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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. Structural and Activity Profile Relationships Between Drug Scaffolds.

    PubMed

    Hu, Ye; Bajorath, Jürgen

    2015-05-01

    Core structures of current drugs have been assembled and their structural relationships and activity profiles have been explored. Drug scaffolds were frequently involved in different types of structural relationships. In addition, a variety of activity profile relationships between structurally related drug scaffolds were detected, ranging from closely overlapping to distinct profiles. Furthermore, when structural and activity profile relationships of scaffolds from drugs and bioactive compounds were compared, systematic differences were detected. Consensus activity profiles were introduced as a new approach for the qualitative and quantitative assessment of activity similarity of structurally related drugs represented by the same scaffold. On the basis of consensus activity profiles, scaffolds representing drugs active against distinct targets can be distinguished from drugs having similar target profiles and target hypotheses can be derived for individual drugs. Given the results of our analysis, drug scaffolds have been systematically organized according to structural and activity profile criteria. Our scaffold sets and the associated information are made freely available. PMID:25697829

  3. Structure-activity relationships in nitrothiophenes.

    PubMed

    Morley, John O; Matthews, Thomas P

    2006-12-01

    The structure and electronic properties of a series of biologically active 2-nitrothiophenes (1) have been calculated using both semi-empirical and ab initio molecular orbital methods. Multi-linear regression analysis suggests that there is a reasonable correlation between the experimental activity of the derivatives against either Escherichia coli or Micrococcus luteus and calculated properties such as the HOMO energies, the total atomic charges and ring angles at the heterocyclic sulfur atom, but there is no correlation with the calculated solvation energies or dipole moments. The presence or absence of an additional nitro group at the 3-position of the ring also has a significant effect on the activity. From the derived QSAR equations, the 2-chloro- or 2-bromo-3,5-dinitrothiophenes (1a and 1c) are predicted to show the highest activity against both bacteria, while 2-nitrothiophene (1n) is predicted to be the least active, in line with the experimental results. PMID:16887355

  4. Structure activity relationships of selected naphthalene derivatives

    SciTech Connect

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

    1983-01-01

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

  5. 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.

  6. Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids.

    PubMed

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

    2015-01-01

    The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined. PMID:26263960

  7. 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

  8. 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

  9. 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.

  10. Structure-activity relationships among guanine-quadruplex telomerase inhibitors.

    PubMed

    Neidle, S; Harrison, R J; Reszka, A P; Read, M A

    2000-03-01

    The ribonucleoprotein telomerase is responsible for maintaining the length of telomeric ends of chromosomes in tumour cells. It is activated in over 85% of the tumour cells, and is emerging as a major target for cancer chemotherapy. A range of molecules containing tricyclic and tetracyclic aromatic chromophores has been shown to inhibit the telomerase enzyme system at the micromolar level. There is evidence that they do so via stabilisation of a guanine-quadruplex structure, which provides a stop signal for further telomere elongation. The known structure-activity relationships for these compounds are summarised, and pointers for the development of future molecules with enhanced selectivity are described. PMID:10739868

  11. 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

  12. 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...

  13. 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...

  14. Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

    PubMed

    Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

    2013-03-01

    A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work. PMID:23374870

  15. Structure activity relationships: their function in biological prediction

    SciTech Connect

    Schultz, T.W.

    1982-01-01

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

  16. 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

  17. Structure activity relationship of selective GABA uptake inhibitors.

    PubMed

    Vogensen, Stine B; Jørgensen, Lars; Madsen, Karsten K; Jurik, Andreas; Borkar, Nrupa; Rosatelli, Emiliano; Nielsen, Birgitte; Ecker, Gerhard F; Schousboe, Arne; Clausen, Rasmus P

    2015-05-15

    A series of ?-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse ?-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1. PMID:25882526

  18. 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.

  19. Amphiphilic transdermal permeation enhancers: structure-activity relationships.

    PubMed

    Vávrová, K; Zbytovská, J; Hrabálek, A

    2005-01-01

    Transdermal drug delivery offers numerous advantages over conventional routes of administration; however, poor permeation of most drugs across the skin barrier constitutes a serious limitation of this methodology. One of the approaches used to enlarge the number of transdermally-applicable drugs uses permeation enhancers. These compounds promote drug permeation through the skin by a reversible decrease of the barrier resistance. Enhancers can act on the stratum corneum intracellular keratin, influence desmosomes, modify the intercellular lipid domains or alter the solvent nature of the stratum corneum. Even though, hundreds of substances have been identified as permeation enhancers to date, yet our understanding of the structure-activity relationships is limited. In general, enhancers can be divided into two large groups: small polar solvents, e.g. ethanol, propylene glycol, dimethylsulfoxide and amphiphilic compounds containing a polar head and a hydrophobic chain, e.g. fatty acids and alcohols, 1-dodecylazepan-2-one (Azone), 2-nonyl-1,3-dioxolane (SEPA 009), and dodecyl-2-dimethylaminopropanoate (DDAIP). In this review we have focused on structure-activity relationships of amphiphilic permeation enhancers, including the properties of the hydrophobic chains, e.g. length, unsaturation, and branching, as well as the polar heads characteristics, e.g. hydrogen bonding ability, lipophilicity, and size. We present over 180 examples of enhancers with different polar head to illustrate the structural requirements and the possible role of the polar head. We have given an overview of the methods used for investigation of the mechanisms of permeation enhancement, namely differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, X-ray diffraction and future perspectives in this field. Furthermore, biodegradability and chirality of the enhancers are discussed. PMID:16178785

  20. Structure-activity relationship of cyanine tau aggregation inhibitors

    PubMed Central

    Chang, Edward; Congdon, Erin E.; Honson, Nicolette S.; Duff, Karen E.; Kuret, Jeff

    2009-01-01

    A structure-activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay. Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3’-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood-brain barrier and cell membrane penetration. Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone. In contrast, high concentrations (?300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity. PMID:19432420

  1. Structure-activity relationship of human bone sialoprotein peptides

    PubMed Central

    Rapuano, Bruce E.; MacDonald, Daniel E.

    2014-01-01

    In the current study, the relationship between the structure of the RGD-containing human bone sialoprotein (hBSP) peptide 278-293 and its attachment activity toward osteoblast-like (MC3T3) cells was investigated. This goal was accomplished by examining the comparative cell attachment activities of several truncated forms of peptide 278-293. Computer modeling of the various peptides was also performed to assess the role of secondary structure in peptide bioactivity. The elimination of the tyrosine-278 at the N-terminus resulted in a more dramatic loss of cell attachment activity compared to the removal of either tyrosine-293 or the arg-ala-tyr (291-293) tripeptide. Although the replacement of the RGD (arg-gly-asp) peptide moiety with peptide KAE (lys-ala-glu) resulted in a dramatic loss of cell attachment activity, a peptide containing RGE (arg-glyglu) in place of RGD retained 70-85 % of the parental peptide's attachment activity. These results suggest that the N-terminal RGD-flanking region of hBSP peptide 278-293, in particular the tyrosine-278 residue, represents a second cell attachment site that stabilizes the RGD-integrin receptor complex. Computer modeling also suggested that a ?-turn encompassing RGD or RGE in some of the hBSP peptides may facilitate its binding to integrins by increasing the exposure of the tripeptide. This knowledge may be useful in the future design of biomimetic peptides which are more effective in promoting the attachment of osteogenic cells to implant surfaces in vivo. PMID:24103036

  2. Capsaicin and its analogues: structure-activity relationship study.

    PubMed

    Huang, X-F; Xue, J-Y; Jiang, A-Q; Zhu, H-L

    2013-01-01

    Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structure-activity relationship of capsaicinoids. PMID:23627937

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

    PubMed

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

    2013-02-01

    Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure-activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William's plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <-2, indicating potential outliers or activity cliffs. The results show that the HOMO-LUMO energy gap contributed most significantly to the binding affinity. A mean training R (2) of 0.80, a mean test set R (2) of 0.76 and a consensus external test set R (2) of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in physiologically based pharmacokinetic/pharmacodynamic models of organophosphate toxicity to determine the rate of acetylcholinesterase inhibition. PMID:22990135

  4. 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.

  5. Structure-Activity Relationship of Nerve-Highlighting Fluorophores

    PubMed Central

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

    2013-01-01

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

  6. Structure-Activity Relationships of Mineral Dusts as Heterogeneous

    E-print Network

    , this computer modeling method would provide an important structure-activity tool for the estimation- cesses, such as being cloud condensation nuclei (4) or being the medium for surface and bulk chemical

  7. Structure activity relationship of synaptic and junctional neurotransmission

    PubMed Central

    Goyal, Raj K; Chaudhury, Arun

    2013-01-01

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

  8. 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

  9. 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...

  10. Precise structure activity relationships in asymmetric catalysis using carbohydrate scaffolds to allow ready fine tuning

    E-print Network

    Davis, Ben G.

    Precise structure activity relationships in asymmetric catalysis using carbohydrate scaffolds construction of 24 stereochemically and functionally diverse carbohydrate ligand structures from a core D construction. Introduction Carbohydrates are powerful sources of chirality for use in syn- thetic asymmetric

  11. 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...

  12. Structure-activity relationship of aliphatic compounds for nematicidal activity against pine wood nematode (Bursaphelenchus xylophilus).

    PubMed

    Seo, Seon-Mi; Kim, Junheon; Kim, Eunae; Park, Hye-Mi; Kim, Young-Joon; Park, Il-Kwon

    2010-02-10

    Nematicidal activity of aliphatic compounds was tested to determine a structure-activity relationship. There was a significant difference in nematicidal activity among functional groups. In a test with alkanols and 2E-alkenols, compounds with C(8)-C(11) chain length showed 100% nematicidal activity against pine wood nematode, Bursaphelenchus xylophilus , at 0.5 mg/mL concentration. C(6)-C(10) 2E-alkenals exhibited >95% nematicidal activity, but the other compounds with C(11)-C(14) chain length showed weak activity. Nematicidal activity of alkyl acetates with C(7)-C(11) chain length was strong. Compounds belonging to hydrocarbons, alkanals, and alkanoic acetates showed weak activity at 0.5 mg/mL concentration. Nematicidal activity of active compounds was determined at lower concentrations. At 0.25 mg/mL concentration, whole compounds except C(8) alkanol, C(8) 2E-alkenol, and C(7) alkanoic acid showed >80% nematicidal activity. C(9)-C(11) alkanols, C(10)-C(11) 2E-alkenols, C(8)-C(9) 2E-alkenals, and C(9)-C(10) alkanoic acids showed >80% nematicidal activity at 0.125 mg/mL concentration. Only C(11) alkanol exhibited strong nematicidal activity at 0.0625 mg/mL concentration, the lowest concentration that was tested. PMID:20055406

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

    PubMed

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

    2013-01-01

    Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. ?-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 µg mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of ?-mangostin and ?-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7-tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity. PMID:22494050

  14. 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

  15. Cytotoxicity and structure activity relationships of phytosterol from Phyllanthus emblica.

    PubMed

    Qi, Wei-Yan; Li, Ya; Hua, Lei; Wang, Ke; Gao, Kun

    2013-01-01

    Fourteen sterols (1-14), including two new sterols, trihydroxysitosterol (2) and 5?,6?,7?-7?-acetoxysitosterol (3), were isolated from the branches and leaves of Phyllanthus emblica L. The isolated compounds and a structurally related sterol 15 from Aphanamixis grandifolia were screened for cytotoxicity in two tumor cell lines (HL-60 and SMMC-7721) and a non-tumor cell line (HL-7702) using RSB assay. Within the series of phytosterol derivatives tested, compound 15 was the most active, displaying potent cytotoxicity against HL-60 with IC(50) of 5.10?mol/L, and most of the active compounds showed selective cytotoxicity against tumor and non-tumor cell lines, especially compound 10 with a safety index of 4.42. PMID:23266735

  16. Structure-activity relationship of immunomodulating pectins from elderberries.

    PubMed

    Ho, Giang Thanh Thi; Ahmed, Abeeda; Zou, Yuan-Feng; Aslaksen, Torun; Wangensteen, Helle; Barsett, Hilde

    2015-07-10

    The berries of Sambucus nigra have traditionally been used and are still used to treat respiratory illnesses such as cold and flu in Europe, Asia and America. The aim of this paper was to elucidate the structures and the immunomodulating properties of the pectic polymers from elderberries. All the purified fractions obtained from 50% ethanol, 50°C water and 100°C water extracts showed potent dose-dependent complement fixating activity and macrophage stimulating activity. The isolated fractions consisted of long homogalacturonan regions, in addition to arabinogalactan-I and arabinogalactan-II probably linked to a rhamnogalacturonan backbone. Reduced bioactivity was observed after reduction of Araf residues and 1?3,6 Gal by weak acid hydrolysis. The rhamnogalacturonan region in SnBe50-I-S3-I and SnBe50-I-S3-II showed higher activity compared to the native polymer, SnBe50-S3, after enzymatic treatment with endo-?-d-(1?4)-polygalacturonase. These results indicated that elderberries contained immunomodulating polysaccharides, where the ramified regions express the activities observed. PMID:25857988

  17. 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...

  18. 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...

  19. 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, ?ER. In the present study we demonstrate a quantitative structure-activity relationship model (QSAR) that describes well the dependence of ?ER 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

  20. Quantitative structure-antifungal activity relationships of some benzohydrazides against Botrytis cinerea.

    PubMed

    Reino, José L; Saiz-Urra, Liane; Hernandez-Galan, Rosario; Aran, Vicente J; Hitchcock, Peter B; Hanson, James R; Gonzalez, Maykel Perez; Collado, Isidro G

    2007-06-27

    Fourteen benzohydrazides have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The best antifungal activity was observed for the N',N'-dibenzylbenzohydrazides 3b-d and for the N-aminoisoindoline-derived benzohydrazide 5. A quantitative structure-activity relationship (QSAR) study has been developed using a topological substructural molecular design (TOPS-MODE) approach to interpret the antifungal activity of these synthetic compounds. The model described 98.3% of the experimental variance, with a standard deviation of 4.02. The influence of an ortho substituent on the conformation of the benzohydrazides was investigated by X-ray crystallography and supported by QSAR study. Several aspects of the structure-activity relationships are discussed in terms of the contribution of different bonds to the antifungal activity, thereby making the relationships between structure and biological activity more transparent. PMID:17542610

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

    EPA Science Inventory

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

  2. 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

  3. Structure-activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity.

    PubMed

    Shimizu, Ryo; Yamaguchi, Masafumi; Uramaru, Naoto; Kuroki, Hiroaki; Ohta, Shigeru; Kitamura, Shigeyuki; Sugihara, Kazumi

    2013-12-01

    The aim of this study was to investigate the possible influence of halogenated compounds on thyroid hormone metabolism via inhibition of iodotyrosine deiodinase (IYD) activity. The structure-activity relationships of 44 halogenated compounds for IYD-inhibitory activity were examined in vitro using microsomes of HEK-293 T cells expressing recombinant human IYD. The compounds examined were 17 polychlorinated biphenyls (PCBs), 15 polybrominated diphenyl ethers (PBDEs), two agrichemicals, five antiparasitics, two pharmaceuticals and three food colorants. Among them, 25 halogenated phenolic compounds inhibited IYD activity at the concentration of 1×10(-4)M or 6×10(-4)M. Rose bengal was the most potent inhibitor, followed by erythrosine B, phloxine B, benzbromarone, 4'-hydroxy-2,2',4-tribromodiphenyl ether, 4-hydroxy-2,3',3,4'-tetrabromodiphenyl ether, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl, 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether, triclosan, and 4-hydroxy-2,2',3,4',5-pentabromodiphenyl ether. However, among PCBs and PBDEs without a hydroxyl group, including their methoxylated metabolites, none inhibited IYD activity. These results suggest that halogenated compounds may disturb thyroid hormone homeostasis via inhibition of IYD, and that the structural requirements for IYD-inhibitory activity include halogen atom and hydroxyl group substitution on a phenyl ring. PMID:24012475

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

    PubMed

    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

  5. Antiradical and reductant activities of anthocyanidins and anthocyanins, structure-activity relationship and synthesis.

    PubMed

    Ali, Hussein M; Almagribi, Wafaa; Al-Rashidi, Mona N

    2016-03-01

    Eight anthocyanidins, seven anthocyanins and two synthesized 4'-hydroxy flavyliums were examined as hydrogen donors to DPPH, ABTS and hydroxyl radicals, and as electron donors in the FRAP assay. Most compounds gave better activities than trolox and catechol. A structure-activity relationship (SAR) study showed that, in the absence of the 3-OH group, radicals of the 4, 5 or 7-OH groups can only be stabilized by resonance through pyrylium oxygen, while 3-OH group improved hydrogen atom donation because of the stabilization by anthocyanidin semiquinone-like resonance. Electron donation was also enhanced by the 3-OH group. Both anthocyanidins and their respective anthocyanins showed similar trends and close activities. Different types of sugar unit bonded to the 3-OH group or counter ion had minor effect on activities. The catechol structure improved both hydrogen and electron donation. Compounds lacking the catechol structure had a decreasing order of H-atom and electron donation (Mv>Pn>Pg>Ap>4'-OH-flavylium) consistent with the decreasing number of their hydroxyl and/or methoxy groups. PMID:26471682

  6. 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

  7. 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 50?M 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

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

    PubMed

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

    2015-05-01

    The activity cliff (AC) concept is widely applied in medicinal chemistry. ACs are formed by compounds with small structural changes having large differences in potency. Accordingly, ACs are a primary source of structure-activity relationship (SAR) information. Through large-scale compound data mining it has been shown that the vast majority of ACs are formed in a coordinated manner by groups of structurally analogous compounds with significant potency variations. In network representations coordinated ACs form clusters of varying size but frequently recurrent topology. Recently, computational methods have been introduced to systematically organize AC clusters and extract SAR information from them. AC clusters are widely distributed over compound activity classes and represent a rich source of SAR information. These clusters can be visualized in AC networks and isolated. However, it is challenging to extract SAR information from such clusters and make this information available to the practice of medicinal chemistry. Therefore, it is essential to go beyond subjective case-by-case analysis and design computational approaches to systematically access SAR information associated with AC clusters. PMID:25715967

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

    PubMed

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

    2014-04-01

    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

  10. Structure-activity relationships of phenyl- and benzoylpyrroles.

    PubMed

    Laatsch, H; Renneberg, B; Hanefeld, U; Kellner, M; Pudleiner, H; Hamprecht, G; Kraemer, H P; Anke, H

    1995-04-01

    Antitumor, antimicrobial, and phytotoxic activities of the marine antibiotic pentabromopseudilin (1a) and related phenyl-, benzyl- and benzoyl pyrroles were compared. All activities depended strongly on the substituent pattern, with the natural compound 1a being the most active one. As judged from model reactions, a covalent bond of nucleophiles to the pyrrole system may be involved in the inhibition of macromolecular syntheses. PMID:7600609

  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. Synthesis and structure activity relationships of schweinfurthin indoles.

    PubMed

    Kodet, John G; Beutler, John A; Wiemer, David F

    2014-04-15

    As part of a program to explore the biological activity of analogues of the natural schweinfurthins, a set of compounds has been prepared where an indole system can be viewed as a substitution for the resorcinol substructure of the schweinfurthin's D-ring. Twelve of these schweinfurthin indoles have been prepared and evaluated in the 60 cell line screen of the National Cancer Institute. While a range of activity has been observed, it is now clear that schweinfurthin indoles can demonstrate the intriguing pattern of activity associated with the natural stilbenes. In the best cases, these indole analogues display both potency and differential activity across the various cell lines comparable to the best resorcinol analogues. PMID:24656801

  13. Synthesis and Structure Activity Relationships of Schweinfurthin Indoles

    PubMed Central

    Kodet, John G.; Beutler, John A.

    2014-01-01

    As part of a program to explore the biological activity of analogues of the natural schweinfurthins, a set of compounds has been prepared where an indole system can be viewed as a substitution for the resorcinol substructure of the schweinfurthin’s D-ring. Twelve of these schweinfurthin indoles have been prepared and evaluated in the 60 cell line screen of the National Cancer Institute. While a range of activity has been observed, it is now clear that schweinfurthin indoles can demonstrate the intriguing pattern of activity associated with the natural stilbenes. In the best cases, these indole analogues display both potency and differential activity across the various cell lines comparable to the best resorcinol analogues. PMID:24656801

  14. 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...

  15. 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…

  16. 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

  17. Structure–activity relationships for ?-calcitonin gene-related peptide

    PubMed Central

    Watkins, Harriet A; Rathbone, Dan L; Barwell, James; Hay, Debbie L; Poyner, David R

    2013-01-01

    Calcitonin gene-related peptide (CGRP) is a member of the calcitonin (CT) family of peptides. It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. With other members of the CT family, it shares an N-terminal disulphide-bonded ring which is essential for biological activity, an area of potential ?-helix, and a C-terminal amide. CGRP binds to the calcitonin receptor-like receptor (CLR) in complex with receptor activity-modifying protein 1 (RAMP1), a member of the family B (or secretin-like) GPCRs. It can also activate other CLR or calcitonin-receptor/RAMP complexes. This 37 amino acid peptide comprises the N-terminal ring that is required for receptor activation (residues 1–7); an ?-helix (residues 8–18), a region incorporating a ?-bend (residues 19–26) and the C-terminal portion (residues 27–37), that is characterized by bends between residues 28–30 and 33–34. A few residues have been identified that seem to make major contributions to receptor binding and activation, with a larger number contributing either to minor interactions (which collectively may be significant), or to maintaining the conformation of the bound peptide. It is not clear if CGRP follows the pattern of other family B GPCRs in binding largely as an ?-helix. LINKED ARTICLES This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7 PMID:23186257

  18. 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 ?2A-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.

  19. Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts.

    PubMed

    Kramer, Christian; Fuchs, Julian E; Liedl, Klaus R

    2015-03-23

    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 (??pKi and ??pIC50 > 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

  20. Structure-activity relationships in diphenyl ethers for insect growth regulating activity against mosquitoes.

    PubMed

    George, N; Vasuki, V; Kalyanasundaram, M

    1989-09-01

    Out of the 30 substituted diphenyl ethers synthesized and tested for insect growth regulating (IGR) activity against mosquitoes, three compounds viz., DPE-16, 19 and 28 showed promising IGR activity. While DPE-16 and 19 were found to be effective against all three vector species tested viz., Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi, with the respective EI50 values of 0.1485, 0.3650, 0.2225 mg/l and 0.1474, 0.1392, 0.1145 mg/l, DPE-28 was found to be highly effective against C. quinquefasciatus with an EI50 value of 0.0022 mg/l. The structure-activity relationship in the diphenyl ethers with respect to their octanol-water partition coefficients showed an increase of lipophilicity when both the ortho positions of the phenolic moiety are substituted by tertiary butyl group. The simulated field trial carried out with DPE-16, 19 and 28 showed that these compounds were effective for 7, 7 and 9 days respectively at 0.1 mg/l against C. quinquefasciatus. PMID:2576420

  1. 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 VivaGel® and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides. PMID:20808791

  2. Structure-activity relationship study of novel peptoids that mimic the structure of antimicrobial peptides.

    PubMed

    Mojsoska, Biljana; Zuckermann, Ronald N; Jenssen, Håvard

    2015-07-01

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

  3. 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

  4. 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

  5. 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...

  6. Structure-activity relationship investigations of a potent and selective benzodiazepine oxytocin antagonist.

    PubMed

    Wyatt, P G; Allen, M J; Chilcott, J; Hickin, G; Miller, N D; Woollard, P M

    2001-05-21

    We have investigated the structure-activity relationships of the 1- and 3-substituents and replacements of the 5-phenyl group of GW405212X 1, a potent selective oxytocin antagonist. The effect of these modifications on oxytocin binding antagonism and on pharmacokinetic parameters is reported. PMID:11392542

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

    EPA Science Inventory

    Determining the structure-activity relationships of aminobiphenyl and benzidine analogues

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

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

    PubMed Central

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

    2014-01-01

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

  9. Synthesis and structure-activity relationships of harmine derivatives as potential antitumor agents.

    PubMed

    Cao, Rihui; Fan, Wenxi; Guo, Liang; Ma, Qin; Zhang, Guoxian; Li, Jianru; Chen, Xuemei; Ren, Zhenghua; Qiu, Liqin

    2013-02-01

    Harmine, a naturally occurring ?-carboline alkaloid, showed good antitumor activities together with remarkable neurotoxic effects in animal models. In order to search for novel leading compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were designed and synthesized by modification of position-2, 7 and 9 of ?-carboline nucleus, and their cytotoxic activities against human tumor cell lines were investigated. Acute toxicities and antitumor activities of the selected compounds in mice were also evaluated. Structure-activity relationships studies confirmed that (1) the 7-methoxy structural moiety was the pharmacophore responsible for the neurotoxic effects of this class of compounds; (2) the substituents in position-2 and 9 played a vital role in modulation of their antitumor activities. PMID:23291116

  10. 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

  11. Structure-function relationship of working memory activity with hippocampal and prefrontal cortex volumes.

    PubMed

    Harms, Michael P; Wang, Lei; Csernansky, John G; Barch, Deanna M

    2013-01-01

    A rapidly increasing number of studies are quantifying the system-level network architecture of the human brain based on structural-to-structural and functional-to-functional relationships. However, a largely unexplored area is the nature and existence of "cross-modal" structural-functional relationships, in which, for example, the volume (or other morphological property) of one brain region is related to the functional response to a given task either in that same brain region, or another brain region. The present study investigated whether the gray matter volume of a selected group of structures (superior, middle, and inferior frontal gyri, thalamus, and hippocampus) was correlated with the fMRI response to a working memory task, within a mask of regions previously identified as involved with working memory. The subjects included individuals with schizophrenia, their siblings, and healthy controls (n = 154 total). Using rigorous permutation testing to define the null distribution, we found that the volume of the superior and middle frontal gyri was correlated with working memory activity within clusters in the intraparietal sulcus (i.e., dorsal parietal cortex) and that the volume of the hippocampus was correlated with working memory activity within clusters in the dorsal anterior cingulate cortex and left inferior frontal gyrus. However, we did not find evidence that the identified structure-function relationships differed between subject groups. These results show that long-distance structural-functional relationships exist within the human brain. The study of such cross-modal relationships represents an additional approach for studying systems-level interregional brain networks. PMID:22362200

  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. Application of the rough sets theory in structure activity relationship of antielectrostatic ammonium compounds.

    PubMed

    Krysi?ski, Jerzy; Skrzypczak, Andrzej; Demski, Grzegorz

    2003-01-01

    The relationships between the chemical structure and the antielectrostatic effect of 112 ammonium compounds were analysed using the method of rough sets. The antielectrostatic activity was determined by measurements of the maximum voltage induced. Using the rough sets approach the smallest set of condition attributes significant for high quality of classification has been found. The resulting decision rules describe relations between the structure and the antielectrostatic properties of ammonium chlorides in terms of significant condition attributes. This may be helpful in predicting the structures of the new antielectrostatic compounds to be synthesized. PMID:13678321

  15. Predicting Electrocatalytic Properties: Modeling Structure-Activity Relationships of Nitroxyl Radicals.

    PubMed

    Hickey, David P; Schiedler, David A; Matanovic, Ivana; Doan, Phuong Vy; Atanassov, Plamen; Minteer, Shelley D; Sigman, Matthew S

    2015-12-30

    Stable nitroxyl radical-containing compounds, such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and its derivatives, are capable of electrocatalytically oxidizing a wide range of alcohols under mild and environmentally friendly conditions. Herein, we examine the structure-function relationships that determine the catalytic activity of a diverse range of water-soluble nitroxyl radical compounds. A strong correlation is described between the difference in the electrochemical oxidation potentials of a compound and its electrocatalytic activity. Additionally, we construct a simple computational model that is able to accurately predict the electrochemical potential and catalytic activity of a wide range of nitroxyl radical derivatives. PMID:26635089

  16. 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

  17. Structure-activity relationship of 39 analogs of laetispicine with antidepressant properties.

    PubMed

    Xie, Hui; Liu, Juan; Yu, Min; Wang, Yong; Yao, Chunyan; Yao, Shuyi; Jin, Di; Hu, Dingyu; Wang, Yanlin; Shen, Jingkang; Pan, Shengli

    2013-01-01

    The natural product Laetispicine ( N -isobutyl-(3,4-methylendioxyphenyl)-2E, 4E, 9E-undecatrienoamide), was isolated from the Piper laetispicum C. DC and screened, for its antidepressant activity and antinociceptive effects. Structure-functional activities of five natural products indicated that biological activity is dependent on double bonds present within the benzene ring and a conjugated double bond located at positions 2-3 and 4-5 in the molecular structure. To further understand the structural-activity relationship of Laetispicine as a new potent and safe antidepressant, the structural-activity relationship of 39 analogs of Laetispicine were synthetized and tested in forced swimming tests in mice whilst also in protective effects against glutamate or H 2 O 2 induced apoptosis in PC12 cells. The results show that the compound 30 - N -isobutyl-11-(4-chlorophenyl) undeca-2E,4E,9E-trienamide exhibited the same activity as the parental compound Laetispicine, and furthermore, the effective dose of this compound is lower than Laetispicine. Therefore, the compound 30 might be a potentially useful therapy in the treatment of depression. For structure, the conjugated double bonds located at 2-3, 4-5 and isolated double bonds from benzene ring are necessary for the antidepressant activities no matter the different length of carbon chain; the isobutyl connected with acylamino also are necessary; and the benzodioxole moiety is replaceable, the halogen atom in phenyl ring at the para-position could enhance this kind of activity. PMID:24228607

  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 ?-estradiol 17-(?-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7'-dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80?M, dose-response curves were used to investigate in detail 86 compounds, identifying 16 low ?M 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. 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

  1. 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.

  2. 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

  3. Quantitative analysis of structure-activity relationships of tetrahydro-2H-isoindole cyclooxygenase-2 inhibitors.

    PubMed

    Khayrullina, V R; Gerchikov, A Ya; Lagunin, A A; Zarudii, F S

    2015-01-01

    Using the GUSAR program, structure-activity relationships on inhibition of cyclooxygenase-2 (COX-2) catalytic activity were quantitatively analyzed for twenty-six derivatives of 4,5,6,7-tetrahydro-2H-isoindole, 2,3-dihydro-1H-pyrrolyzine, and benzothiophene in the concentration range of 0.6-700 nmol/liter IC50 values. Six statistically significant consensus QSAR models for prediction of IC50 values were designed based on MNA- and QNA-descriptors and their combinations. These models demonstrated high accuracy in the prediction of IC50 values for structures of both training and test sets. Structural fragments of the COX-2 inhibitors capable of strengthening or weakening the desired property were determined using the same program. This information can be taken into consideration on molecular design of new COX-2 inhibitors. It was shown that in most cases, the influence of structural fragments on the inhibitory activity of the studied compounds revealed with the GUSAR program coincided with the results of expert evaluation of their effects based on known experimental data, and this can be used for optimization of structures to change the value of their biological activity. PMID:25754042

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

    PubMed

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

    2014-11-15

    Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure-activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold. PMID:25442321

  5. 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

  6. Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group.

    PubMed

    Tevyashova, Anna N; Olsufyeva, Evgenia N; Solovieva, Svetlana E; Printsevskaya, Svetlana S; Reznikova, Marina I; Trenin, Aleksei S; Galatenko, Olga A; Treshalin, Ivan D; Pereverzeva, Eleonora R; Mirchink, Elena P; Isakova, Elena B; Zotchev, Sergey B; Preobrazhenskaya, Maria N

    2013-08-01

    A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties. PMID:23716057

  7. 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 ...

  8. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors

    PubMed Central

    Cuny, Gregory D.; Ulyanova, Natalia P.; Patnaik, Debasis; Liu, Ji-Feng; Lin, Xiangjie; Auerbach, Ken; Ray, Soumya S.; Xian, Jun; Glicksman, Marcie A.; Stein, Ross L.; Higgins, Jonathan M.G.

    2012-01-01

    Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented. PMID:22335895

  9. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors.

    PubMed

    Cuny, Gregory D; Ulyanova, Natalia P; Patnaik, Debasis; Liu, Ji-Feng; Lin, Xiangjie; Auerbach, Ken; Ray, Soumya S; Xian, Jun; Glicksman, Marcie A; Stein, Ross L; Higgins, Jonathan M G

    2012-03-01

    Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented. PMID:22335895

  10. Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library.

    PubMed

    Franzini, Raphael M; Ekblad, Torun; Zhong, Nan; Wichert, Moreno; Decurtins, Willy; Nauer, Angela; Zimmermann, Mauro; Samain, Florent; Scheuermann, Jörg; Brown, Peter J; Hall, Jonathan; Gräslund, Susanne; Schüler, Herwig; Neri, Dario

    2015-03-23

    Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA-encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL-100K, a DNA-encoded chemical library containing 103?200 structurally compact compounds. Affinity screening experiments and DNA-sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate-specific membrane antigen and tankyrase?1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small-molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding. PMID:25650139

  11. 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 ?-methyl, ?-ketothioester substrates and four ketoreductases. Since interactions with the ?-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

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

    PubMed Central

    2009-01-01

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

  13. Structure-Activity Relationship Studies of Cyclopropenimines as Enantioselective Brønsted Base Catalysts

    PubMed Central

    Bandar, Jeffrey S.; Barthelme, Alexandre P.; Mazori, Alon Y.; Lambert, Tristan H.

    2015-01-01

    We recently demonstrated that chiral cyclopropenimines are viable Brønsted base catalysts in enantioselective Michael and Mannich reactions. Herein, we describe a series of structure-activity relationship studies that provide an enhanced understanding of the effectiveness of certain cyclopropenimines as enantioselective Brønsted base catalysts. These studies underscore the crucial importance of dicyclohexylamino substituents in mediating both reaction rate and enantioselectivity. In addition, an unusual catalyst CH···O interaction, which provides both ground state and transition state organization, is discussed. Cyclopropenimine stability studies have led to the identification of new catalysts with greatly improved stability. Finally, additional demonstrations of substrate scope and current limitations are provided herein. PMID:26504512

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

    PubMed

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

    2015-12-01

    Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed. PMID:26522948

  15. 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

  16. Quantitative structure-activity/ecotoxicity relationships (QSAR/QEcoSAR) of a series of phosphonates.

    PubMed

    Petrescu, Alina-Maria; Putz, Mihai V; Ilia, Gheorghe

    2015-11-01

    In this paper the structure-toxicity relationship studies were performed for a series of 60 phosphonates. The toxicity of the compounds was determined by two ways: by quantifying the measured toxicity values, Mlog(1/MRIC50) collected by literature, for rodents species; second by using EcoSAR software version 1.11, for calculating the toxicity for fish species, considered as dependent variables and they were related to structural features obtained by molecular and quantum mechanics calculations. The QSAR/QEcoSAR was validated by multiple linear regression (MLR), although the purpose of this work was not to validate the model proposed, but rather to test the influence of structural parameters of the proposed model QSAR/QEcoSAR. The obtained models showed that the toxicity of phosphonates was influenced by steric and molecular geometry which cause inhibition of cholinesterase activity. PMID:26462182

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

    PubMed Central

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

    2009-01-01

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

  18. 7-Azetidinylquinolones as antibacterial agents. Synthesis and structure-activity relationships.

    PubMed

    Frigola, J; Parés, J; Corbera, J; Vañó, D; Mercè, R; Torrens, A; Más, J; Valentí, E

    1993-04-01

    A series of novel antibacterial quinolones and naphthyridones has been prepared which contain 7-azetidinyl substituents in place of the usual piperazine or aminopyrrolidine groups. These azetidinyl derivatives were evaluated for in vitro activity by determining minimum inhibitory concentrations against a variety of bacteria. In vivo efficacy in the mouse infection model and blood levels in the mouse were determined for several compounds. The influence on the structure-activity relationships of varying substituents in the azetidine ring and at position 8 (CH, CF, CCl, N) and N-1 (ethyl, fluoroethyl, cyclopropyl, tert-butyl, 4-fluorophenyl, and 2,4-difluorophenyl) was also studied. Compounds with outstandingly broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels were identified in this work. 7-Azetidinyl-8-chloroquinolones were considered as warranting further development. PMID:8464033

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

    PubMed

    Sosi?, Izidor; Anderluh, Marko; Sova, Matej; Gobec, Martina; Mlinari? Raš?an, 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

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

    EPA Science Inventory

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

  1. 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...

  2. 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

  3. 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

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

    PubMed

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

    2016-01-01

    Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (P<0.01 or P<0.001) which provides further evidence that DF1 and DF2 also exerts a direct protection against the neuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity. PMID:26484597

  5. Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119.

    PubMed

    Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui

    2014-01-15

    The purpose of the current study was to apply a high throughput assay to investigate the structure-activity relationships of fatty acid amides for activating and desensitizing G protein-coupled receptor 119, a promising therapeutic target for both type 2 diabetes and obesity. A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring G protein-coupled receptor 119-mediated increase of cyclic adenosine monophosphate (cAMP) levels was validated and applied in this study. Using novel fatty acid amides and detailed potency and efficacy analyses, we have demonstrated that degree of saturation in acyl chain and charged head groups of fatty acid amides have profound effects on the ability of these compounds to activate G protein-coupled receptor 119. In addition, we have demonstrated for the first time that pretreatments with G protein-coupled receptor 119 agonists desensitize the receptor and the degrees of desensitization caused by fatty acid amides correlate well with their structure-activity relationships in activating the receptor. PMID:24184668

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

    PubMed

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

    2014-01-01

    The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed. Using a leave-one-out validation routine, the best GPR119 model had an overall concordance of 99%, a sensitivity of 99%, and a specificity of 100%. Our findings from the in-depth fragment analysis of several known GPR119 agonists were consistent with previously reported GPR119 structure-activity relationship (SAR) analyses. Overall, while our results indicate that we have developed a highly predictive cat-SAR model that can be potentially used to rapidly screen for prospective GPR119 ligands, the applicability domain must be taken into consideration. Moreover, our study demonstrates for the first time that the cat-SAR expert system can be used to model G protein-coupled receptor ligands, many of which are important therapeutic agents. PMID:25401513

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

    PubMed

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

    2013-10-01

    Vertebrate testing under the European Union's regulation on Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) is discouraged, and the use of alternative nontesting approaches such as quantitative structure-activity relationships (QSARs) is encouraged. However, robust QSARs predicting chronic ecotoxicity of organic compounds to fish are not available. The Ecological Structure Activity Relationships (ECOSAR) Class Program is a computerized predictive system that estimates the acute and chronic toxicity of organic compounds for several chemical classes based on their log octanol-water partition coefficient (K(OW)). For those chemical classes for which chronic training data sets are lacking, acute to chronic ratios are used to predict chronic toxicity to aquatic organisms. Although ECOSAR reaches a high score against the Organisation for Economic Co-operation and Development (OECD) principles for QSAR validation, the chronic QSARs in ECOSAR are not fully compliant with OECD criteria in the framework of REACH or CLP (classification, labeling, and packaging) regulation. The objective of the present study was to develop a chronic ecotoxicity QSAR for fish for compounds acting via nonpolar and polar narcosis. These QSARs were built using a database of quality screened toxicity values, considering only chronic exposure durations and relevant end points. After statistical multivariate diagnostic analysis, literature-based, mechanistically relevant descriptors were selected to develop a multivariate regression model. Finally, these QSARs were tested for their acceptance for regulatory purposes and were found to be compliant with the OECD principles for the validation of a QSAR. PMID:23775559

  8. Structure–Activity Relationships and Molecular Modeling of Sphingosine Kinase Inhibitors

    PubMed Central

    2013-01-01

    The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure–activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention. PMID:24164513

  9. 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

  10. Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of goniothalamin analogs.

    PubMed

    Mohideen, Mazlin; Zulkepli, Suraya; Nik-Salleh, Nik-Salmah; Zulkefeli, Mohd; Weber, Jean-Frédéric Faizal; Weber, Jean-Frédéric Faizal Abdullah; Rahman, A F M Motiur

    2013-07-01

    A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 ?M). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity. PMID:23543632

  11. Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors

    PubMed Central

    Suree, Nuttee; Yi, Sung Wook; Thieu, William; Marohn, Melanie; Damoiseaux, Robert; Chan, Albert; Jung, Michael E.; Clubb, Robert T.

    2010-01-01

    Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structureactivity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC50 values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors. PMID:19781950

  12. 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

  13. Quantitative structure activity relationship modeling for predicting radiosensitization effectiveness of nitroimidazole compounds.

    PubMed

    Long, Wei; Liu, Peixun

    2010-01-01

    This paper provides quantitative structure activity relationship (QSAR) models for predicting the radiosensitization effectiveness of nitroimidazole compounds. A new method, combining a heuristic method and projection pursuit regression, was used to build an advanced QSAR model. Compared to the conventional multi-linear regression model, this model showed better predictive ability and reliability, with the values of regression coefficient (R(2)) and root mean square error (RMSE) 0.92 and 0.18 for the training set and 0.90 and 0.17 for the test set, respectively. The provided models were useful tools to predict the radiosensitization effectiveness of nitroimidazole compounds. Also, the new finding descriptors derived from this study will help us to facilitate the design of new radiation sensitizers with better activities. PMID:20921823

  14. Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models.

    PubMed

    Keefer, Christopher E; Kauffman, Gregory W; Gupta, Rishi Raj

    2013-02-25

    A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year. PMID:23343412

  15. 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

  16. 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.

  17. 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

  18. 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 of Ni-based catalyst materials. Chapter V discusses the synthesis of tin-titanium oxide nanoparticles with tunable lattice constants. These materials could be used to make high-surface-area supports for thin layers of OER catalysts, which is important for maximizing catalyst surface area, minimizing the use of precious-metal catalysts, and optimizing 3D structure for enhanced mass/bubble transport. Finally, Chapter VI summarizes this work and outlines directions for future research.

  19. 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.

  20. Toxicity of ionic liquids: database and prediction via quantitative structure-activity relationship method.

    PubMed

    Zhao, Yongsheng; Zhao, Jihong; Huang, Ying; Zhou, Qing; Zhang, Xiangping; Zhang, Suojiang

    2014-08-15

    A comprehensive database on toxicity of ionic liquids (ILs) is established. The database includes over 4000 pieces of data. Based on the database, the relationship between IL's structure and its toxicity has been analyzed qualitatively. Furthermore, Quantitative Structure-Activity relationships (QSAR) model is conducted to predict the toxicities (EC50 values) of various ILs toward the Leukemia rat cell line IPC-81. Four parameters selected by the heuristic method (HM) are used to perform the studies of multiple linear regression (MLR) and support vector machine (SVM). The squared correlation coefficient (R(2)) and the root mean square error (RMSE) of training sets by two QSAR models are 0.918 and 0.959, 0.258 and 0.179, respectively. The prediction R(2) and RMSE of QSAR test sets by MLR model are 0.892 and 0.329, by SVM model are 0.958 and 0.234, respectively. The nonlinear model developed by SVM algorithm is much outperformed MLR, which indicates that SVM model is more reliable in the prediction of toxicity of ILs. This study shows that increasing the relative number of O atoms of molecules leads to decrease in the toxicity of ILs. PMID:24996150

  1. 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.

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

    PubMed Central

    Putz, Mihai V.; Lacr?m?, 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.

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

    SciTech Connect

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

    1996-10-01

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

  4. Neuroprotective coumarins from the root of Angelica gigas: structure-activity relationships.

    PubMed

    Kang, So Young; Kim, Young Choong

    2007-11-01

    An n-butanol-soluble fraction of the root of Angelica gigas Nakai (Umbelliferae) exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. Using neuroprotective activity-guided fractionation, nine coumarins; marmesinin (1), nodakenin (2), columbianetin-O-beta-D-glucopyranoside (3), (S)-peucedanol-7-O-beta-D-glucopyranoside (4), (S)-peucedanol-3'-O-beta-D-glucopyranoside (5), skimmin (6), apiosylskimmin (7), isoapiosylskimmin (8) and magnolioside (9), were isolated from the n-butanol fraction. Of these nine coumarins, three dihydrofuranocoumarins; 1, 2 and 3, exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viabilities of about 50% at concentrations ranging from 0.1 to 10 microM. To explore the structure-activity relationships of coumarins, sixteen previously isolated compounds; 10-25, were simultaneously evaluated in the same system. Our results revealed that cyclization of the isoprenyl group, such as dihydropyran or dihydrofuran, or the furan ring at the C-6 position of coumarin, as well as lipophilicity played an important role in the neuroprotective activity of coumarins. PMID:18087802

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

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2013-09-23

    It is well-known that different molecular representations, e.g., graphs, numerical descriptors, fingerprints, or 3D models, change the numerical results of molecular similarity calculations. Because the assessment of structure-activity relationships (SARs) requires similarity and potency comparisons of active compounds, this representation dependence inevitably also affects SAR analysis. But to what extent? How exactly does SAR information change when alternative fingerprints are used as descriptors? What is the proportion of active compounds with substantial changes in SAR information induced by different fingerprints? To provide answers to these questions, we have quantified changes in SAR information across many different compound classes using six different fingerprints. SAR profiling was carried out on 128 target-based data sets comprising more than 60,000 compounds with high-confidence activity annotations. A numerical measure of SAR discontinuity was applied to assess SAR information on a per compound basis. For ~70% of all test compounds, changes in SAR characteristics were detected when different fingerprints were used as molecular representations. Moreover, the SAR phenotype of ~30% of the compounds changed, and distinct fingerprint-dependent local SAR environments were detected. The fingerprints we compared were found to generate SAR models that were essentially not comparable. Atom environment and pharmacophore fingerprints produced the largest differences in compound-associated SAR information. Taken together, the results of our systematic analysis reveal larger fingerprint-dependent changes in compound-associated SAR information than would have been anticipated. PMID:23968259

  6. 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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

    Tuberculosis is considered to be one of the major health problem not only in the less developed countries but in the economically developed countries as well. Roughly one third of the world's population are infected with Mycobacterium tuberculosis and a significant part of them are carriers of latent tuberculosis. From ten percent of these latent infections are developing the active TB disease and fifty percent of them die from the illness without appropriate treatment. The drug-resistant Mycobacterium tuberculosis (MDR-TB, XDR-TB) and TB-HIV co-infection attracted attention to the most serious infectious disease. Inhibition of alternative signaling pathways were an important part of the research strategies for cancer and inflammatory diseases in recent years. In case of Mycobacterium tuberculosis such pathways were also identified, for example, three serine-threonine kinases (PknA, PknB, PknG) which are necessary and essential for bacterial growth. In this paper we summarize our best anti-TB active compounds, their biological effects and structure-activity relationships using in silico modeling, biochemical measurements and tests on active bacteria. PMID:24369587

  9. Amyloid-? probes: Review of structure–activity and brain-kinetics relationships

    PubMed Central

    Eckroat, Todd J; Mayhoub, Abdelrahman S

    2013-01-01

    Summary 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-? 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

  10. Metal toxicity in two rodent species and redox potential: Evaluation of quantitative structure-activity relationships

    SciTech Connect

    Lewis, D.F.V.; Dobrota, M.; Taylor, M.G.; Parke, D.V.

    1999-10-01

    A quantitative structure-activity relationship study of acute toxicity in the mouse and rat is described for the soluble salts of a relatively large number of metals (between 25 and 30 in total). Electrode potential is the major determinant of acute metal toxicity for an intraperitoneal dose in the mouse, whereas the addition of ionic radius and polarizability enables the inclusion of notable outliers in the original expression, such as beryllium and barium, thus giving a good correlation with toxicity for 27 metal compounds. These findings are rationalized on the basis of relative ease of ionization, electron affinity, and transport factors of the metals and their ions, thus being consistent with the hard and soft acids and bases properties of metals and their biological reactivities.

  11. 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

  12. Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

    PubMed Central

    2014-01-01

    EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure–activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3–5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis. PMID:24900841

  13. Improved Quantitative Structure-Activity Relationship Models to Predict Antioxidant Activity of Flavonoids in Chemical, Enzymatic, and Cellular Systems

    PubMed Central

    Khlebnikov, Andrei I.; Schepetkin, Igor A.; Domina, Nina G.; Kirpotina, Liliya N.; Quinn, Mark T.

    2007-01-01

    Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all 3 assay systems using the FP method (0.966, 0.948, and 0.965 for datasets in evaluated in the biochemical, enzymatic, and whole cells assay systems, respectively). Furthermore, high leave-one-out cross-validation coefficients (q2) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential. PMID:17166721

  14. Improved quantitative structure-activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems.

    PubMed

    Khlebnikov, Andrei I; Schepetkin, Igor A; Domina, Nina G; Kirpotina, Liliya N; Quinn, Mark T

    2007-02-15

    Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using (i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and (ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all three assay systems using the FP method (0.966, 0.948, and 0.965 for datasets evaluated in the biochemical, enzymatic, and whole cell assay systems, respectively). Furthermore, high leave-one-out cross-validation coefficients (q2) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential. PMID:17166721

  15. 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 ?-hydroxymethylserine) and hydrophobic (?-methyl phenylalanine and p-(t)butyl phenylalanine) groups were designed to improve the antimicrobial activity, and their ?-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

  16. Quantitative Structure-Activity Relationship Studies of 4-Imidazolyl- 1,4-dihydropyridines as Calcium Channel Blockers

    PubMed Central

    Hadizadeh, Farzin; Vahdani, Saadat; Jafarpour, Mehrnaz

    2013-01-01

    Objective(s): The structure- activity relationship of a series of 36 molecules, showing L-type calcium channel blocking was studied using a QSAR (quantitative structure–activity relationship) method. Materials and Methods: Structures were optimized by the semi-empirical AM1 quantum-chemical method which was also used to find structure-calcium channel blocking activity trends. Several types of descriptors, including electrotopological, structural and thermodynamics were used to derive a quantitative relationship between L-type calcium channel blocking activity and structural properties. The developed QSAR model contributed to a mechanistic understanding of the investigated biological effects. Results: Multiple linear regressions (MLR) was employed to model the relationships between molecular descriptors and biological activities of molecules using stepwise method and genetic algorithm as variable selection tools. The accuracy of the proposed MLR model was illustrated using cross-validation, and Y-randomisation -as the evaluation techniques. Conclusion: The predictive ability of the model was found to be satisfactory and could be used for designing a similar group of 1,4- dihydropyridines , based on a pyridine structure core which can block calcium channels. PMID:24106595

  17. 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

  18. Adapted Transfer of Distance Measures for Quantitative Structure-Activity Relationships

    NASA Astrophysics Data System (ADS)

    Rückert, Ulrich; Girschick, Tobias; Buchwald, Fabian; Kramer, Stefan

    Quantitative structure-activity relationships (QSARs) are regression models relating chemical structure to biological activity. Such models allow to make predictions for toxicologically or pharmacologically relevant endpoints, which constitute the target outcomes of trials or experiments. The task is often tackled by instance-based methods (like k-nearest neighbors), which are all based on the notion of chemical (dis-)similarity. Our starting point is the observation by Raymond and Willett that the two big families of chemical distance measures, fingerprint-based and maximum common subgaph based measures, provide orthogonal information about chemical similarity. The paper presents a novel method for finding suitable combinations of them, called adapted transfer, which adapts a distance measure learned on another, related dataset to a given dataset. Adapted transfer thus combines distance learning and transfer learning in a novel manner. In a set of experiments, we compare adapted transfer with distance learning on the target dataset itself and inductive transfer without adaptations. In our experiments, we visualize the performance of the methods by learning curves (i.e., depending on training set size) and present a quantitative comparison for 10% and 100% of the maximum training set size.

  19. Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors.

    PubMed

    Congdon, Molly D; Childress, Elizabeth S; Patwardhan, Neeraj N; Gumkowski, James; Morris, Emily A; Kharel, Yugesh; Lynch, Kevin R; Santos, Webster L

    2015-11-01

    Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1. PMID:25862200

  20. The quorum-sensing inhibiting effects of stilbenoids and their potential structure-activity relationship.

    PubMed

    Sheng, Ji-Yang; Chen, Tong-Tong; Tan, Xiao-Juan; Chen, Ting; Jia, Ai-Qun

    2015-11-15

    Stilbenoids, known an important phytoalexins in plants, were renowned for their beneficial effects on cardiovascular, neurological and hepatic systems. In the present study, quorum sensing inhibition activity of ten stilbenoids were tested using Chromobacterium violaceum CV026 as the bio-indicator strain and the structure-activity relationship was also investigated. Among them, resveratrol (1), piceatannol (2) and oxyresveratrol (3) showed potential anti-QS activities. At the sub-MIC concentrations, 1-3 demonstrated a statistically significant reduction of violacein in C. violaceum CV026 in a concentration dependent manner. Furthermore, the effects of 1-3 on QS regulated virulence factors in Pseudomonas aeruginosa PAO1 were also evaluated. Our results showed that the stilbenoids 1-3 can markedly decreased the production of pyocyanin and swarming motility of P. aeruginosa PAO1. Further transcriptome analyses showed that 1-3 suppressed the expression of QS-induced genes: lasR, lasI, rhlR and rhlI. PMID:26453007

  1. Structure-activity relationship of highly potent galactonoamidine inhibitors toward ?-galactosidase (Aspergillus oryzae).

    PubMed

    Fan, Qiu-Hua; Claunch, Kailey A; Striegler, Susanne

    2014-11-13

    A small library of 22 N-substituted galactonoamidines was synthesized, and their structure-activity relationship for inhibition of the hydrolytic activity of ?-galactosidase (Aspergillus oryzae) was evaluated. A fast screening assay in 96-well plate format was used to follow the enzymatic hydrolysis of 2-chloro-4-nitrophenyl-?-D-galactopyranoside using UV-vis spectroscopy. The aglycon moiety of all compounds was found to have a profound effect on their inhibitory ability. In general, galactonoamidines derived from cyclic aliphatic and linear amines show higher inhibition activity than those derived from benzylamines. Hydrophobic interactions of the methyl group rather than ?-? stacking interactions of the aromatic ring in p-methylbenzyl-D-galactonoamidine were identified to cause its transition-state-like character and the remarkably high inhibitory ability (K(i) = 8 nM). A flexible 3-carbon methylene spacer between the exo N atom of the sugar moiety and a phenyl group furthermore increased the observed apparent inhibition drastically. PMID:25295392

  2. 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 GTP?S 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

  3. 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.

  4. Structural and spectroscopic characterisation of C4 oxygenates relevant to structure/activity relationships of the hydrogenation of ?,?-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.

  5. Structural and spectroscopic characterisation of C4 oxygenates relevant to structure/activity relationships of the hydrogenation of ?,?-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

  6. 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...

  7. Analysis of the Internal Representations Developed by Neural Networks for Structures Applied to Quantitative Structure-Activity Relationship Studies of Benzodiazepines

    E-print Network

    Sperduti, Alessandro

    to Quantitative Structure-Activity Relationship Studies of Benzodiazepines A. Micheli, A. Sperduti,*, and A,4-benzodiazepin- 2-ones is analyzed by the proposed approach. It compares favorably versus the traditional QSAR

  8. Genotoxicity of the hydroquinone metabolite of ochratoxin A: structure-activity relationships for covalent DNA adduction.

    PubMed

    Tozlovanu, Mariana; Faucet-Marquis, Virginie; Pfohl-Leszkowicz, Annie; Manderville, Richard A

    2006-09-01

    Ochratoxin A (OTA) is a mycotoxin that shows potent nephrotoxicity and renal carcinogenicity in rodents. One hypothesis for OTA-induced tumor formation is based on its genotoxic properties that are promoted by oxidative metabolism. Like other chlorinated phenols, OTA undergoes an oxidative dechlorination process to generate a quinone (OTQ)/hydroquinone (OTHQ) redox couple that may play a role in OTA-mediated genotoxicity. To determine whether the OTQ/OTHQ redox couple of OTA contributes to genotoxicity, the DNA adduction properties, as evidenced by the (32)P-postlabeling technique, of the hydroquinone analogue (OTHQ) have been compared to OTA in the absence and presence of metabolic activation (pig kidney microsomes) and within human bronchial epithelial (WI26) and human kidney (HK2) cells. Our experiments show that OTHQ generates DNA adduct spots in the absence of metabolic activation. These adducts are ascribed to covalent DNA adduction by OTQ generated through autoxidation of the hydroquinone precursor, OTHQ. Although OTA does not interact with DNA in the absence of metabolism, the OTQ-mediated DNA adduct spots noted with OTHQ are also observed with OTA following treatment with pig kidney microsomes and NADPH, suggesting that OTA undergoes oxidative activation to OTQ by cytochrome P450 or enzymes with peroxidase activity. Comparison of DNA adduction by OTHQ and OTA in human cell lines shows that OTQ-mediated adduct spots form in a dose- and time-dependent manner. The adduct spots form at a faster rate with OTHQ, which is consistent with more facile generation of OTQ from its hydroquinone precursor. These results establish structure-activity relationships for OTA-mediated DNA adduction and provide new evidence for the potential role of the OTQ/OTHQ redox couple in OTA-induced genotoxicity. PMID:16978030

  9. Structure-activity relationship of trifluoromethyl-containing metallocenes: electrochemistry, lipophilicity, cytotoxicity, and ROS production.

    PubMed

    Maschke, Marcus; Alborzinia, Hamed; Lieb, Max; Wölfl, Stefan; Metzler-Nolte, Nils

    2014-06-01

    We report the synthesis of trifluoromethylated metallocenes (M=Fe, Ru) and related metal-free compounds for comparison of their biological properties with the aim to establish structure-activity relationships toward the anti-proliferative activity of this compound class. All new compounds were comprehensively characterized by NMR spectroscopy ((1) H, (13) C, (19) F), mass spectrometry, IR spectroscopy, and elemental analysis. A single-crystal X-ray structure was obtained on the Ru derivative, 1-(1-hydroxy-1-hexafluoromethylethyl)ruthenocene (3). The cytotoxicity of all compounds was tested on MCF-7, HT-29, and PT-45 cells, and IC50 values as low as 12 ?M were observed. Both the metallocene moiety and the hydroxy function are crucial for cytotoxicity. In addition, the activity decreased sharply even if only one trifluoromethyl group was replaced with a methyl group. Electrochemical investigations by cyclic voltammetry revealed that all CF3 -containing compounds are harder to oxidize than the unsubstituted metallocenes. Moreover, log?P determination by RP-HPLC showed the fluorinated derivatives to have higher lipophilicity, with log?P values up to 4.6. At the same time, the generation of reactive oxygen species (ROS) in Jurkat cells by these compounds was investigated by flow cytometry. Strong ROS production was shown exclusively for the bis-CF3 derivative 1-(1-hydroxy-1-hexafluoromethylethyl)ferrocene (1) after 6 and 24 h. Also on the Jurkat cell line, only compound 1 strongly induces necrosis after 24 and 48 h, as shown by annexin V/propidium iodide staining. No induction of apoptosis was observed. We propose that compound 1 is more efficiently incorporated into cancer cells relative to all other derivatives, causing significant induction of oxidative stress within the cell, which ultimately leads to cell death. PMID:24838930

  10. Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities.

    PubMed

    Cardoso, Marcos Veríssimo de Oliveira; Moreira, Diogo Rodrigo Magalhães; Oliveira Filho, Gevanio Bezerra; Cavalcanti, Suellen Melo Tiburcio; Coelho, Lucas Cunha Duarte; Espíndola, José Wanderlan Pontes; Gonzalez, Laura Rubio; Rabello, Marcelo Montenegro; Hernandes, Marcelo Zaldini; Ferreira, Paulo Michel Pinheiro; Pessoa, Cláudia; Alberto de Simone, Carlos; Guimarães, Elisalva Teixeira; Soares, Milena Botelho Pereira; Leite, Ana Cristina Lima

    2015-05-26

    The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNF?, IFN?, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups. PMID:25942060

  11. Structure-activity relationship of flavonoids on their anti-Escherichia coli activity and inhibition of DNA gyrase.

    PubMed

    Wu, Ting; Zang, Xixi; He, Mengying; Pan, Siyi; Xu, Xiaoyun

    2013-08-28

    Flavonoids are potential sources of natural preservatives. The inhibitory activities of three polymethoxylated flavones (PMFs), three flavones, and four flavonols against Escherichia coli were determined using the microbroth dilution method. Flavonoid inhibitory activities against DNA gyrase from E. coli were estimated by DNA supercoiling. Kaempferol exhibited the greatest antibacterial activity [minimal inhibitory concentration (MIC) = 25 ?g/mL], while nobiletin showed the lowest activity (MIC = 177 ?g/mL). A good correlation was found between the pIC50 values and the corresponding pMIC values for the purified DNA gyrase (r = 0.9582). The structure-activity relationship analysis suggests that, for a good inhibitory effect, the hydroxyl group substitution at C-5 in the A ring and C-4' in the B ring and the methoxyl group substitution at C-3 and C-8 in the A ring are essential. The presence of the hydroxyl group at C-6 in the A ring, C-3' and C-5' in the B ring, and C-3 in the C ring and the methoxyl group at C-3' in the B ring greatly reduced inhibition of bacteria. These findings provide a theoretical basis for the development of high-bioactive and low-toxicity natural preservatives. PMID:23926942

  12. Biological activity, design, synthesis and structure activity relationship of some novel derivatives of curcumin containing sulfonamides.

    PubMed

    Lal, Jaggi; Gupta, Sushil K; Thavaselvam, D; Agarwal, Dau D

    2013-06-01

    Five series of curcumin derivatives with sulfonamides 3a-3e, 4a-4e, 5a-5e, 6a-6e and 7a-7e have been synthesized and evaluated for in vitro antibacterial activity against selected medically important gram-(+) and gram-(-) bacterial species viz. Staphylococcus aureus, Bacillus cereus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli, and antifungal activity against few pathogenic fungal species viz. Aspergillus niger, Aspergillus flavus, Trichoderma viride and Curvularia lunata. The cytotoxicity has been determined by measuring IC50 values against human cell lines HeLa, Hep G-2, QG-56 and HCT-116. Among the compounds screened, 3a-3e showed the most potent biological activity against tested bacteria and fungi. Compounds 3a-3e displayed higher cytotoxicity than curcumin. The curcumin derivatives were also evaluated for in vivo anti-inflammatory activity. In contrast, the compounds 6a-6e and 7a-7e showed dramatically decrease in biological activity. PMID:23685942

  13. 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

  14. 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

  15. The effects and mechanism of flavonoid-rePON1 interactions. Structure-activity relationship study.

    PubMed

    Atrahimovich, Dana; Vaya, Jacob; Khatib, Soliman

    2013-06-01

    Flavonoids are plant phenolic secondary metabolites that are widely distributed in the human diet. These antioxidants have received much attention because of their neuroprotective, cardioprotective, and chemopreventive actions. While a major focus has been on the flavonoids' antioxidant properties, there is an emerging view that many of the potential health benefits of flavonoids and their in vivo metabolites are due to modulatory actions in cells through direct interactions with proteins, and not necessarily due to their antioxidant function. This view relies on the observations that flavonoids are present in the circulation at very low concentrations, which are not sufficient to exert effective antioxidant effects. The enzyme paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL), and is responsible for many of HDLs' antiatherogenic properties. We previously showed that the flavonoid glabridin binds to rePON1 and affects the enzyme's 3D structure. This interaction protects the enzyme from inhibition by an atherogenic component of the human carotid plaque. Here, we broadened our study to an investigation of the structure-activity relationships (SARs) of 12 flavonoids from different subclasses with rePON1 using Trp-fluorescence quenching, modeling calculations and Cu(2+)-induced low-density lipoprotein (LDL) oxidation methods. Our findings emphasize the 'protein-binding' mechanism by which flavonoids exert their beneficial biological role toward rePON1. Flavonoids' capacity to interact with the enzyme's rePON1 hydrophobic groove mostly dictates their pro/antioxidant behavior. PMID:23623675

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

    PubMed

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

    2014-01-01

    PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide. PMID:24350995

  17. 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

  18. Structure-Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors.

    PubMed

    Papillon, Julien P N; Adams, Christopher M; Hu, Qi-Ying; Lou, Changgang; Singh, Alok K; Zhang, Chun; Carvalho, Jose; Rajan, Srinivan; Amaral, Adam; Beil, Michael E; Fu, Fumin; Gangl, Eric; Hu, Chii-Whei; Jeng, Arco Y; LaSala, Daniel; Liang, Guiqing; Logman, Michael; Maniara, Wieslawa M; Rigel, Dean F; Smith, Sherri A; Ksander, Gary M

    2015-06-11

    CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing's disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs. PMID:25953419

  19. Structure-activity relationships in the peptide antibiotic nisin: antibacterial activity of fragments of nisin.

    PubMed

    Chan, W C; Leyland, M; Clark, J; Dodd, H M; Lian, L Y; Gasson, M J; Bycroft, B W; Roberts, G C

    1996-07-22

    The post-translationally modified peptide antibiotic nisin has been cleaved by a number of proteases and the fragments produced purified, characterised chemically, and assayed for activity in inhibiting the growth of Lactococcus lactis MG1614 and Micrococcus luteus NCDO8166. These results provide information on the importance of different parts of the nisin molecule for its growth-inhibition activity. Removal of the C-terminal five residues leads to approximately a 10-fold decrease in potency, while removal of a further nine residues, encompassing two of the lanthionine rings, leads to a 100-fold decrease. There are some differences between analogous fragments of nisin and subtilin, suggesting possible subtle differences in mode of action. Cleavage within, or removal of, lanthionine ring C essentially abolishes the activity of nisin. The fragment nisin1-12 is inactive itself, and specifically antagonises the growth-inhibitory action of nisin. These results are discussed in terms of current models for the mechanism of action of nisin. PMID:8706842

  20. Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids

    PubMed Central

    Wiley, Jenny L.; Marusich, Julie A.; Huffman, John W.

    2013-01-01

    Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as “spice” or “herbal incense.” While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018’s naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids. PMID:24071522

  1. Structure activity relationship of phenolic acid inhibitors of ?-synuclein fibril formation and toxicity

    PubMed Central

    Ardah, Mustafa T.; Paleologou, Katerina E.; Lv, Guohua; Abul Khair, Salema B.; Kazim, Abdulla S.; Minhas, Saeed T.; Al-Tel, Taleb H.; Al-Hayani, Abdulmonem A.; Haque, Mohammed E.; Eliezer, David; El-Agnaf, Omar M. A.

    2014-01-01

    The aggregation of ?-synuclein (?-syn) is considered the key pathogenic event in many neurological disorders such as Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, giving rise to a whole category of neurodegenerative diseases known as synucleinopathies. Although the molecular basis of ?-syn toxicity has not been precisely elucidated, a great deal of effort has been put into identifying compounds that could inhibit or even reverse the aggregation process. Previous reports indicated that many phenolic compounds are potent inhibitors of ?-syn aggregation. The aim of the present study was to assess the anti-aggregating effect of gallic acid (GA) (3,4,5-trihydroxybenzoic acid), a benzoic acid derivative that belongs to a group of phenolic compounds known as phenolic acids. By employing an array of biophysical and biochemical techniques and a cell-viability assay, GA was shown not only to inhibit ?-syn fibrillation and toxicity but also to disaggregate preformed ?-syn amyloid fibrils. Interestingly, GA was found to bind to soluble, non-toxic oligomers with no ?-sheet content, and to stabilize their structure. The binding of GA to the oligomers may represent a potential mechanism of action. Additionally, by using structure activity relationship data obtained from fourteen structurally similar benzoic acid derivatives, it was determined that the inhibition of ?-syn fibrillation by GA is related to the number of hydroxyl moieties and their position on the phenyl ring. GA may represent the starting point for designing new molecules that could be used for the treatment of PD and related disorders. PMID:25140150

  2. A cytotoxic principle of Tamarindus indica, di-n-butyl malate and the structure-activity relationship of its analogues.

    PubMed

    Kobayashi, A; Adenan, M I; Kajiyama, S; Kanzaki, H; Kawazu, K

    1996-01-01

    Bioassay-guided fractionation of the methanolic extract of Tamarindus indica fruits led to the isolation of L-(-)-di-n-butyl malate which exhibited a pronounced cytotoxic activity against sea urchin embryo cells. In order to study structure-activity relationships, close-structure relatives of di-n-butyl malate were synthesized using D-(+)- and L-(-)-malic acid as starting materials, and their cytotoxic activities were examined for the sea urchin embryo assay. L-(-)-Di-n-pentyl malate was the most effective inhibitor to the development of the fertilized eggs. Significant inhibitory activity was not seen in the esters of D-(-)-isomer. PMID:8639230

  3. Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity.

    PubMed

    Chen, Yilin; Cass, Shelley L; Kutty, Samuel K; Yee, Eugene M H; Chan, Daniel S H; Gardner, Christopher R; Vittorio, Orazio; Pasquier, Eddy; Black, David StC; Kumar, Naresh

    2015-11-15

    Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells. PMID:26432036

  4. 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

  5. Synthesis and structure-activity relationships and effects of phenylpropanoid amides of octopamine and dopamine on tyrosinase inhibition and antioxidation.

    PubMed

    Wu, Zhengrong; Zheng, Lifang; Li, Yang; Su, Feng; Yue, Xiaoxuan; Tang, Wei; Ma, Xiaoyan; Nie, Junyu; Li, Hongyu

    2012-09-15

    Phenylpropanoid amides of octopamine (OA) 1a-1e and dopamine (DA) 2a-2e were synthesised and the structure-activity relationships (SARs) for antioxidant and tyrosinase inhibition activities were analysed. Among synthesised compounds, 2c, which contains two catechol moieties, exhibited the most DPPH radical-scavenging activity (EC(50)=16.2 ± 2.4 ?M), and 1d exhibited significant tyrosinase inhibitory activity (IC(50)=5.3 ± 1.8 ?M). Interestingly, with the same acid moiety, OA derivatives showed more inhibitory effect on tyrosinase than did compounds derived from DA, whereas DA derivatives were found to have higher antioxidant activity than compounds derived from OA. The relationship between their structures and their potencies, demonstrated in the current study, will be useful for the design of optimal agents. PMID:23107737

  6. Synthesis and structure-activity relationships of novel 9-oxime acylides with improved bactericidal activity.

    PubMed

    Han, Xu; Lv, Wei; Guo, Si-Yang; Cushman, Mark; Liang, Jian-Hua

    2015-10-01

    9-Oxime acylides have different SAR and binding modes from 9-oxime ketolides. An aminopyridyl or carbamoylpyridyl group anchored at the end of the 9-oxime 2-propargyl group is beneficial for antimicrobial activity. Both the 2-pyridyl and 3-pyridyl groups derived from 3-OH have stacking interactions with the base pair G2505/C2610 (Escherichia coli numbering) of the bacterial rRNA. Compounds 3 presented characteristic features that belong to bactericidal agents when used against constitutive-erm resistant Staphylococcus aureus, susceptible and mef-encoded Streptococcus pneumoniae, inducible-erm resistant Streptococcus pyogenes, and Moraxella catarrhalis. A docking model indicated that the carbamoylpyridyl group of 3h may hydrogen bond to G2061 in addition to ?-? stacking over the adenine of A2062 that proved to gate the tunnel for the egress of the nascent peptide. This study suggests that the 9-oxime acylides possess a bactericidal mechanism that is different from the traditional near-complete inhibition of protein synthesis. These studies provide a foundation for the rational design of macrolide antibiotics. PMID:26349628

  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 demonstrate the practical application of the RQSAR approach, the structure of vildagliptin, a high-CL and a high-Vdss compound, is modified based on the atomic contributions to its predicted CL and Vdss to propose compounds with lower CL and lower Vdss. PMID:23451981

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

    PubMed

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

    2013-10-01

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

  9. 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.

  10. CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats.

    PubMed

    Toropova, A P; Toropov, A A; Benfenati, E; Gini, G; Leszczynska, D; Leszczynski, J

    2011-09-01

    For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/). The total number of considered compounds is 689. New additional global attributes of the simplified molecular input line entry system (SMILES) have been examined for improvement of the optimal SMILES-based descriptors. These global SMILES attributes are representing the presence of some chemical elements and different kinds of chemical bonds (double, triple, and stereochemical). The "classic" scheme of building up quantitative structure-property/activity relationships and the balance of correlations (BC) with the ideal slopes were compared. For all six random splits, best prediction takes place if the aforementioned BC along with the global SMILES attributes are included in the modeling process. The average statistical characteristics for the external test set are the following: n = 119 ± 6.4, R(2) = 0.7371 ± 0.013, and root mean square error = 0.360 ± 0.037. PMID:21656789

  11. Structure–Activity Relationships of ?-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase

    PubMed Central

    Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L.

    2008-01-01

    A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases. PMID:17559203

  12. 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

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

    PubMed Central

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

    2010-01-01

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O ? Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 ± 0.16 ?M) comparable to that of free cisplatin (3.87 ± 0.37 ?M), and superior to carboplatin (14.75 ± 0.38 ?M). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-rasLSL/+/Ptenfl/fl ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. PMID:20616005

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

    PubMed

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

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. PMID:20616005

  15. 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.

  16. 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 ...

  17. Gene Expression, Mutation, and Structure-Function Relationship of Scorpion Toxin BmP05 Active on SKCa Channels

    E-print Network

    Tian, Weidong

    Gene Expression, Mutation, and Structure-Function Relationship of Scorpion Toxin BmP05 Active+ channels (SKCa) have been isolated from the venom of the Chinese scorpion Buthus martensi, named BmP01, Bm and identified from the venom of scorpions belonging to the Buthidae family. Most of the long-chain scorpion

  18. 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)

    ?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

    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.

  19. 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

  20. Synthesis, Biological Evaluation and Structure-Activity Relationships of Dithiolethiones as Inducers of Cytoprotective Phase 2 Enzymes

    PubMed Central

    Munday, Rex; Zhang, Yuesheng; Paonessa, Joseph D.; Munday, Christine M.; Wilkins, Alistair L.; Babu, Jacob

    2010-01-01

    Dithiolethiones are a family of promising cancer chemopreventive agents, and induction of Phase 2 enzymes is key to their chemopreventive activities. Two dithiolethiones have been evaluated in humans for cancer prevention. While some chemopreventive activities were detected in several human studies, potential side effects are a concern. Herein, we report structure-activity relationships of 25 dithiolethiones. Several compounds show exceedingly potent and bladder specific activity in Phase 2 enzyme induction. Structural features responsible for such activity, as well as those inhibiting the activity, are discussed. Moreover, the compounds activate and depend on Nrf2 for their inductive activities. Nrf2 is a major transcriptional stimulator of cytoprotective genes and is critical for cancer prevention. Thus, several new dithiolethiones that are highly promising for bladder cancer prevention have been identified. Because the compounds act specifically in the bladder, the likelihood of potential systemic toxicity may be low. PMID:20481594

  1. Development of ribonucleotide reductase inhibitors: a review on structure activity relationships.

    PubMed

    Moorthy, Narayana S H N; Cerqueira, Nuno M F S A; Ramos, Maria J; Fernandes, Pedro A

    2013-11-01

    Ribonucleotide reductase (RNR, E.C. 1.17.4.1), which is composed of two dissimilar proteins (subunits), often referred as R1 (containing polythiols) and R2 (containing non-heme iron and a free tyrosyl radical), which contribute to the role played by the enzyme. RNRs are one of the important targets in anticancer and antiviral drug development and many RNR inhibitors have been discovered at the end of the 20(th) century; many of them are already in clinical use. Triapine (3-AP) is one of the important RNR inhibitors belonging to the class of thiosemicarbazone derivatives, used in the treatment of various cancers. The structure activity relationship (SAR) studies on the investigated RNR inhibitors showed that the nitrogen atom in the pyridine (or other heterocycles) forms coordination complexes with the metal ions along with the imine, oxo and thio atoms of the thiosemicarbazone or semicarbazone pharmacophores. The computational analyses results in the adenine and purine derivatives suggest that the nitrogen atoms in the adenine rings make several hydrogen bonds with the water molecules present in the active site, as well as Gly249 and Glu288 residues. The OH group in third position of the sugar moiety interacts with the Ser217 (C=O) and the water molecules through hydrogen bonds. The aromatic rings in the molecules interact with the tyrosine residues. The thiosemicarbazone or semicarbazone derivatives explain that the flexibility and polar properties in the thiosemicarbazone or semicarbazone pharmacophoric regions allow the molecules to coordinate with the metal ion (especially iron) present in the RNR enzymes. This review concluded that RNR inhibitors composed of different fragments such as aryl, heteroaryl, sugar moiety, polar groups, flexible bonds, etc which are required for the binding of the molecules to the RNR enzymes. Further, the fragmental analysis of the RNR inhibitors on different toxicological and metabolic targets can provide significant novel molecules with acceptable pharmacokinetic properties. PMID:24032510

  2. 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

  3. Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity.

    PubMed

    Blaