fe_OH) and dehydrated iron oxide (Fe_O) have been prepared by either deposition-precipitation (DP) or colloidal-deposition (CD) methods. Different structural and textural characterizations were applied to the dried, calcined and used gold-iron oxide samples. The transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) described the high homogeneity in the supported Au nanoparticles. The ex-situ and in-situ X-ray absorption fine structure (XAFS) characterization monitored the electronic and short-range local structure of active gold species. The synchrotron-based in-situ X-ray diffraction (XRD), together with the corresponding temperature-programmed reductionmore » by hydrogen (H₂-TPR), indicated a structural evolution of the iron-oxide supports, correlating to their reducibility. An inverse order of catalytic activity between DP (Au/Fe_OH < Au/Fe_O) and CD (Au/Fe_OH > Au/Fe_O) was observed. Effective gold-support interaction results in a high activity for gold nanoparticles, locally generated by the sintering of dispersed Au atoms on the oxide support in the DP synthesis, while a hydroxylated surface favors the reactivity of externally introduced Au nanoparticles on Fe_OH support for the CD approach. This work reveals why differences in the synthetic protocol translate to differences in the catalytic performance of Au/FeOx catalysts with very similar structural characteristics in CO oxidation.« less

  15. Uniform 2 nm gold nanoparticles supported on iron oxides as active catalysts for CO oxidation reaction: Structure-activity relationship

    SciTech Connect

    Guo, Yu; Senanayake, Sanjaya; Gu, Dong; Jin, Zhao; Du, Pei -Pei; Si, Rui; Xu, Wen -Qian; Huang, Yu -Ying; Tao, Jing; Song, Qi -Sheng; Jia, Chun -Jia; Schueth, Ferdi

    2015-01-12

    Uniform Au nanoparticles (~2 nm) with narrow size-distribution (standard deviation: 0.5–0.6 nm) supported on both hydroxylated (Fe_OH) and dehydrated iron oxide (Fe_O) have been prepared by either deposition-precipitation (DP) or colloidal-deposition (CD) methods. Different structural and textural characterizations were applied to the dried, calcined and used gold-iron oxide samples. The transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) described the high homogeneity in the supported Au nanoparticles. The ex-situ and in-situ X-ray absorption fine structure (XAFS) characterization monitored the electronic and short-range local structure of active gold species. The synchrotron-based in-situ X-ray diffraction (XRD), together with the corresponding temperature-programmed reduction by hydrogen (H₂-TPR), indicated a structural evolution of the iron-oxide supports, correlating to their reducibility. An inverse order of catalytic activity between DP (Au/Fe_OH < Au/Fe_O) and CD (Au/Fe_OH > Au/Fe_O) was observed. Effective gold-support interaction results in a high activity for gold nanoparticles, locally generated by the sintering of dispersed Au atoms on the oxide support in the DP synthesis, while a hydroxylated surface favors the reactivity of externally introduced Au nanoparticles on Fe_OH support for the CD approach. This work reveals why differences in the synthetic protocol translate to differences in the catalytic performance of Au/FeOx catalysts with very similar structural characteristics in CO oxidation.

  16. Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.

    PubMed Central

    Powell, C. J.; Grasso, P.; Ioannides, C.; Wilson, J.; Bridges, J. W.

    1991-01-01

    The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:1768609

  17. 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. PMID:16256196

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

    PubMed

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

    2009-04-01

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

  19. Nature-inspired design of tetraindoles: Optimization of the core structure and evaluation of structure-activity relationship.

    PubMed

    Abdu-Allah, Hajjaj H M; Huang, Shih-Ting; Chang, Tzu Ting; Chen, Chia-Ling; Wu, Han-Chung; Li, Wen-Shan

    2016-09-15

    Building on the initial successful optimization of a novel series of tetraindoles, a second generation of the compounds with changes in the core phenyl ring was synthesized to improve anticancer properties. 17 new compounds with different rigidity, planarity, symmetry and degree of conjugation of their core structures to 5-hydroxyindole units were synthesized. All the compounds were fully characterized and tested against breast cancer cell line (MDA-MB-231). The results revealed that the core structure is required for activity and it should be aromatic, rigid, planar, symmetrical and conjugated for optimal activity. Compound 29, which has strong anticancer activity against various tumor-derived cell lines, including Mahlavu (hepatocellular), SK-HEP-1 (hepatic), HCT116 (colon), MIA PaCa-2 (pancreatic), H441 (lung papillary), A549 (lung), H460 (non-small cell lung) and CL1-5 (lung carcinoma) with IC50 values ranging from 0.19 to 3.50μM, was generated after series of successive optimizations. It was found to induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in the non-obese diabetic-severe combined immunodeficiency (NOD/SCID) mice bearing xenografted MIA PaCa-2 human pancreatic cancer. PMID:27503685

  20. Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels.

    PubMed

    Park, Jae H; Carlin, Kevin P; Wu, Gang; Ilyin, Victor I; Musza, Laszlo L; Blake, Paul R; Kyle, Donald J

    2014-08-14

    The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.7 and Nav1.2 channels were investigated. Other tail region modifications to this chimera explored the effects of tail length and tertiary structure on sodium channel activity. In addition, the activity of various C-terminal modifications of the native ProTx II was assayed and resulted in the identification of protoxin II-NHCH3, a molecule with greater potency against Nav1.7 channels (IC50=42 pM) than the original ProTx II. PMID:25026046

  1. Inhibition of monoamine oxidase-A activity in rat brain by synthetic hydrazines: structure-activity relationship (SAR).

    PubMed

    Dar, Ahsana; Khan, Khalid M; Ateeq, Humayun S; Khan, Shagufta; Rahat, Shagufta; Perveen, Shahnaz; Supuran, Claudiu T

    2005-06-01

    A series of hydrazine derivatives was synthesized in order to evaluate their monoamine oxidase A (MAO-A) inhibitory effects. MAO-A inhibitory activity of 4-tosyl benzoic acid carbohydrazide was quite potent, similarly to that of the corresponding 4-benzyloxy-benzoic acid carbohydrazide and its N-cyanoethylated derivative. Structural variations of these compounds, such as the replacement of the 4-substitutent, of the aromatic ring on which the carbohydrazide moiety is grafted, as well as cyclization of the hydrazide moiety in five- or six-membered rings caused either significant decline or complete loss of MAO inhibitory properties. The most active compound (4-tosyl benzoic acid carbohydrazide) was also subjected to the forced swim test, an animal model of depression, eliciting a marked reduction in immobility time in rats, without affecting the locomotor activity, implying that it possesses anti-depressant properties due to inhibition of MAO type-A. PMID:16119198

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

    PubMed

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

    2016-05-01

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

  3. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship

    NASA Astrophysics Data System (ADS)

    Akhtar, Muhammad Nadeem; Sakeh, Nurshafika M.; Zareen, Seema; Gul, Sana; Lo, Kong Mun; Ul-Haq, Zaheer; Shah, Syed Adnan Ali; Ahmad, Syahida

    2015-04-01

    Browning of fruits and vegetables is a serious issue in the food industry, as it damages the organoleptic properties of the final products. Overproduction of melanin causes aesthetic problems such as melisma, freckles and lentigo. In this study, a series of chalcones (1-10) have been synthesized and examined for their tryrosinase inhibitory activity. The results showed that flavokawain B (1), flavokawain A (2) and compound 3 were found to be potential tyrosinase inhibitors, indicating IC50 14.20-14.38 μM values. This demonstrates that 4-substituted phenolic compound especially at ring A exhibited significant tyrosinase inhibition. Additionally, molecular docking results showed a strong binding affinity for compounds 1-3 through chelation between copper metal and ligands. The detailed molecular docking and SARs studies correlate well with the tyrosinase inhibition studies in vitro. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and single X-ray crystallographic techniques. These findings could lead to design and discover of new tyrosinase inhibitors to control the melanine overproduction and overcome the economic loss of food industry.

  4. Isomer-specific biodegradation of nonylphenol in an activated sludge bioreactor and structure-biodegradability relationship.

    PubMed

    Lu, Zhijiang; Reif, Rubén; Gan, Jay

    2015-01-01

    Nonylphenol (NP), one of the priority hazardous substances, is in fact a mixture of numerous isomers. It is inconclusive whether or not biodegradation during wastewater treatment process is isomer-specific, leading to the environmental release of NP in different isomer profiles. In this study, we evaluated the isomer selectivity of 19 NP isomers in a laboratory-scale continuous flow conventional activated sludge bioreactor under various operational conditions. The removal efficiency of NP isomers ranged from 90 to 99%, depending on the operational conditions and isomer structures. Isomer selective biodegradation resulted in the increase of composition of recalcitrant isomers, such as, NP₁₉₃a/b, NP₁₁₀a and NP₁₉₄ in the effluent. Moreover, biodegradability was related to the bulkiness of α-substituents and followed α-dimethyl > α-ethyl-α-methyl > α-methyl-α-n-propyl > α-iso-propyl-α-methyl. Steric effect index, a quantitative descriptor of steric hindrance, was linearly correlated with residues of NP isomers in the effluent (R² = 0.76). Decrease of temperature to 10 °C decreased the overall biodegradability and also enhanced the relative enrichment of recalcitrant isomers. These findings suggest that isomer compositions of NP entering the environment may be different from those in technical mixtures and that isomeric selectivity should be taken into account to better understand the occurrence, fate, and ecological risks of NP. PMID:25462736

  5. Structure-activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication.

    PubMed

    Di Mola, Antonia; Peduto, Antonella; La Gatta, Annalisa; Delang, Leen; Pastorino, Boris; Neyts, Johan; Leyssen, Pieter; de Rosa, Mario; Filosa, Rosanna

    2014-11-01

    Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus, causes an acute febrile illness in humans, that is, accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts. Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6, respectively, higher than that of ARB (4.6). PMID:25282648

  6. Mammary Carcinogen-Protein Binding Potentials: Novel and Biologically Relevant Structure-Activity Relationship Model Descriptors

    PubMed Central

    Cunningham, A.R.; Qamar, S.; Carrasquer, C.A.; Holt, P.A.; Maguire, J.M.; Cunningham, S.L.; Trent, J.O.

    2010-01-01

    Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen non-carcinogen model had a concordance between experimental and predicted results of 71% and the mammary carcinogen non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and estrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin, the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets. PMID:20818582

  7. Biosynthesis, Chemical Structure, and Structure-Activity Relationship of Orfamide Lipopeptides Produced by Pseudomonas protegens and Related Species.

    PubMed

    Ma, Zongwang; Geudens, Niels; Kieu, Nam P; Sinnaeve, Davy; Ongena, Marc; Martins, José C; Höfte, Monica

    2016-01-01

    Orfamide-type cyclic lipopeptides (CLPs) are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study, we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudomonas species. Genetic characterization together with chemical identification revealed that the main orfamide compound produced by the P. protegens group is orfamide A, while the related strains Pseudomonas sp. CMR5c and CMR12a produce orfamide B. Comparison of orfamide fingerprints led to the discovery of two new orfamide homologs (orfamide F and orfamide G) in Pseudomonas sp. CMR5c. The structures of these two CLPs were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. Mutagenesis and complementation showed that orfamides determine the swarming motility of parental Pseudomonas sp. strain CMR5c and their production was regulated by luxR type regulators. Orfamide A and orfamide B differ only in the identity of a single amino acid, while orfamide B and orfamide G share the same amino acid sequence but differ in length of the fatty acid part. The biological activities of orfamide A, orfamide B, and orfamide G were compared in further bioassays. The three compounds were equally active against Magnaporthe oryzae on rice, against Rhizoctonia solani AG 4-HGI in in vitro assays, and caused zoospore lysis of Phytophthora and Pythium. Furthermore, we could show that orfamides decrease blast severity in rice plants by blocking appressorium formation in M. oryzae. Taken all together, our study shows that orfamides produced by P. protegens and related species have potential in biological control of a broad spectrum of fungal plant pathogens. PMID:27065956

  8. Biosynthesis, Chemical Structure, and Structure-Activity Relationship of Orfamide Lipopeptides Produced by Pseudomonas protegens and Related Species

    PubMed Central

    Ma, Zongwang; Geudens, Niels; Kieu, Nam P.; Sinnaeve, Davy; Ongena, Marc; Martins, José C.; Höfte, Monica

    2016-01-01

    Orfamide-type cyclic lipopeptides (CLPs) are biosurfactants produced by Pseudomonas and involved in lysis of oomycete zoospores, biocontrol of Rhizoctonia and insecticidal activity against aphids. In this study, we compared the biosynthesis, structural diversity, in vitro and in planta activities of orfamides produced by rhizosphere-derived Pseudomonas protegens and related Pseudomonas species. Genetic characterization together with chemical identification revealed that the main orfamide compound produced by the P. protegens group is orfamide A, while the related strains Pseudomonas sp. CMR5c and CMR12a produce orfamide B. Comparison of orfamide fingerprints led to the discovery of two new orfamide homologs (orfamide F and orfamide G) in Pseudomonas sp. CMR5c. The structures of these two CLPs were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. Mutagenesis and complementation showed that orfamides determine the swarming motility of parental Pseudomonas sp. strain CMR5c and their production was regulated by luxR type regulators. Orfamide A and orfamide B differ only in the identity of a single amino acid, while orfamide B and orfamide G share the same amino acid sequence but differ in length of the fatty acid part. The biological activities of orfamide A, orfamide B, and orfamide G were compared in further bioassays. The three compounds were equally active against Magnaporthe oryzae on rice, against Rhizoctonia solani AG 4-HGI in in vitro assays, and caused zoospore lysis of Phytophthora and Pythium. Furthermore, we could show that orfamides decrease blast severity in rice plants by blocking appressorium formation in M. oryzae. Taken all together, our study shows that orfamides produced by P. protegens and related species have potential in biological control of a broad spectrum of fungal plant pathogens. PMID:27065956

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

    PubMed

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

    2015-07-15

    Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired. PMID:26004577

  10. 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

  11. Amide-Modified Prenylcysteine based Icmt Inhibitors: Structure Activity Relationships, Kinetic Analysis and Cellular Characterization

    PubMed Central

    Majmudar, Jaimeen D.; Hodges-Loaiza, Heather B.; Hahne, Kalub; Donelson, James L.; Song, Jiao; Shrestha, Liza; Harrison, Marietta L.; Hrycyna, Christine A.; Gibbs, Richard A.

    2012-01-01

    Human protein isoprenylcysteine carboxyl methyltransferase (hIcmt) is the enzyme responsible for the α-carboxyl methylation of the C-termimal isoprenylated cysteine of CaaX proteins, including Ras proteins. This specific posttranslational methylation event has been shown to be important for cellular transformation by oncogenic Ras isoforms. This finding led to interest in hIcmt inhibitors as potential anti-cancer agents. Previous analog studies based on N-acetyl-S-farnesylcysteine identified two prenylcysteine-based low micromolar inhibitors (1a and 1b) of hIcmt, each bearing a phenoxyphenyl amide modification. In this study, a focused library of analogs of 1a and 1b was synthesized and screened versus hIcmt, delineating structural features important for inhibition. Kinetic characterization of the most potent analogs 1a and 1b established that both inhibitors exhibited mixed-mode inhibition and that the competitive component predominated. Using the Cheng – Prusoff method, the Ki values were determined from the IC50 values. Analog 1a has a KIC of 1.4 ± 0.2 μM and a KIU of 4.8 ± 0.5 μM while 1b has a KIC of 0.5 ± 0.07 μM and a KIU of 1.9 ± 0.2 μM. Cellular evaluation of 1b revealed that it alters the subcellular localization of GFP-KRas, and also inhibits both Ras activation and Erk phosphorylation in Jurkat cells. PMID:22142613

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

    PubMed

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

    2016-04-01

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

  13. Studying the explanatory capacity of artificial neural networks for understanding environmental chemical quantitative structure-activity relationship models.

    PubMed

    Yang, Lei; Wang, Peng; Jiang, Yilin; Chen, Jian

    2005-01-01

    Although artificial neural networks (ANNs) have been shown to exhibit superior predictive power in the study of quantitative structure-activity relationships (QSARs), they have also been labeled a "black box" because they provide little explanatory insight into the relative influence of the independent variables in the predictive process so that little information on how and why compounds work can be obtained. Here, we have turned our interests to their explanatory capacities; therefore, a method was proposed for assessing the relative importance of variables indicating molecular structure, on the basis of axon connection weights and partial derivatives of the ANN output with respect to its input, which can identify variables that significantly contribute to network predictions, and providing a variable selection method for ANNs. We show that, by extending this approach to ANNs, the "black box" mechanics of ANNs can be greatly illuminated, thereby making it very useful in understanding environmental chemical QSAR models. PMID:16309287

  14. Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies.

    PubMed

    Nuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, Daniele

    2016-03-23

    4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation. PMID:26866968

  15. Synthesis and structure-activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors

    PubMed Central

    Titchenell, Paul M.; Hollis Showalter, H. D.; Pons, Jean-François; Barber, Alistair J.; Jin, Yafei

    2013-01-01

    Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NFκB driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. PMID:23566515

  16. Insights into the structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives.

    PubMed

    Berger, Gilles; Fusaro, Luca; Luhmer, Michel; Czapla-Masztafiak, Joanna; Lipiec, Ewelina; Szlachetko, Jakub; Kayser, Yves; Fernandes, Daniel L A; Sá, Jacinto; Dufrasne, François; Bombard, Sophie

    2015-07-01

    The structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid-base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles. PMID:25982100

  17. Steric structure-activity relationship of cyproheptadine derivatives as inhibitors of histone methyltransferase Set7/9.

    PubMed

    Fujiwara, Takashi; Ohira, Kasumi; Urushibara, Ko; Ito, Akihiro; Yoshida, Minoru; Kanai, Misae; Tanatani, Aya; Kagechika, Hiroyuki; Hirano, Tomoya

    2016-09-15

    Set7/9 is a histone lysine methyltransferase, but it is also thought to be involved in a wide variety of pathophysiological functions. We previously identified cyproheptadine, which has a characteristic butterfly-like molecular conformation with bent tricyclic dibenzosuberene and chair-form N-methylpiperidine moieties, as a Set7/9 inhibitor. In this work, we synthesized several derivatives in order to examine the steric structure-inhibitory activity relationship. We found that even a small change of molecular shape due to reduction or replacement of the 10,11-olefinic bond of the tricyclic ring generally resulted in a drastic decrease of the inhibitory activity. Our results should be useful not only for development of more potent and selective inhibitors, but also for the construction of novel inhibitor scaffolds. PMID:27448773

  18. 1,5-Benzodiazepine derivatives as potential antimicrobial agents: design, synthesis, biological evaluation, and structure-activity relationships.

    PubMed

    Wang, Lan-Zhi; Li, Xiao-Qing; An, Ying-Shuang

    2015-05-21

    36 Novel 1,5-benzodiazepine derivatives were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,5-benzodiazepines, thiophene or thiazole and ester group. The structures of the target compounds have been characterized by IR, (1)H NMR, (13)C NMR, MS and elemental analysis. The structure of 1v was further determined using X-ray single crystal diffraction. All synthesized 1,5-benzodiazepine derivatives were evaluated for their in vitro antimicrobial activity against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. The bioactive assay results revealed that most of the 1,5-benzodiazepine derivatives exhibited considerable potency against all of the tested strains. In particular, compounds 1v and 1w (MIC: 2-6 μg mL(-1), MFC: 10-14 μg mL(-1)) exhibited excellent antifungal activity and were found to be 32-64 and 9-12.8 times more potent than the reference drugs against C. neoformans, respectively. Moreover, compound (MIC: 40 μg mL(-1)) displayed equipotent antibacterial activity against E. coli and S. aureus compared to the reference drugs. The most potent of the synthesized compounds 1v and 1w were further studied by evaluating their cytotoxicities, and the results showed that they had relatively low level cytotoxicity for BV2 cell. A preliminary study of the structure-activity relationship revealed that substituents in the phenyl ring and the thiophene ring had a great effect on the antimicrobial activity of these compounds. In addition, the thiazole ring at C2 may be a pharmacophore of these compounds and COOC2H5 group at C3 is the best substituent for the maintenance of antimicrobial activities at low concentrations (1.5625 μg per disc). PMID:25875695

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

    PubMed

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

    2015-08-01

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

  20. Structure-Activity Relationships of a Novel Pyranopyridine Series of Gram-negative Bacterial Efflux Pump Inhibitors

    PubMed Central

    Nguyen, Son T.; Kwasny, Steven M.; Ding, Xiaoyuan; Cardinale, Steven C.; McCarthy, Courtney T.; Kim, Hong-Suk; Nikaido, Hiroshi; Peet, Norton P.; Williams, John D.; Bowlin, Terry L.; Opperman, Timothy J.

    2015-01-01

    Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli. PMID:25818767

  1. A glutathione S-transferase inducer from papaya: rapid screening, identification and structure-activity relationship of isothiocyanates.

    PubMed

    Nakamura, Y; Morimitsu, Y; Uzu, T; Ohigashi, H; Murakami, A; Naito, Y; Nakagawa, Y; Osawa, T; Uchida, K

    2000-09-01

    We have developed a simple system for rapid detection and measurement of glutathione S-transferase placental form (GSTP1) that detoxify polycyclic aromatic hydrocarbons using the cultured rat normal liver epithelial cell line, (RL34) cells. Survey of fruit extracts for GST inducing ability identified both papaya and avocado as significant sources. Benzyl isothiocyanate (BITC) was isolated from papaya methanol extract as a principal inducer of GST activity. Further, the GST inducing ability of a total of 20 isothiocyanates (ITCs) and their derivatives was investigated. Some ITCs showed significant induction, and BITC was one of the most potent inducers among all compounds tested in the present study. The modification of isothiocyanate group (-NCS) or introduction of substituent group to the alpha-carbon modifies GST induction. Moreover, a significant correlation (P<0.01, r=0.913) between the GST activity enrichment and GSTP1 protein induction by ITCs was observed. We also indicated that phenethyl ITC and nitrophenyl ITC, potently inducing GST activity, but not inactive benzyl isocyanate, are potential inducers of intracellular reactive oxygen intermediates (ROIs). Our system of GSTP1 induction is appropriate for the chemical research such as screening and identification of novel type of inducers as well as the structure-activity relationship studies, providing mechanistic insight into essential structural elements for GSTP1 induction. PMID:10936680

  2. Design, synthesis and investigation on the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.

    PubMed

    Pieroni, Marco; Wan, Baojie; Cho, Sanghyun; Franzblau, Scott G; Costantino, Gabriele

    2014-01-24

    Tuberculosis (TB) is one of the deadliest infectious diseases of all times, and its recent resurgence is a supreme matter of concern. Co-infection with HIV and, in particular, the continuous isolation of new resistant strains, makes the discovery of novel anti-TB agents a strategic priority. The research of novel agents should be driven by the accessibility of the synthetic procedure and, in particular, by the lack of cross-resistance with the drugs already marketed. Moreover, in order to shorten the duration of the therapy, and therefore decrease the rate of resistance, these molecules should be active also against the nonreplicating persistent form (NRP-TB) of the infection. The availability of an in-house small library of compounds prompted us to investigate their anti-TB activity. Two compounds, embodying a 2-aminothiazole scaffold, were found to possess a certain inhibitory activity toward Mycobacterium tuberculosis H37Rv, and therefore a medicinal chemistry campaign was initiated in order to increase the activity of the hit compounds and, especially, construct a plausible body of structure-activity relationships. The potency of the hit compound was successfully improved, and, much more importantly, some of the molecules synthesized were found to be active toward the persistent phenotype, and, also, toward a panel of resistant strains. These findings encourage further investigations around this interesting antitubercular chemotype. PMID:24333612

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

    PubMed

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

    2001-10-01

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

  4. Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives.

    PubMed

    Gao, Jing; Chen, Ming; Tong, Xue; Zhu, He; Yan, Hongbin; Liu, Daichun; Li, Wanjing; Qi, Shengyu; Xiao, Dake; Wang, Yongzhi; Lu, Yuanyuan; Jiang, Feng

    2015-01-01

    A series of benzo[a]pyrano[2,3-c]phenazine derivatives with a wide range of substitutions at ring C of the benzophenazine were designed and synthesized using the one-pot, four-component domino reactions. The targeted compounds were evaluated for their antitumor activities against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro. The most active compound 6{1,2,1,9} featured the CN and p-dimethylamino phenyl substituents on γ-pyran structure on ring C. Significantly, compound 6{1,2,1,9} was found to have the highest growth inhibitory activity against the HepG2 cell line with IC50 values of 6.71 µM, which was 1.6-fold more potent than positive control anticancer drug Hydroxycamptothecine (HCPT). Furthermore, structure-activity relationship (SAR) studies on the substitutions at ring C were discussed in details. PMID:26369405

  5. Relationships between structure and vascular activity in a series of benzylisoquinolines

    PubMed Central

    Chulia, Susana; Dolores Ivorra, Maria; Martinez, Sonia; Elorriaga, Martin; Valiente, Miguel; Antonia Noguera, Maria; Lugnier, Claire; Advenier, Charles; D'Ocon, Pilar

    1997-01-01

    1D-adrenoceptors are coupled to phosphoinositide metabolism in rat aorta. Unlike papaverine, which has a significant effect on all the PDE isoforms, the three alkaloids assayed did not have an inhibitory effect on the different forms of PDE isolated from bovine aorta. These results provide evidence that papaverine derivatives with a partially or totally reduced isoquinoline ring have a greater affinity for α1-adrenoceptors and a lower affinity for benzothiazepine sites in the Ca2+-channel than papaverine. This structural feature also implies a loss of the inhibitory activity on PDE isoforms. The planarity of the isoquinoline ring (papaverine) impairs the interaction with the α1-adrenoceptor site and facilitates it with the Ca2+-channels and PDEs, whereas the more flexible tetrahydroisoquinoline ring increases the binding to α1-adrenoceptors. PMID:9351495

  6. DNA adducts in human carcinogenesis: etiological relevance and structure-activity relationship.

    PubMed

    Bartsch, H

    1996-06-01

    Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3

  7. Structural and Lithologic Characteristics of the Wenchuan Earthquake Fault Zone and its Relationship with Seismic Activity

    NASA Astrophysics Data System (ADS)

    Wang, H.; Li, H.; Pei, J.; Li, T.; Huang, Y.; Zhao, Z.

    2010-12-01

    The Wenchuan earthquake (Ms 8.0) struck the Longmen Shan area, the eastern margin of the Tibetan Plateau in Sichuan, China.It produced a large co-seismic surface rupture zone along the Yingxiu-Beichuan and Guanxian-Anxian fault zones. Our research focuses on the central fault of the Longmuanshan fault belt: the Yingxiu-Beichuan fault zone. Detailed studies were done on the coseismic surface rupture in Bajiaomiao village, Hongkou town. Combining with analyses of the cores from the No.1 Well of the Wenchuan Earthquake Fault Scientific Drilling (WFSD-1) Project, the composition features and structures of the Longmenshan fault belt are discussed. Our research indicates that the Yingxiu-Beichuan fault zone is composed of many small sub-faults (damage zone), which consist of fault breccia, cataclasite and/or fault gouge, and small amounts pseudotachylite in some faults. The thickness of the gouge in the fault zone ranges from several millimeters to 25 centimeters, which is consistent with the fault characteristics recorded in the cores of WFSD-1. Gouge is the product of the frictional effect during the earthquake, representing the principal slip zone (PSZ). The width of the Yingxiu-Beichuan fault zone is about 120 m viewed from outcrops in Bajiaomiao village. More than 80 small sub-faults that contain gouge are distributed in this area. Only several millimeters to approximately 2 centimeters gouge can be formed in one earthquake, from the results of the Taiwan Chelungpu-fault Drilling Project (TCDP) and Wenchuan Earthquake Fault Scientific Drilling (WFSD) Project, so we can infer that each layer of gouge in Yingxiu-Beichuan fault zone might be produced by at least 1 to 13 large earthquakes. The total thickness of the gouge in this area is about 150 cm, indicating at least 183 earthquake events, and suggesting that strong earthquakes repeatedly occurred along the Yingxiu-Beichuan fault zone. Each earthquake does not completely slip along the principal slip zone (PSZ) of

  8. Peroxisome induction potential and lipid-regulating activity in rats. Quantitative microscopy and chemical structure-activity relationships.

    PubMed Central

    McGuire, E. J.; Lucas, J. A.; Gray, R. H.; de la Iglesia, F. A.

    1991-01-01

    Structurally diverse lipid-regulating agents induce hepatomegaly, hepatic peroxisome proliferation, and hepatocarcinoma in rats by mechanisms not fully understood. Nevertheless the initial hepatic response is a prompt, florid proliferation of peroxisomes. In investigations reported here, changes in the rat hepatic peroxisome compartment were measured by quantitative microscopy to determine chemical structure requirements that relate to peroxisome proliferation and lipid regulation. Aryloxyalkanoic acids plus amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and generally decreased plasma triglyceride and total cholesterol levels. These compounds contain an acidic function or are readily metabolized to a chemical with an acidic function. Substitution of the acidic function with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on lipid profile, increasing triglycerides and decreasing total cholesterol. A previously unreported, direct correlation emerged between peroxisome proliferation and plasma high-density lipoprotein-cholesterol levels. These effects could not be elicited separately, negating identification of functional groups that could be associated with either activity. Chemical structure and resulting peroxisome proliferation with changes in plasma lipoproteins are therefore closely interrelated in rats. Images Figure 1 PMID:1853935

  9. Structure-activity relationships in aminosterol antibiotics: the effect of stereochemistry at the 7-OH group.

    PubMed

    Tessema, Tsemre-Dingel; Gassler, Frank; Shu, Youheng; Jones, Stephen; Selinsky, Barry S

    2013-06-01

    Squalamine and three aminosterol analogs have been shown to inhibit bacterial cell growth and induce lysis of large unilamellar phospholipid vesicles. The analogs differ in the identity of the polyamine attached at C3 of the sterol, and the stereochemistry of a hydroxyl substituent at C7. Analogs with a tetraammonium spermine polyamine are somewhat more active than analogs with a shorter trisammonium spermidine polyamine, and analogs with an axial (α) hydroxyl substituent at C7 are more active than analogs with the corresponding equatorial (β) hydroxyl group. There is some variability noted; the 7β-OH spermine analog is the most active compound against Escherichia coli, but the least effective against Pseudomonas aeruginosa. Lytic activity correlates well with antimicrobial activity of the compounds, but the lytic activity varies with the phospholipid composition of the vesicles. PMID:23618624

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

    PubMed

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

    2016-10-01

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

  11. Structure-Activity Relationship Studies on the Mosquito Toxicity and Biting Deterrency of Callicarpenal Derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Callicarpenal (13,14,15,16-tetranor-3-cleroden-12-al) has previously demonstrated significant mosquito bite-deterring activity against Aedes aegypti and Anopheles stephensi in addition to repellent activity against host-seeking nymphs of the blacklegged tick, Ixodes scapularis. In the present study...

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

    PubMed

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

    2016-06-01

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

  13. Application of PCA and HCA to the Structure-Activity Relationship Study of Fluoroquinolones

    NASA Astrophysics Data System (ADS)

    Li, Xiao-hong; Zhang, Xian-zhou; Cheng, Xin-lu; Yang, Xiang-dong; Zhu, Zun-lue

    2006-04-01

    Density functional theory (DFT) was used to calculate molecular descriptors (properties) for 12 fluoroquinolone with anti-S.pneumoniae activity. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to reduce dimensionality and investigate in which variables should be more effective for classifying fluoroquinolones according to their degree of an-S.pneumoniae activity. The PCA results showed that the variables ELUMO, Q3, Q5, QA, logP, MR, VOL and ΔEHL of these compounds were responsible for the anti-S.pneumoniae activity. The HCA results were similar to those obtained with PCA. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-S.pneumoniae activity. By using the chemometric results, 6 synthetic compounds were analyzed through the PCA and HCA and two of them are proposed as active molecules with anti-S.pneumoniae, which is consistent with the results of clinic experiments.

  14. The pharmacology of batrachotoxin. VII. Structure-activity relationships and the effects of pH.

    PubMed

    Warnick, J E; Albuquerque, E X; Onur, R; Jansson, S E; Daly, J; Tokuyama, T; Witkop, B

    1975-04-01

    The effects of the depolarizing agent, batrachotoxin (BTX), and of various analogs were studied on rat phrenic nerve-diaphragm muscle preparations at 37 degrees C. The structural modifications of BTX included: 1) replacement of the 20alpha-pyrrole-3-carboxylate moiety; 2) alterations of substituents on the pyrrole moiety; 3) clevage of the 3alpha, 9alpha-hemiketal linkage; and 4) quaternization of the tertiary nitrogen of BTX. All of the compounds except batrachotoxinin A (BTX-A), which lacks the 20alpha-substituent, depolarized the postsynaptic membrane, transiently increased the frequency of spontaneous transmitter release to 400 to 600 sec- minus 1 and finally produced blockade of the directly and indirectly elicited muscle twitches. Of the compounds tested, only BTX-A potentiated the muscle twitches. The concentration which elicits a 50% depolarization of the muscle membrane in 1 hour was determined for all the compounds except for BTX-A and for dihydrobatrachotoxin which lacks the 3alpha, 9alpha-hemiketal linkage; these two analogs never depolarized the postsynaptic membrane by more than 10 to 15%. BTX, the 20alpha-2, 4, 5-trimethylpyrrole-3-carboxylate of BTX-A and the 20alpha-ester of BTX-A with 2-ethyl-4-methylpyrrole-3-carboxylic acid (homobatrachotoxin) were the three most potent toxins with doses of 4.5, 12 and 18 times 10- minus 9 M eliciting a 50% membrane depolarization in 1 hour. The quaternary derivative of BTX, the 20alpha-4, 5-dimethylpyrrole-3-carboxylate of BTX-A and 20alpha-2,4-dimethyl-5-acetylpyrrole-3-carboxylate of BTX-A were 24-, 65- and 110-fold less potent than BTX as depolarizing agents, whereas the 20alpha-p-bromobenzoate of BTX-A was 220-fold less potent. Each of these derivatives had the ability to increase sodium permeability since the increase in spontaneous miniature end-plate potential frequency and membrane depolarization were reversed by tetrodotoxin or by reducing the external sodium concentration. BTX was found to be more

  15. Synthesis and Structure-Activity Relationships of Tambjamines and B-Ring Functionalized Prodiginines as Potent Antimalarials.

    PubMed

    Kancharla, Papireddy; Kelly, Jane Xu; Reynolds, Kevin A

    2015-09-24

    Synthesis and antimalarial activity of 94 novel bipyrrole tambjamines (TAs) and a library of B-ring functionalized tripyrrole prodiginines (PGs) against a panel of Plasmodium falciparum strains are described. The activity and structure-activity relationships demonstrate that the ring-C of PGs can be replaced by an alkylamine, providing for TAs with retained/enhanced potency. Furthermore, ring-B of PGs/TAs can be substituted with short alkyl substitutions at either 4-position (replacement of OMe) or 3- and 4-positions without impacting potency. Eight representative TAs and two PGs have been evaluated for antimalarial activity against multidrug-resistant P. yoelii in mice in the dose range of 5-100 mg/kg × 4 days by oral administration. The KAR425 TA offered greater efficacy than previously observed for any PG, providing 100% protection to malaria-infected mice until day 28 at doses of 25 and 50 mg/kg × 4 days, and was also curative in this model in a single oral dose (80 mg/kg). This study presents the first account of antimalarial activity in tambjamines. PMID:26305125

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

    PubMed

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

    2013-08-15

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

  17. Structure Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

    PubMed Central

    Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J.; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V.; Tekwani, Babu L.; Madgula, Vamsi; Khan, Shabana I.; Wang, Bin; Mayer, Alejandro M. S.; Jacob, Melissa R.; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T.

    2010-01-01

    Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinol isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g. Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3β (GSK-3β), which is a putative target of manzamines. Based on the results presented here it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases. PMID:20017491

  18. Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups.

    PubMed

    Obata, R; Sunazuka, T; Li, Z; Tian, Z; Harigaya, Y; Tabata, N; Tomoda, H; Omura, S

    1996-11-01

    Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase (ACAT) activity in vitro and to lower cholesterol absorption in vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) improved the in vitro ACAT inhibitory activity (IC50 = 13 nM) about 7 times better than pyripyropene A. Introduction of methanesulfonyl group at 11-hydroxyl group (17a) increased both in vitro activity (IC50 = 19 nM) and in vivo efficacy (ED50 = 10 mg/kg). PMID:8982343

  19. Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues

    NASA Astrophysics Data System (ADS)

    Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

    2014-03-01

    A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

  20. Quantitative relationships between structure and cytotoxic activity of flavonoid derivatives. An application of Hirshfeld surface derived descriptors.

    PubMed

    Kupcewicz, Bogumiła; Małecka, Magdalena; Zapadka, Mariusz; Krajewska, Urszula; Rozalski, Marek; Budzisz, Elzbieta

    2016-07-15

    Quantitative relationships between the structure and cytotoxic activity of series flavonoid derivatives were examined. The first regression-based model, developed for 18 flavanone-2-pyrazoline hybrids, involved two interpretable descriptors: a Mor04v and partial atomic charge. The second model, developed for structurally diverse set of compounds, was based on descriptors derived from Hirshfeld surface analysis. This model suggests that cytotoxic activity of compounds can be successfully predicted based on a fraction of H⋯H contacts and a fraction of interactions involving a halogen atom. For non-halogen derivatives, the data reveal that cytotoxic activity is inversely proportional to the percentage of O⋯H and N⋯H close contacts to Hirshfeld surface, while directly proportional to the percentage of H⋯H interactions. Chlorine (1k) and bromine (1l) derivatives of compounds, containing flavanone fused with N-methyl-2-pyrazoline, exhibited high cytotoxic potential against HL-60 cancer cell line (IC50<10μM). The cytotoxicity of 1k and 1l towards normal cells (HUVEC) was 10 and 25-fold lower, respectively. PMID:27234147

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

    PubMed

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

    2015-06-01

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

  2. 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. PMID:26854381

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

    PubMed

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

    2015-12-10

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

  4. Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships.

    PubMed

    Brandt, Gary E L; Schmidt, Matthew D; Prisinzano, Thomas E; Blagg, Brian S J

    2008-10-23

    Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree ( Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified. PMID:18816111

  5. Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors

    SciTech Connect

    Williams, David K; Chen, Xiao-Tao; Tarby, Christine; Kaltenbach, Robert; Cai, Zhen-Wei; Tokarski, John S; An, Yongmi; Sack, John S; Wautlet, Barri; Gullo-Brown, Johnni; Henley, Benjamin J; Jeyaseelan, Robert; Kellar, Kristen; Manne, Veeraswamy; Trainor, George L; Lombardo, Louis J; Fargnoli, Joseph; Borzilleri, Robert M

    2010-09-03

    Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

  6. Chemical modification and structure-activity relationships of pyripyropenes. 2. 1,11-Cyclic analogs.

    PubMed

    Obata, R; Sunazuka, T; Kato, Y; Tomoda, H; Harigaya, Y; Omura, S

    1996-11-01

    A series of 1,11-cyclic analogs of pyripyropene A were prepared. Replacement of the 1,11-acyl groups of pyripyropenes with 1,11-cyclic acetals effectively improved in vitro acyl CoA:cholesterol acyltransferase (ACAT) inhibitory activity. Especially noteworthy is benzylidene acetal analog 35, the most potent inhibitor (IC50 = 5.6 nM) among the derivatives prepared so far, which showed 16 times more potent inhibitory activity than pyripyropene A. PMID:8982344

  7. Rational Quantitative Structure-Activity Relationship (RQSAR) Screen for PXR and CAR Isoform-Specific Nuclear Receptor Ligands

    PubMed Central

    Dring, Ann M.; Anderson, Linnea E.; Qamar, Saima; Stoner, Matthew A.

    2010-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

  8. Ethyl cinnamate derivatives as promising high-efficient acaricides against Psoroptes cuniculi: synthesis, bioactivity and structure-activity relationship.

    PubMed

    Zhang, Bingyu; Lv, Chao; Li, Weibo; Cui, Zhiming; Chen, Dongdong; Cao, Fangjun; Miao, Fang; Zhou, Le

    2015-01-01

    This paper reported the synthesis, structure-activity relationship (SAR) and acaricidal activity in vitro against Psoroptes cuniculi, a mange mite, of 25 ethyl cinnamate derivatives. All target compounds were synthesized and elucidated by means of MS, (1)H- and (13)C-NMR analysis. The results showed that 24 out of 25 tested compounds at 1.0 mg/mL demonstrated acaricidal activity in varying degrees. Among them, 6, 15, 26, 27 and 30 showed significant activity with median lethal concentration values (LC50) of 89.3, 119.0, 39.2, 29.8 and 41.2 µg/mL, respectively, which were 2.1- to 8.3-fold the activity of ivermectin (LC50=247.4 µg/mL), a standard drug in the treatment of Psoroptes cuniculi. Compared with ivermectin, with a median lethal time value (LT50) of 8.9 h, 27 and 30 showed smaller LT50 values of 7.9 and 1.3 h, respectively, whereas 6, 15 and 26 showed slightly larger LT50 values of 10.6, 11.0 and 10.4 h at 4.5 µmol/mL. SARs showed that the presence of o-NO2 or m-NO2 on the benzene ring significantly improved the activity, whereas the introduction of a hydroxy, methoxy, acetoxy, methylenedioxy, bromo or chloro group reduced the activity. (E)-Cinnamates were more effective than their (Z)-isomer. Nevertheless, the carbon-carbon double bond in the acrylic ester moiety was proven not to be essential to improve the activity of cinnamic acid esters. Thus, the results strongly indicate that cinnamate derivatives, especially their dihydro derivatives, should be promising candidates or lead compounds for the development of novel acaricides for the effective control of animal or human acariasis. PMID:25739666

  9. Structure-activity relationship studies on chalcone derivatives. the potent inhibition of chemical mediators release.

    PubMed

    Ko, Horng-Huey; Tsao, Lo-Ti; Yu, Kun-Lung; Liu, Cheng-Tsung; Wang, Jih-Pyang; Lin, Chun-Nan

    2003-01-01

    Some chalcones exert potent anti-inflammatory activities. 2',5'-Dialkoxychalcones and 2',5'-dihydroxy-4-chloro-dihydrochalcone inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-activated N9 microglial cells and in LPS-activated RAW 264.7 macrophage-like cells have been demonstrated in our previous reports. These compounds also suppressed the inducible NO synthase (iNOS) expression and cyclooxygenase-2 (COX-2) activity in RAW 264.7 cells. In an effort to continually develop potent anti-inflammatory agent, a series of chalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and then evaluated their inhibitory effects on the activation of mast cells, neutrophils, macrophages, and microglial cells. Most of the 2',5'-dihydroxychaclone derivatives exhibited potent inhibitory effects on the release of beta-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Some chalcones showed potent inhibitory effects on superoxide anion generation in rat neutrophils in response to fMLP/CB. Compounds 1 and 5 exhibited potent inhibitory effects on NO production in macrophages and microglial cells. Compound 11 showed inhibitory effect on NO production and iNOS protein expression in RAW 264.7 cells. The present results demonstrated that most of the 2',5'-dihydroxychaclones have anti-inflammatory effects. The potent inhibitory effect of 2',5'-dihydroxy-dihydrochaclones on NO production in LPS-activated macrophage, probably through the suppression of iNOS protein expression, is proposed to be useful for the relief of septic shock. PMID:12467713

  10. Design, diversity-oriented synthesis and structure activity relationship studies of quinolinyl heterocycles as antimycobacterial agents.

    PubMed

    Rachakonda, Venkatesham; Alla, Manjula; Kotipalli, Sudha Sravanti; Ummani, Ramesh

    2013-01-01

    The current study reports design and diversity oriented synthesis of novel bis heterocycles with a common 2-methyl, C-4 unsubstituted quinoline moiety as the central key heterocycle. Employing reagent based skeletal diversity approach; a facile synthesis of bis heterocycles with different heterocyclic rings at C-3 position of the quinoline moiety has been accomplished. A broad range of heterocyclic frameworks thus obtained were evaluated for their antimycobacterial activity. The active scaffolds were further explored by a parallel library generation in order to establish SAR. Further, low cytotoxicity against A549 cell line enhances the potential of the synthesized molecules as promising antimycobacterial agents. PMID:24189497

  11. Synthesis and structure-activity relationship of benzetimide derivatives as human CXCR3 antagonists.

    PubMed

    Bongartz, Jean-Pierre; Buntinx, Mieke; Coesemans, Erwin; Hermans, Bart; Lommen, Guy Van; Wauwe, Jean Van

    2008-11-01

    The synthesis and evaluation of benzetimide derivatives showing potent CXCR3 antagonism are described. Optimization of the screening hits led to the identification of more potent CXCR3 antagonists devoid of anti-cholinergic activity and identification of the key pharmacophore moieties of the series. PMID:18922694

  12. Discovery and structure activity relationships of 2-pyrazolines derived from chalcones from a pest management perspective

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Synthesis of chalcones and 2-pyrazoline derivatives has been an active field of research due to the established pharmacological effects of these compounds. In this study, a series of chalcone (1a-i), 2-pyrazoline-1-carbothioamides (2a-i) and 2-pyrazoline-1-carboxamide derivatives (3a-g) were synthes...

  13. Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.

    PubMed

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

    2011-10-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

  14. Synthesis and structure-activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents.

    PubMed

    Gao, Chao; Ye, Ting-Hong; Wang, Ning-Yu; Zeng, Xiu-Xiu; Zhang, Li-Dan; Xiong, Ying; You, Xin-Yu; Xia, Yong; Xu, Ying; Peng, Cui-Ting; Zuo, Wei-Qiong; Wei, Yuquan; Yu, Luo-Ting

    2013-09-01

    N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. PMID:23886691

  15. Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inuloxins A-D (1-4) and a-costic acid (5), the phytotoxic compounds previously isolated from Inula viscosa, as well as synthetic derivatives of inuloxin A (compounds 6-10), inuloxin C (compound 11) and inuloxin D (compound 12) were tested in vitro for their activity against Leishmania donovani, the ...

  16. Relationship between Family Structure and Heterosexual Activity in College Aged Women.

    ERIC Educational Resources Information Center

    Hutchison, Theresa; And Others

    College-aged women (N=95) were surveyed to determine the effects of parental divorce on their heterosexual activity and on their attitudes and feelings concerning dating. The 67 participants from divorced families were grouped according to the subject's age when her parents were divorced: 6 years and younger, 7-12 years old, and 13-18 years old.…

  17. Key structure-activity relationships in the vanadium phosphorus oxide catalyst system

    SciTech Connect

    Thompson, M.R. ); Ebner, J.R. )

    1990-04-01

    The crystal structure of vanadyl pyrophosphate has been redetermined using single crystals obtained from a near solidified melt of a microcrystalline catalyst sample. Crystals that index as vanadyl pyrophosphate obtained from this melt are variable in color. Crystallographic refinement of the single crystal x-ray diffraction data indicates that structural differences among these materials can be described in terms of crystal defects associated with linear disorder of the vanadium atoms. The importance of the disorder is outlined in the context of its effect on the proposed surface topology parallel to (1,0,0). Models of the surface topology simply and intuitively account for the non-stoichometric surface atomic P/V ratio exhibited by selective catalysts of this phase. These models also point to the possible role of the excess phosphorus in providing site isolation of reactive centers at the surface. 33 refs., 7 figs.

  18. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  19. Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1

    PubMed Central

    Czikora, Á; Lizanecz, E; Bakó, P; Rutkai, I; Ruzsnavszky, F; Magyar, J; Pórszász, R; Kark, T; Facskó, A; Papp, Z; Édes, I; Tóth, A

    2012-01-01

    BACKGROUND AND PURPOSE The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca2+) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1−/− mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca2+ in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat. PMID:21883148

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

    PubMed

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

    2005-01-01

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

  1. Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure-activity relationship and a pharmacophore model.

    PubMed

    Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam

    2016-09-15

    Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. The structure-activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values. PMID:27353886

  2. 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. PMID:22766422

  3. Structure-Activity Relationship Study of the Neuritogenic Potential of the Glycan of Starfish Ganglioside LLG-3 ‡

    PubMed Central

    Yamagishi, Megumi; Hosoda-Yabe, Ritsuko; Tamai, Hideki; Konishi, Miku; Imamura, Akihiro; Ishida, Hideharu; Yabe, Tomio; Ando, Hiromune; Kiso, Makoto

    2015-01-01

    LLG-3 is a ganglioside isolated from the starfish Linchia laevigata. To clarify the structure-activity relationship of the glycan of LLG-3 toward rat pheochromocytoma PC12 cells in the presence of nerve growth factor, a series of mono- to tetrasaccharide glycan derivatives were chemically synthesized and evaluated in vitro. The methyl group at C8 of the terminal sialic acid residue was crucial for neuritogenic activity, and the terminal trisaccharide moiety was the minimum active motif. Furthermore, the trisaccharide also stimulated neuritogenesis in human neuroblastoma SH-SY5Y cells via mitogen-activated protein kinase (MAPK) signaling. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was rapidly induced by adding 1 or 10 nM of the trisaccharide. The ratio of phosphorylated ERK to ERK reached a maximum 5 min after stimulation, and then decreased gradually. However, the trisaccharide did not induce significant Akt phosphorylation. These effects were abolished by pretreatment with the MAPK inhibitor U0126, which inhibits enzymes MEK1 and MEK2. In addition, U0126 inhibited the phosphorylation of ERK 1/2 in response to the trisaccharide dose-dependently. Therefore, we concluded that the trisaccharide promotes neurite extension in SH-SY5Y cells via MAPK/ERK signaling, not Akt signaling. PMID:26690179

  4. 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. PMID:27012893

  5. Discovery of Tricyclic Clerodane Diterpenes as Sarco/Endoplasmic Reticulum Ca(2+)-ATPase Inhibitors and Structure-Activity Relationships.

    PubMed

    De Ford, Christian; Calderón, Carlos; Sehgal, Pankaj; Fedosova, Natalya U; Murillo, Renato; Olesen, Claus; Nissen, Poul; Møller, Jesper V; Merfort, Irmgard

    2015-06-26

    Tricyclic clerodane diterpenes (TCDs) are natural compounds that often show potent cytotoxicity for cancer cells, but their mode of action remains elusive. A computationally based similarity search (CDRUG), combined with principal component analysis (ChemGPS-NP) and docking calculations (GOLD 5.2), suggested TCDs to be inhibitors of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump, which is also the target of the sesquiterpene lactone thapsigargin. Biochemical studies were performed with 11 TCDs on purified rabbit skeletal muscle sarcoplasmic reticulum membranes, which are highly enriched with the SERCA1a isoform. Casearborin D (2) exhibited the highest affinity, with a KD value of 2 μM and giving rise to complete inhibition of SERCA1a activity. Structure-activity relationships revealed that functionalization of two acyl side chains (R1 and R4) and the hydrophobicity imparted by the aliphatic chain at C-9, as well as a C-3,C-4 double bond, play crucial roles for inhibitory activity. Docking studies also suggested that hydrophobic interactions in the binding site, especially with Phe256 and Phe834, may be important for a strong inhibitory activity of the TCDs. In conclusion, a novel class of SERCA inhibitory compounds is presented. PMID:25993619

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

    PubMed Central

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

    2011-01-01

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

  7. Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents.

    PubMed

    Zhou, Shunguang; Liao, Huimin; He, Chao; Dou, Yanan; Jiang, Mingyan; Ren, Lixiang; Zhao, Yanfang; Gong, Ping

    2014-08-18

    A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- to 2.3-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. PMID:24996144

  8. Quantitative structure-activity relationships for skin sensitization potential of urushiol analogues.

    PubMed

    Roberts, D W; Benezra, C

    1993-08-01

    The relative alkylation index (RAI), a theoretically derived parameter intended to quantify the relative extent of carrier haptenation resulting from a given dose of a given sensitizer, has previously been successfully applied to the analysis of relative sensitization potential and dose-response data for a variety of contact allergens which are directly electrophilic. Here the RAI concept is applied to analysis of data on compounds related to urushiol (i.e., 3-substituted catechols), the naturally occurring mixture of allergens responsible for contact allergy to poison ivy and poison oak. These allergens are believed to act as pro-electrophiles, being oxidized to electrophilic orthoquinones in vivo. It is found that the various types of urushiol derivatives fit the same sort of RAI-sensitization relationships as expected theoretically and as found previously with direct acting electrophiles. There is evidence that in many cases, the test conditions were such that overload effects, whereby the degree of sensitization induced decreases with increasing carrier haptenation, applied. It is also concluded that the question as to the relative sensitization potencies of the naturally occurring urushiols remains open. The commonly held view that with these materials, sensitization potential increases with increasing unsaturation in the 3-hydrocarbyl chain of the 3-hydrocarbyl catechols, is based on evidence that is capable of alternative interpretation. PMID:8365181

  9. Long-acting contraceptive agents: structure activity relationships in a series of norethisterone and levonorgestrel esters.

    PubMed

    Bialy, G; Blye, R P; Enever, R P; Naqvi, R H; Lindberg, M C

    1983-03-01

    A large number of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling mature rats. In the norethisterone series several esters exhibited duration of activity comparable to that of norethisterone enanthate. In the levonorgestrel series the butanoic, cyclobutylcarboxylic and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methylpregn-4-ene-3,20-dione) when prepared as aqueous microcrystalline suspensions. PMID:6419411

  10. Structure-activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport.

    PubMed

    Miyata, Ken-Ichi; Nakagawa, Yoshiaki; Kimura, Yasuhisa; Ueda, Kazumitsu; Akamatsu, Miki

    2016-07-15

    We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation. PMID:27262425

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

    SciTech Connect

    Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D.

    2009-07-10

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

  12. Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

    PubMed

    Green, Jeremy; Cao, Jingrong; Bandarage, Upul K; Gao, Huai; Court, John; Marhefka, Craig; Jacobs, Marc; Taslimi, Paul; Newsome, David; Nakayama, Tomoko; Shah, Sundeep; Rodems, Steve

    2015-06-25

    The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation. PMID:26039570

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

    PubMed

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

    2015-12-15

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

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

    PubMed

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

    2016-10-01

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

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

  16. Aedes aegypti (Diptera: Culicidae) biting deterrence: structure-activity relationship of saturated and unsaturated fatty acids.

    PubMed

    Ali, Abbas; Cantrell, Charles L; Bernier, Ulrich R; Duke, Stephen O; Schneider, John C; Agramonte, Natasha M; Khan, Ikhlas

    2012-11-01

    In this study we evaluated the biting deterrent effects of a series of saturated and unsaturated fatty acids against Aedes aegypti (L), yellow fever mosquito (Diptera: Culicidae) using the K & Dbioassay module system. Saturated (C6:0 to C16:0 and C18:0) and unsaturated fatty acids (C11:1 to C14:1, C16:1, C18:1, and C18:2) showed biting deterrence index (BDI) values significantly greater than ethanol, the negative control. Among the saturated fatty acids, mid chain length acids (C10:0 to C13:0) showed higher biting deterrence than short (C6:0 to C9:0) and long chain length acids (C14:0 to C18:0), except for C8:0 and C16:0 that were more active than the other short and long chain acids. The BDI values of mid chain length acids (C10:0 to C13:0) were not significantly less than N, N-diethyl-meta-toluamide (DEET), the positive control. Among the unsaturated fatty acids, C11:1 showed the highest activity (BDI = 1.05) and C18:2 had the lowest activity (BDI = 0.7). In C11:1, C12:1, and C14:1 BDI values were not significantly less than DEET. After the preliminary observations, residual activity bioassays were performed on C11:0, C12:0, C11:1, and C12:1 over a 24-h period. All the fatty acids (C11:0, C12:0, C11:1, and C12:1) and DEET showed significantly higher activity at all test intervals than the solvent control. At treatment and 1-h posttreatment, all fatty acids showed proportion not biting (PNB) values not significantly less than DEET. At 3-, 6-, and 12-h posttreatment, all fatty acids showed PNB values significantly greater than DEET. At 24-h posttreatment, only the PNB value for C12:0 was significantly higher than DEET. The dose-responses of C12:0 and DEET were determined at concentrations of 5-25 nmol/cm2. As in the residual activity bioassays, the PNB values for C12:0 and DEET at 25 nmol/cm(2) were not significantly different. However, at lower concentrations, the PNB values for C12:0 were significantly greater than DEET. These results clearly indicate that mid

  17. Structure-olfactory activity relationship in a group of substituted phenols.

    PubMed

    Kaliszan, R; Pankowski, M; Szymula, L; Lamparczyk, H; Nasal, A; Tomaszewska, B; Grzybowski, J

    1982-07-01

    Using phenol as the standard relative olfactory thresholds have been determined for a series of substituted phenols in experiments with 8--10 human subjects. Significant relations have been obtained describing the activity as a square function of the hydrophobicity parameter corrected for ionization. Chromatographic measurement of phenol polarity has been proposed based on retention indices determined on phases of different polarity. The human sense of smell system has been discussed as a model for studies on drug-receptor interactions involving the living organism as a whole. PMID:7134257

  18. HLA-A3 supermotif defined by quantitative structure-activity relationship analysis.

    PubMed

    Guan, Pingping; Doytchinova, Irini A; Flower, Darren R

    2003-01-01

    Activation of a cytotoxic T cell requires specific binding of antigenic peptides to major histocompatibility complex (MHC) molecules. This paper reports a study of peptides binding to members of the HLA-A3 superfamily using a recently developed 2D-QSAR method, called the additive method. Four alleles with high phenotype frequency were included in the study: A*0301, A*1101, A*3101 and A*6801. The influence of each of the 20 amino acids at each position of the peptide on binding was studied. A refined A3 supertype motif was defined in the study. PMID:12646688

  19. Structure/antileishmanial activity relationship study of naphthoquinones and dependency of the mode of action on the substitution patterns.

    PubMed

    Ali, Ahmad; Assimopoulou, Andreana Nikolaos; Papageorgiou, Vassilios Peter; Kolodziej, Herbert

    2011-12-01

    A series of naphthoquinones was tested for activity against both extracellular promastigote and intracellular amastigote Leishmania major GFP in vitro. In parallel, the compounds were evaluated for cytotoxic effects against bone marrow-derived macrophages (BMM Φ) as a mammalian host cell control. Most of the compounds noticeably inhibited the growth of extracellular parasites (IC (50) 0.5 to 6 µM) and the intracellular survival of L. major GFP amastigotes (IC (50) 1 to 7 µM) when compared with the antileishmanial drug amphotericin B (IC (50) of 2.5 and 0.2 µM, respectively). In general, antiprotozoal activity and host cell cytotoxicity seemed to increase in parallel. Conspicuously, the cytotoxic effect was less pronounced on infected host cells when compared with that on noninfected cells. Concerning structure/activity relationships for the tested naphthoquinones, some interesting structural features emerged from this study. Introduction of a methyl or methoxyl group at C-2 of the parent 1,4-naphthoquinone slightly increased the antileishmanial activity against clinically relevant amastigotes, while the presence of a hydroxyl function in this position dramatically reduced the effectiveness. In contrast, hydroxylation at C-5 and dihydroxy substitution at C-5 and C-8 significantly enhanced the antiprotozoal activity. Similarly, the presence of a side chain hydroxyl group PERI to a carbonyl function as represented in the series of shikonin/alkannin derivatives increased the activity when compared with substituted analogs. Within the series of naphthoquinones tested, the dimeric mixture of vaforhizin and isovaforhizin showed the highest activity IN VITRO against the clinically relevant intracellular amastigote with an IC (50) of 1.1 µM. With IC (50) values mostly in the range of 1-3 µM, the shikonin/alkannin derivatives proved to be similarly considerably leishmanicidal. None of the compounds tested was capable to induce NO production known to play a

  20. New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.

    PubMed

    Roy, Pierre-Philippe; D'Souza, Kenneth; Cuperlovic-Culf, Miroslava; Kienesberger, Petra C; Touaibia, Mohamed

    2016-08-01

    Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities. PMID:27155760

  1. Molecular orbital studies on the structure-activity relationships of catechol O-methyltransferase inhibitors.

    PubMed

    Shinagawa, Y

    1992-02-01

    Quantum chemical studies were applied to analyze the activities of catechol O-methyltransferase (COMT) inhibitors. Molecular orbital calculations of inhibitor molecules were made by semi-empirical molecular orbital calculations, CNDO/2 (complete neglect of differential overlap) methods. Regression analysis among theoretical reaction indices based on the frontier electron theory and COMT inhibitory activities were carried out. The COMT inhibitory actions of two series of inhibitors, a series of 1,5-substituted 3,4-dihydroxy benzenes and a series of substituted 3-hydroxy-4-methoxy benzenes, were investigated. The resulting regression equations contain two common reaction indices as regression variables: the electron density on the oxygen atom of the hydroxyl group and the super-delocalizability on the 5th carbon atom of the benzene ring. These two atomic positions are considered to play an important role in the interaction of these inhibitors with COMT. The hydroxyl of atomic position 3 is probably indispensable to the COMT inhibitory action by these inhibitors. PMID:1507526

  2. Structure-property-composition relationships in doped zinc oxides: enhanced photocatalytic activity with rare earth dopants.

    PubMed

    Goodall, Josephine B M; Illsley, Derek; Lines, Robert; Makwana, Neel M; Darr, Jawwad A

    2015-02-01

    In this paper, we demonstrate the use of continuous hydrothermal flow synthesis (CHFS) technology to rapidly produce a library of 56 crystalline (doped) zinc oxide nanopowders and two undoped samples, each with different particle properties. Each sample was produced in series from the mixing of an aqueous stream of basic zinc nitrate (and dopant ion or modifier) solution with a flow of superheated water (at 450 °C and 24.1 MPa), whereupon a crystalline nanoparticle slurry was rapidly formed. Each composition was collected in series, cleaned, freeze-dried, and then characterized using analytical methods, including powder X-ray diffraction, transmission electron microscopy, Brunauer-Emmett-Teller surface area measurement, X-ray photoelectron spectroscopy, and UV-vis spectrophotometry. Photocatalytic activity of the samples toward the decolorization of methylene blue dye was assessed, and the results revealed that transition metal dopants tended to reduce the photoactivity while rare earth ions, in general, increased the photocatalytic activity. In general, low dopant concentrations were more beneficial to having greater photodecolorization in all cases. PMID:25602735

  3. Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation.

    PubMed

    Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A; Patnaik, Debasis; Fass, Daniel M; Tsai, Li-Huei; Mazitschek, Ralph; Haggarty, Stephen J

    2016-02-15

    Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease. PMID:26804233

  4. Synthesis and Structure-Activity Relationships of Imidazole-Coumarin Conjugates against Hepatitis C Virus.

    PubMed

    Tsay, Shwu-Chen; Lin, Shu-Yu; Huang, Wen-Chieh; Hsu, Ming-Hua; Hwang, Kuo Chu; Lin, Chun-Cheng; Horng, Jia-Cherng; Chen, I-Chia; Hwu, Jih Ru; Shieh, Fa-Kuen; Leyssen, Pieter; Neyts, Johan

    2016-01-01

    A series of new conjugated compounds with a -SCH₂- linkage were synthesized by chemical methods from imidazole and coumarin derivatives. The experimental results indicate that of the twenty newly synthesized imidazole-coumarin conjugates, three of them exhibited appealing EC50 values (5.1-8.4 μM) and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1) position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents. PMID:26901180

  5. Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.

    PubMed

    Arias, Hugo R; Feuerbach, Dominik; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof

    2011-09-01

    The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca²⁺ influx in human embryonic muscle AChRs with the following potency sequence (IC(50) in μM): (±)-18-methylaminocoronaridine (5.9±0.3)∼(±)-18-methoxycoronaridine (18-MC) (6.8±0.8)>(-)-ibogaine (17±3)∼(+)-catharanthine (20±1)>(±)-albifloranine (46±13), (b) bind to the [³H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [³H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [³H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC₅₀) that correlate very well with the pK(i) values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 ų for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization. PMID:21642011

  6. Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester.

    PubMed

    Glaser, Jan; Schultheis, Martina; Hazra, Sudipta; Hazra, Banasri; Moll, Heidrun; Schurigt, Uta; Holzgrabe, Ulrike

    2014-01-01

    Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization. PMID:24473204

  7. 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.

  8. Combating the threat of anthrax: a quantitative structure-activity relationship approach.

    PubMed

    Verma, Rajeshwar P; Hansch, Corwin

    2008-01-01

    Bacterial agents or products more likely to be used as biological weapons of mass destruction are Bacillus anthracis, Francisella tularensis, Yersinia pestis, and the neurotoxin of Clostridium botulinum. Anthrax is an acute infectious disease with a high mortality rate caused by Bacillus anthracis, reinforcing the need for better adjunctive therapy and prevention strategies. In this paper, we developed 7 QSAR models on penicillin-based inhibitors of the class A and B beta-lactamases from B. anthracis and inhibitors of anthrax lethal factor to understand the chemical-biological interactions. Hydrophobic and steric factors are found to be the most important determinants of the activity. Internal (cross-validation ( q (2)), quality factor ( Q), Fischer statistics ( F), and Y-randomization) and external validation tests have validated all the QSAR models. PMID:18611038

  9. Quantitative structure-activity relationship of carbonylcyanide phenylhydrazones as uncouplers of mitochondrial oxidative phosphorylation.

    PubMed

    Baláz, S; Sturdík, E; Durcová, E; Antalík, M; Sulo, P

    1986-08-13

    The dependence of the uncoupling activity in the series of 16 carbonylcyanide phenylhydrazones on their physico-chemical properties (partition coefficient, dissociation constant and rate constant for reaction with thiols) is investigated using two physiologically based models, one for protonophoric mechanism of uncoupling and the other assuming the covalent modification of a membrane constituent to be the key step in this process. As indicated by uptake experiments, at the given conditions a lipophilic-hydrophilic equilibrium is attained without any loss of the compounds via chemical reactions. Using this fact to reduce the number of adjustable parameters, a better fit to the data on stimulation of respiration is obtained with the former (protonophoric) model. PMID:3015209

  10. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.

    PubMed

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

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

    PubMed

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

    2016-07-15

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

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

    PubMed

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

    2012-12-01

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

  13. Investigation of structure-activity relationships in organophosphates-cholinesterase interaction using docking analysis.

    PubMed

    Moralev, Serge N; Tikhonov, Denis B

    2010-09-01

    It is known than the most potent homologues in various series of O,O-dialkylphosphates are the dibutyl or diamyl derivatives toward mammalian cholinesterases (ChEs) (both Acetyl- and Butyryl-ChEs), and the dimethyl or diethyl ones toward insect AChEs. To investigate the ChE interaction with organophosphorus inhibitors (OPIs) in more detail, we have performed in silico docking of the series of O,O-dialkylfluorophosphates into active center of different ChEs - both from mammals (human and mouse AChEs and horse BChE), and from insects (spring grain aphid AChE belonging to AChE-1 type, and housefly AChE belonging to AChE-2 type). According to the modeling results, one radical is directed to the anionic site W84, another to the acyl pocket. In addition to well-known residues 288 and 290 (Torpedo AChE sequence numbering), we showed an essential influence of residue 400 - a short alkyl residue in mammalian ChEs and phenylalanine in insect ChEs. Phenylalanine in this position creates sterical hindrance for proper orientation of the OPI molecule, which increases the distance between the catalytic serine gamma-oxygen and phosphorus, and decreases the angle of nucleophylic attack. This suggestion was supported by docking of dibutylfluorophosphate into the active center of AChEs with in silico mutations. Thus, we suggest both the angle of nucleophylic attack and the distance between the catalytic serine and phosphorus atom as measures of productivity of OPI binding. PMID:20347727

  14. Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    relationships, the structure-antagonistic activity relationships of antagonists and the characteristics of α7 nAChR-ligand recognitions were received a reasonable summary as well. These attempts emerged herein would not only provide helpful guidance for the design of α7 nAChR antagonists, but shed new light on the subsequent researches in antagonistic mechanism. PMID:25963024

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

    PubMed

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

    2004-03-01

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

  16. Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres.

    PubMed

    Gehringer, Matthias; Forster, Michael; Pfaffenrot, Ellen; Bauer, Silke M; Laufer, Stefan A

    2014-11-01

    The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models. PMID:25139757

  17. CLEFMA- An Anti-Proliferative Curcuminoid from Structure Activity Relationship Studies on 3,5-bis(benzylidene)-4-piperidones

    PubMed Central

    Lagisetty, Pallavi; Vilekar, Prachi; Sahoo, Kaustuv; Anant, Shrikant; Awasthi, Vibhudutta

    2010-01-01

    3,5-bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC50 < 30 μM), and sixteen compounds possessed reduced cell-killing efficacy (IC50 > 50 μM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers. PMID:20638855

  18. Structures, Biological Activities and Phylogenetic Relationships of Terpenoids from Marine Ciliates of the Genus Euplotes

    PubMed Central

    Guella, Graziano; Skropeta, Danielle; Di Giuseppe, Graziano; Dini, Fernando

    2010-01-01

    In the last two decades, large scale axenic cell cultures of the marine species comprising the family Euplotidae have resulted in the isolation of several new classes of terpenoids with unprecedented carbon skeletons including the (i) euplotins, highly strained acetylated sesquiterpene hemiacetals; (ii) raikovenals, built on the bicyclo[3.2.0]heptane ring system; (iii) rarisetenolides and focardins containing an octahydroazulene moiety; and (iv) vannusals, with a unique C30 backbone. Their complex structures have been elucidated through a combination of nuclear magnetic resonance spectroscopy, mass spectrometry, molecular mechanics and quantum chemical calculations. Despite the limited number of biosynthetic experiments having been performed, the large diversity of ciliate terpenoids has facilitated the proposal of biosynthetic pathways whereby they are produced from classical linear precursors. Herein, the similarities and differences emerging from the comparison of the classical chemotaxonomy approach based on secondary metabolites, with species phylogenesis based on genetic descriptors (SSU-rDNA), will be discussed. Results on the interesting ecological and biological properties of ciliate terpenoids are also reported. PMID:20714425

  19. Structure-activity relationships of ruthenium Fischer-Tropsch catalysts (metal particle size effects)

    SciTech Connect

    White, M.W. Jr.

    1989-01-01

    In the group VIII transition metal catalytic conversion of hydrogen/carbon monoxide mixtures to hydrocarbons, it is known that certain catalysts catalyze the production of a narrow boiling range (C{sub 6}-C{sub 12}) product which does not fit the traditional Anderson-Schulz-Flory (ASF) chain growth model. Among the proposed explanations for this selectivity is one based on control of hydrocarbon chain propagation by metal particle size. The focus of this work was to study the effect of metal particle size on catalytic activity for the F-T synthesis. The silica-supported and unsupported Ru catalysts catalyzed the production of a hydrocarbon product which followed the ASF chain growth model and which consisted primarily of n-aklanes and linear 1-alkenes. An equation was derived relating the weight fraction of alkenes and alkanes to the residence times of the alkenes in the reactor and this equation produced a reasonable fit to the experimental data. It was observed that hydrocarbon, CO{sub 2} and CH{sub 4} production increased with time apparently reaching steady state after {approximately}200H. It was also found that increasing reactant gas space velocities (SHSV's) increased the steady state turnover numbers for hydrocarbon, CO{sub 2} and CH{sub 4} production, while at the same time, the AFS probabilities of chain growth and alkene/alkane ratios remained effectively constant.

  20. Identification and Structure-Activity Relationships of Diarylhydrazides as Novel Potent and Selective Human Enterovirus Inhibitors.

    PubMed

    Han, Xin; Sun, Ningyuan; Wu, Haoming; Guo, Deyin; Tien, Po; Dong, Chune; Wu, Shuwen; Zhou, Hai-Bing

    2016-03-10

    Enterovirus 71 (EV71) plays an important role in hand-foot-and-mouth disease. In this study, a series of diarylhydrazide analogues was synthesized, and the systematic exploration of SAR led to potent enterovirus inhibitors, of which compound 15 exhibits significant improvements in inhibition potency with an EC50 value of 0.02 μM against EV71. It is very interesting that this class of diarylhydrazides exhibits activities against a series of human enteroviruses at the picomolar level, including EV71 and Coxsackieviruses B1 (CVB1), CVB2, CVB3, CVB4, CVB5, and CVB6 (EC50 as low as 0.5 nM). Compared with the reference antienterovirus drug 1 (enviroxime) and known inhibitor 5 (WIN 51711), the four highly selective compounds 15, 27, 41 and 47 inhibited EV71 replication with EC50 values of 0.17-0.02 μM and SI values in a range of 978.4-12338. A preliminary mechanistic study indicated that VP1 might be the target site for this type of compound. PMID:26885567

  1. Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis

    PubMed Central

    Meissner, Anja; Boshoff, Helena I.; Vasan, Mahalakshmi; Duckworth, Benjamin P.; Barry, Clifton E.; Aldrich, Courtney C.

    2013-01-01

    A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous resistance with a high frequency of ~10−5. PMID:24075144

  2. Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.

    PubMed

    La Regina, Giuseppe; Edler, Michael C; Brancale, Andrea; Kandil, Sahar; Coluccia, Antonio; Piscitelli, Francesco; Hamel, Ernest; De Martino, Gabriella; Matesanz, Ruth; Díaz, José Fernando; Scovassi, Anna Ivana; Prosperi, Ennio; Lavecchia, Antonio; Novellino, Ettore; Artico, Marino; Silvestri, Romano

    2007-06-14

    The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241. PMID:17497841

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

    SciTech Connect

    Prouillac, Caroline; Lecoeur, Sylvaine

    2012-03-15

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

  4. Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals

    SciTech Connect

    Venkatapathy, Raghuraman Wang Chingyi; Bruce, Robert Mark; Moudgal, Chandrika

    2009-01-15

    Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to identify alternative toxicity measures that may be used as surrogates for carcinogenic potency. Alternative toxicity measures for carcinogenic potency currently being used in the literature include lethal dose (dose that kills 50% of a study population [LD{sub 50}]), lowest-observed-adverse-effect-level (LOAEL) and maximum tolerated dose (MTD). The purpose of this study was to investigate the correlation between tumor dose (TD{sub 50}) and three alternative toxicity measures as an estimator of carcinogenic potency. A second aim of this study was to develop a Classification and Regression Tree (CART) between TD{sub 50} and estimated/experimental predictor variables to predict the carcinogenic potency of new chemicals. Rat TD{sub 50}s of 590 structurally diverse chemicals were obtained from the Cancer Potency Database, and the three alternative toxicity measures considered in this study were estimated using TOPKAT, a toxicity estimation software. Though poor correlations were obtained between carcinogenic potency and the three alternative toxicity (both experimental and TOPKAT) measures for the CPDB chemicals, a CART developed using experimental data with no missing values as predictor variables provided reasonable estimates of TD{sub 50} for nine chemicals that were part of an external validation set. However, if experimental values for the three alternative measures, mutagenicity and logP are not available in the literature, then either the CART developed using missing experimental values or estimated values may be used for making a prediction.

  5. Structure activity relationships in alkylammonium C12-gemini surfactants used as dermal permeation enhancers.

    PubMed

    Silva, Sérgio M C; Sousa, João J S; Marques, Eduardo F; Pais, Alberto A C C; Michniak-Kohn, Bozena B

    2013-10-01

    The purpose of this study was to determine the ability and the safety of a series of alkylammonium C12-gemini surfactants to act as permeation enhancers for three model drugs, namely lidocaine HCl, caffeine, and ketoprofen. In vitro permeation studies across dermatomed porcine skin were performed over 24 h, after pretreating the skin for 1 h with an enhancer solution 0.16 M dissolved in propylene glycol. The highest enhancement ratio (enhancement ratio (ER)=5.1) was obtained using G12-6-12, resulting in a cumulative amount of permeated lidocaine HCl of 156.5 μg cm−2. The studies with caffeine and ketoprofen revealed that the most effective gemini surfactant was the one with the shorter spacer, G12-2-12. The use of the latter resulted in an ER of 2.4 and 2.2 in the passive permeation of caffeine and ketoprofen, respectively. However, Azone was found to be the most effective permeation enhancer for ketoprofen, attaining a total of 138.4 μg cm−2 permeated, 2.7-fold over controls. This work demonstrates that gemini surfactants are effective in terms of increasing the permeation of drugs, especially in the case of hydrophilic ionized compounds, that do not easily cross the stratum corneum. Skin integrity evaluation studies did not indicate the existence of relevant changes in the skin structure after the use of the permeation enhancers, while the cytotoxicity studies allowed establishing a relative cytotoxicity profile including this class of compounds, single chain surfactants, and Azone. A dependence of the toxicity to HEK and to HDF cell lines on the spacer length of the various gemini molecules was found. PMID:23959685

  6. A quantitative structure activity relationships (QSAR) analysis of triarylmethane dye tracers

    NASA Astrophysics Data System (ADS)

    Mon, Jarai; Flury, Markus; Harsh, James B.

    2006-01-01

    Dyes are important hydrological tracers. Many different dyes have been proposed as optimal tracers, but none of these dyes can be considered an ideal water tracer. Some dyes are toxic and most sorb to subsurface materials. The objective of this study was to find the molecular structure of an optimal water tracer. We used QSAR to screen a large number of hypothetical molecules, belonging to the class of triarylmethane dyes, in regard to their sorption characteristics to a sandy soil. The QSAR model was based on experimental sorption data obtained from four triarylmethane dyes: C.I. Food Blue 2 (C.I. 42090; Brilliant Blue FCF), C.I. Food Green 3 (C.I. 42053; FD&C Green No. 3), C.I. Acid Blue 7 (C.I. 42080; ORCOacid Blue A 150%), and C.I. Acid Green 9 (C.I. 42100; ORCOacid Fast Green B). Sorption characteristics of the dyes to the sandy soil were expressed with the Langmuir isotherm. Our premise was that dye sorption can be reduced by attachment of sulfonic acid (SO 3) groups to the triarylmethane template. About 70 hypothetical dyes were created and QSAR were used to estimate sorption characteristics. The results indicated that both the position and the number of SO 3 groups affected dye sorption. Sorption decreased with increasing number of SO 3 groups attached to the molecule. Increasing the number of sulfonic acid groups also decreases the toxicity of the compounds. An optimal triarylmethane water tracer contains 4 to 6 SO 3 groups.

  7. Knockdown and larvicidal activity of six monoterpenes against Aedes aegypti (Diptera: Culicidae) and their structure-activity relationships.

    PubMed

    Lucia, Alejandro; Zerba, Eduardo; Masuh, Hector

    2013-12-01

    The relationships between physicochemical parameters of majority components of Eucalyptus essential oils and their insecticide effect were evaluated on Aedes aegypti (L.) (Diptera: Culicidae). The octanol-water partition coefficients of the monoterpenes were estimated by the atom/fragment contribution method and the vapor pressures were determined by our laboratory in previous studies. The larvicidal activity (LC50 (ppm)) and knockdown effect (KT50 (min)) of each component was determined. The results show that the toxicity of EOs main components of Eucalyptus on adults and larvae of A. aegypti is strongly related to their physicochemical properties (vapor pressure and Log P). However, the interaction of both variables (vapor pressure * Log P) explains the toxicological phenomenon more precisely. The regression models were expressed as follows: KT 50(min) =  - 10.9 + 3.7 * Log P + 1.9 * 1/Pvapor (R(2) = 0.80; F = 42.5) and LC 50(ppm) =  - 94.3 + 438.6 *  1/Log P + 2.8 *  1/Pvapor (F = 57.8; R(2) = 0.85). The six evaluated components present different functional groups. Therefore, it was considered to evaluate the monoterpenes as a group and separated in two groups: oxygenated monoterpenes (α-terpineol, 4-terpineol, and 1,8-cineole) and terpene hydrocarbons (γ-terpinene, p-cymene, and α-pinene). The results show the regression models for each group as follows: (A) oxygenated terpenes: KT 50(min) = - 515.3 + 1613.2 * 1/Log P + 5, 2 * 1/Pvapor (F = 3176.7 R(2) = 0.99) and LC 50(ppm)  =  - 1679.4 + 5402.1 * 1/Log P + 12.7 *  1/Pvapor (F = 282.9; R(2) = 0.99). (B) Hydrocarbons terpenes: KT 50(min) = 18.2 - 58.3 * 1/Log P + 2.7 * 1/Pvapor (F = 171.7;  R(2) = 0.97) and LC 50(ppm) = - 21.1 + 174.9 * 1/Log P - 14.3 * 1/Pvapor (F = 410.0; R(2) = 0.99). The association between

  8. INCREASED [3H]-PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLS BY POLYCHLORINATED BIPHENYL MIXTURES AND CONGENERS: STRUCTURE-ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Our previous reports indicate that the neuroactivity of polychlorinated biphenyl (PCB) congeners may be associated with perturbations in cellular Ca2-homeostasis, and protein kinase C (PKC) activation/translocation. e have now studied the structure-activity relationship of severa...

  9. Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 1.

    PubMed

    Ohtawa, Masaki; Yamazaki, Hiroyuki; Ohte, Satoshi; Matsuda, Daisuke; Ohshiro, Taichi; Rudel, Lawrence L; Omura, Satoshi; Tomoda, Hiroshi; Nagamitsu, Tohru

    2013-03-01

    In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). We have successfully developed novel PPPA derivatives with a 7-O-substituted benzoyl substituent that significantly exhibit more potent ACAT2 inhibitory activity and higher ACAT2 isozyme selectivity than 1. PMID:23369538

  10. Structure-activity relationship study of alkynyl ether insecticide synergists and the development of MB-599 (verbutin).

    PubMed

    Bertók, Béla; Pap, László; Arvai, Géza; Bakonyvári, Ildikó; Kuruczné Ribai, Zsuzsanna

    2003-04-01

    Structure-activity relationships of aryl alkynyl synergists of the general formula of Ar-Q-R, where Q represents a bridging structure, were studied using a standardised testing system and Relative Potency values. Ethers, esters, oxime ethers, amides and amines were prepared and evaluated. The length of the R-alkynyl chain, the role of the bridge and the substitution of the aromatic ring were examined systematically. The most potent compounds possessed an aromatic ring connected via a bridge of three atoms to an alkynyl chain, forming together a linear side-chain of six atoms. Several highly potent compounds were synthesised of which one (MB-599; proposed common name verbutin) was selected for development as a selective insecticide synergist in crop protection. Its high potential at practical insecticide:synergist ratios makes possible the reduction of the total amount of insect-control chemicals applied, and its use as an additive to produce new formulations of existing insecticides makes it highly advantageous in resistance management, giving a new tool to sustain the effectiveness of a wide range of insecticides. A product containing a (1+1) mixture of verbutin and beta-cypermethrin was launched in Hungary in 2002. PMID:12701698

  11. Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.

    PubMed

    Soubhye, Jalal; Aldib, Iyas; Elfving, Betina; Gelbcke, Michel; Furtmüller, Paul G; Podrecca, Manuel; Conotte, Raphaël; Colet, Jean-Marie; Rousseau, Alexandre; Reye, Florence; Sarakbi, Ahmad; Vanhaeverbeek, Michel; Kauffmann, Jean-Michel; Obinger, Christian; Nève, Jean; Prévost, Martine; Zouaoui Boudjeltia, Karim; Dufrasne, Francois; Van Antwerpen, Pierre

    2013-05-23

    Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed. PMID:23581551

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

    PubMed

    Oszwałdowski, Sławomir; Timerbaev, Andrei R

    2008-02-01

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

  13. Quantitative structure-activity relationship study of antioxidative peptide by using different sets of amino acids descriptors

    NASA Astrophysics Data System (ADS)

    Li, Yao-Wang; Li, Bo; He, Jiguo; Qian, Ping

    2011-07-01

    A database consisting of 214 tripeptides which contain either His or Tyr residue was applied to study quantitative structure-activity relationships (QSAR) of antioxidative tripeptides. Partial Least-Squares Regression analysis (PLSR) was conducted using parameters individually of each amino acid descriptor, including Divided Physico-chemical Property Scores (DPPS), Hydrophobic, Electronic, Steric, and Hydrogen (HESH), Vectors of Hydrophobic, Steric, and Electronic properties (VHSE), Molecular Surface-Weighted Holistic Invariant Molecular (MS-WHIM), isotropic surface area-electronic charge index (ISA-ECI) and Z-scale, to describe antioxidative tripeptides as X-variables and antioxidant activities measured with ferric thiocyanate methods were as Y-variable. After elimination of outliers by Hotelling's T 2 method and residual analysis, six significant models were obtained describing the entire data set. According to cumulative squared multiple correlation coefficients ( R2), cumulative cross-validation coefficients ( Q2) and relative standard deviation for calibration set (RSD c), the qualities of models using DPPS, HESH, ISA-ECI, and VHSE descriptors are better ( R2 > 0.6, Q2 > 0.5, RSD c < 0.39) than that of models using MS-WHIM and Z-scale descriptors ( R2 < 0.6, Q2 < 0.5, RSD c > 0.44). Furthermore, the predictive ability of models using DPPS descriptor is best among the six descriptors systems (cumulative multiple correlation coefficient for predict set ( Rext2) > 0.7). It was concluded that the DPPS is better to describe the amino acid of antioxidative tripeptides. The results of DPPS descriptor reveal that the importance of the center amino acid and the N-terminal amino acid are far more than the importance of the C-terminal amino acid for antioxidative tripeptides. The hydrophobic (positively to activity) and electronic (negatively to activity) properties of the N-terminal amino acid are suggested to play the most important significance to activity, followed

  14. 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

  15. Syntheses and Structure-Activity Relationships of Novel 3′-Difluoromethyl and 3′-Trifluoromethyl-Taxoids

    PubMed Central

    Kuznetsova, Larissa V.; Pepe, Antonella; Ungureanu, Ioana M.; Pera, Paula; Bernacki, Ralph J.; Ojima, Iwao

    2009-01-01

    A series of novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N3), while those in the 3-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps. PMID:19448839

  16. 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. PMID:23929244

  17. Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.

    PubMed

    Dighe, Satish N; Deora, Girdhar Singh; De la Mora, Eugenio; Nachon, Florian; Chan, Stephen; Parat, Marie-Odile; Brazzolotto, Xavier; Ross, Benjamin P

    2016-08-25

    Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series. PMID:27405689

  18. Blood-brain barrier permeable anticholinesterase aurones: synthesis, structure-activity relationship, and drug-like properties.

    PubMed

    Liew, Kok-Fui; Chan, Kit-Lam; Lee, Chong-Yew

    2015-04-13

    A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease. PMID:25768702

  19. TRANSFORMATION OF DEVELOPMENTAL NEUROTOXICITY DATA INTO STRUCTURE-SEARCHABLE TOXML DATABASE IN SUPPORT OF STRUCTURE-ACTIVITY RELATIONSHIP (SAR) WORKFLOW.

    EPA Science Inventory

    Early hazard identification of new chemicals is often difficult due to lack of data on the novel material for toxicity endpoints, including neurotoxicity. At present, there are no structure searchable neurotoxicity databases. A working group was formed to construct a database to...

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

    PubMed

    Ishimata, Nao; Ito, Hideyuki; Tai, Akihiro

    2016-08-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-01-01

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

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

    PubMed

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

    2016-01-15

    In the present work, we have investigated the conformational isomerism and calculated the vibrational spectra of the C4 oxygenates: 3-butyne-2-one, 3-butene-2-one, 2-butanone and 2-butanol using density functional theory. The calculations are validated by comparison to structural data where available and new, experimental inelastic neutron scattering and infrared spectra of the compounds. We find that for 3-butene-2-one and 2-butanol the spectra show clear evidence for the presence of conformational isomerism and this is supported by the calculations. Complete vibrational assignments for all four molecules are provided and this provides the essential information needed to generate structure/activity relationships for the sequential catalytic hydrogenation of 3-butyne-2-one to 2-butanol. PMID:26318704

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

    PubMed Central

    Chandra De, Utpal; Debnath, Tanusree; Sen, Debanjan; Debnath, Sudhan

    2015-01-01

    Aldose reductase (AR) plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux). A model with partial least squares factor 5, standard deviation 0.2482, R2 = 0.9502 and variance ratio of regression 122 has been found as the best statistical model. PMID:25709964

  4. Design, synthesis, and structure-activity relationship studies of novel thienopyrrolidone derivatives with strong antifungal activity against Aspergillus fumigates.

    PubMed

    Cao, Xufeng; Xu, Yuanyuan; Cao, Yongbing; Wang, Ruilian; Zhou, Ran; Chu, Wenjing; Yang, Yushe

    2015-09-18

    In order to further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (I), two series of novel azoles featuring thieno[2,3-c]pyrrolidone and thieno[3,2-c]pyrrolidone nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SARs of antifungal triazoles. Most of target compounds exhibited excellent activity against Candida and Cryptococcus spp., with MIC values in the range of 0.0625 μg/ml to 0.0156 μg/ml. The thieno[3,2-c]pyrrolidone unit was more suited for improving activity against Aspergillus spp. The most potent compound, 18a, was selected for further development due to its significant in vitro activity against Aspergillus spp. (MIC = 0.25 μg/ml), as well as its high metabolic stability in human liver microsomes. PMID:26310892

  5. Predicting the Structure-Activity Relationship of Hydroxyapatite-Binding Peptides by Enhanced-Sampling Molecular Simulation.

    PubMed

    Zhao, Weilong; Xu, Zhijun; Cui, Qiang; Sahai, Nita

    2016-07-12

    Understanding the molecular structural and energetic basis of the interactions between peptides and inorganic surfaces is critical to their applications in tissue engineering and biomimetic material synthesis. Despite recent experimental progresses in the identification and functionalization of hydroxyapatite (HAP)-binding peptides, the molecular mechanisms of their interactions with HAP surfaces are yet to be explored. In particular, the traditional method of molecular dynamics (MD) simulation suffers from insufficient sampling at the peptide-inorganic interface that renders the molecular-level observation dubious. Here we demonstrate that an integrated approach combining bioinformatics, MD, and metadynamics provides a powerful tool for investigating the structure-activity relationship of HAP-binding peptides. Four low charge density peptides, previously identified by phage display, have been considered. As revealed by bioinformatics and MD, the binding conformation of the peptides is controlled by both the sequence and the amino acid composition. It was found that formation of hydrogen bonds between lysine residue and phosphate ions on the surface dictates the binding of positively charged peptide to HAP. The binding affinities of the peptides to the surface are estimated by free energy calculation using parallel-tempering metadynamics, and the results compare favorably to measurements reported in previous experimental studies. The calculation suggests that the charge density of the peptide primarily controls the binding affinity to the surface, while the backbone secondary structure that may restrain side chain orientation toward the surface plays a minor role. We also report that the application of enhanced-sampling metadynamics effects a major advantage over the steered MD method by significantly improving the reliability of binding free energy calculation. In general, our novel integration of diverse sampling techniques should contribute to the rational

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

    PubMed

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

    2014-02-01

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

  7. Three-dimensional quantitative structure-activity relationship study on anti-cancer activity of 3,4-dihydroquinazoline derivatives against human lung cancer A549 cells

    NASA Astrophysics Data System (ADS)

    Cho, Sehyeon; Choi, Min Ji; Kim, Minju; Lee, Sunhoe; Lee, Jinsung; Lee, Seok Joon; Cho, Haelim; Lee, Kyung-Tae; Lee, Jae Yeol

    2015-03-01

    A series of 3,4-dihydroquinazoline derivatives with anti-cancer activities against human lung cancer A549 cells were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular similarity indices analysis (CoMSIA) approaches. The most potent compound, 1 was used to align the molecules. As a result, the best prediction was obtained with CoMSIA combined the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields (q2 = 0.720, r2 = 0.897). This model was validated by an external test set of 6 compounds giving satisfactory predictive r2 value of 0.923 as well as the scrambling stability test. This model would guide the design of potent 3,4-dihydroquinazoline derivatives as anti-cancer agent for the treatment of human lung cancer.

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

    PubMed Central

    2011-01-01

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

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

    SciTech Connect

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

    2011-07-01

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

  10. Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities.

    PubMed

    Leverrier, Aurélie; Bero, Joanne; Cabrera, Julián; Frédérich, Michel; Quetin-Leclercq, Joëlle; Palermo, Jorge A

    2015-07-15

    In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 μM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 μM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s. PMID:26063305

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

    PubMed

    Le Calvé, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaëlle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Françoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Véronique; Dufrasne, François; Van Antwerpen, Pierre; Poumay, Yves; David-Cordonnier, Marie-Hélène; Evidente, Antonio; Kiss, Robert

    2011-07-01

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro. PMID:21504755

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

    PubMed

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

    2013-09-01

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

  13. 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. PMID:27172125

  14. Transformation of organophosphorus pesticides in the presence of aqueous chlorine: kinetics, pathways, and structure-activity relationships.

    PubMed

    Duirk, Stephen E; Desetto, Lisa M; Davis, Gary M

    2009-04-01

    The fate of organophosphorus (OP) pesticides in the presence of aqueous chlorine was investigated under simulated drinking water treatment conditions. Intrinsic rate coefficients were found for the reaction of hypochlorous acid (k(HOCl,OP)) and hypochlorite ion (k(OCl,OP) for several OP pesticides. The reaction of hypochlorous acid (HOCl) with each OP pesticide was relatively rapid near neutral pH, k(HOCl,OP) = 0.86 - 3.56 x 10(6) M(-1)h(-1). HOCI reacts at the thiophosphate (P = S) moiety of the OP pesticide resulting in the formation of the corresponding oxon (P=0), which is more toxic than the parent pesticide. Hypochlorite ion (OCl-) was found not to oxidize OP pesticides but act like a nucleophile accelerating hydrolysis, k(OCl,OP) = 37.3-15910 M(-1)h(-1). Both the k(HOCl,OP) and the k(OCl,OP) were found to correlate well with molecular descriptors within each subgroup of the OP pesticide class. A model was developed to predict the transformation of OP pesticides in the presence of aqueous chlorine. With hydrolysis rate coefficients, the transformation of OP pesticides under drinking water treatment conditions was found to be adequately predicted. The structure-activity relationships and model developed here could be used by risk assessors to determine exposure to OP pesticides and their transformation products in potable water. PMID:19452883

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

    PubMed

    Velagapudi, Sai Pradeep; Disney, Matthew D

    2013-10-15

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

  16. Structure-Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics.

    PubMed

    Mohamed, Tarek; Shakeri, Arash; Tin, Gary; Rao, Praveen P N

    2016-05-12

    A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward Aβ40/42. Structure-activity relationship data identified compound 3k (N (4)-(4-bromobenzyl)quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (Aβ40 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC50 = 1.5 μM). The corresponding N (2)-isomer 4k (N (2)-(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent Aβ aggregation (Aβ40 IC50 = 1.7 μM). However, compound 4k exhibited superior inhibition of Aβ42 aggregation (Aβ42 IC50 = 1.7 μM) compared to compound 3k (Aβ42 IC50 = 14.8 μM) and was ∼1.8-fold more potent compared to curcumin (Aβ42 IC50 = 3.1 μM). These results were supported by Aβ aggregation kinetics investigations and transmission electron microscopy studies, which demonstrate the suitability of DAQ ring system to develop antiamyloid agents as pharmacological tools to study Aβ aggregation. PMID:27190601

  17. Quantitative Structure-Activity Relationships Study on the Rate Constants of Polychlorinated Dibenzo-p-Dioxins with OH Radical

    PubMed Central

    Qi, Chuansong; Zhang, Chenxi; Sun, Xiaomin

    2015-01-01

    The OH-initiated reaction rate constants (kOH) are of great importance to measure atmospheric behaviors of polychlorinated dibenzo-p-dioxins (PCDDs) in the environment. The rate constants of 75 PCDDs with the OH radical at 298.15 K have been calculated using high level molecular orbital theory, and the rate constants (kα, kβ, kγ and kOH) were further analyzed by the quantitative structure-activity relationships (QSAR) study. According to the QSAR models, the relations between rate constants and the numbers and positions of Cl atoms, the energy of the highest occupied molecular orbital (EHOMO), the energy of the lowest unoccupied molecular orbital (ELUMO), the difference ΔEHOMO-LUMO between EHOMO and ELUMO, and the dipole of oxidizing agents (D) were discussed. It was found that EHOMO is the main factor in the kOH. The number of Cl atoms is more effective than the number of relative position of these Cl atoms in the kOH. The kOH decreases with the increase of the substitute number of Cl atoms. PMID:26274950

  18. Determination of boiling point of petrochemicals by gas chromatography-mass spectrometry and multivariate regression analysis of structural activity relationship.

    PubMed

    Fakayode, Sayo O; Mitchell, Breanna S; Pollard, David A

    2014-08-01

    Accurate understanding of analyte boiling points (BP) is of critical importance in gas chromatographic (GC) separation and crude oil refinery operation in petrochemical industries. This study reported the first combined use of GC separation and partial-least-square (PLS1) multivariate regression analysis of petrochemical structural activity relationship (SAR) for accurate BP determination of two commercially available (D3710 and MA VHP) calibration gas mix samples. The results of the BP determination using PLS1 multivariate regression were further compared with the results of traditional simulated distillation method of BP determination. The developed PLS1 regression was able to correctly predict analytes BP in D3710 and MA VHP calibration gas mix samples, with a root-mean-square-%-relative-error (RMS%RE) of 6.4%, and 10.8% respectively. In contrast, the overall RMS%RE of 32.9% and 40.4%, respectively obtained for BP determination in D3710 and MA VHP using a traditional simulated distillation method were approximately four times larger than the corresponding RMS%RE of BP prediction using MRA, demonstrating the better predictive ability of MRA. The reported method is rapid, robust, and promising, and can be potentially used routinely for fast analysis, pattern recognition, and analyte BP determination in petrochemical industries. PMID:24881546

  19. 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. PMID:26513561

  20. 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

  1. Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

    PubMed Central

    Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G.; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Šimůnek, Tomáš; Richardson, Des R.; Polanski, Jaroslaw

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2015-02-14

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

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

    PubMed

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

    2014-10-20

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

  5. A novel quantitative structure-activity relationship model for prediction of biomagnification factor of some organochlorine pollutants.

    PubMed

    Fatemi, Mohammad Hossein; Baher, Elham

    2009-08-01

    The biomagnification factor (BMF) is an important property for toxicology and environmental chemistry. In this work, quantitative structure-activity relationship (QSAR) models were used for the prediction of BMF for a data set including 30 polychlorinated biphenyls and 12 organochlorine pollutants. This set was divided into training and prediction sets. The result of diversity test reveals that the structure of the training and test sets can represent those of the whole ones. After calculation and screening of a large number of molecular descriptors, the methods of stepwise multiple linear regression and genetic algorithm (GA) were used for the selection of most important and significant descriptors which were related to BMF. Then multiple linear regression and artificial neural network (ANN) techniques were applied as linear and non-linear feature mapping techniques, respectively. By comparison between statistical parameters of these methods it was concluded that an ANN model, which used GA selected descriptors, was superior over constructed models. Descriptors which were used by this model are: topographic electronic index, complementary information content, XY shadow/XY rectangle and difference between partial positively and negatively charge surface area. The standard errors for training and test sets of this model are 0.03 and 0.20, respectively. The degree of importance of each descriptor was evaluated by sensitivity analysis approach for the nonlinear model. A good results (Q (2) = 0.97 and SPRESS = 0.084) is obtained by applying cross-validation test that indicating the validation of descriptors in the obtained model in prediction of BMF for these compounds. PMID:19219557

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

    PubMed

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

    2016-07-01

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

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

    SciTech Connect

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

    1991-02-01

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

  8. SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

    PubMed Central

    Tovmasyan, Artak; Roberts, Emily R. H.; Vujaskovic, Zeljko; Leong, Kam W.; Spasojevic, Ivan

    2014-01-01

    Abstract Significance: Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O2·−; no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored. Recent Advances: Structure-activity relationship (half-wave reduction potential [E1/2] versus log kcat), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E1/2 of ∼+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O2·−) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants. Critical Issues: Although log kcat(O2·−) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor κB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells. Future Directions: Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs. Antioxid. Redox Signal. 20, 2372–2415. PMID:23875805

  9. Structure-function relationships in novel peptide dodecamerswith broad-spectrum bactericidal and endotoxin-neutralizing activities.

    PubMed Central

    Mayo, K H; Haseman, J; Young, H C; Mayo, J W

    2000-01-01

    A series of designed peptide 33-mers (betapep peptides) areknown to be bactericidal [Mayo, Haseman, Ilyina and Gray (1998)Biochim. Biophys. Acta 1425, 81-92]. Here dodecapeptides (SC-1-SC-8), which 'walk through' the sequence ofbetapep-25, were investigated for their ability to kill Gram-negativeand -positive bacteria and to neutralize endotoxin. SC-4 (KLFKRHLKWKI I-NH(2); the -NH(2) at the right of each sequenceindicates amidation of the C-terminal carboxylate group) is the mosteffective, more so than betapep-25, at killing Gram-negative bacteriawith nanomolar LD(50) values. Against Gram-positive bacteria,SC-4 also shows good activity with submicromolar LD(50)values. Leakage studies indicate rapid bacterial membrane permeability,with t(1/2) valuesof 10-15 min. SC-4 in the micromolar range also effectivelyneutralizes endotoxin and is not haemolytic below 10(-4)M. For all SC peptides, CD and NMR data indicate the presence of both 3(10)- and alpha-helix. For SC-4, nuclear-Overhauser-effect-based computational modelling yields an amphipathic helix with K1, K4,R5, and K8 arrayed on the same face (K is lysine, R is arginine).Activity differences among SC peptides and single-site variants of SC-4allow some structure-function relationships to be deduced.Relative to other known bactericidal peptides in the linear peptide,helix-forming category, SC-4 is the most potent broad-spectrumantibacterial identified to date. The present study contributes to thedevelopment of agents involved in combating the ever-recurring problemof drug-resistant micro-organisms. PMID:10903132

  10. Evaluation of Cancer Preventive Activity and Structure-Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogues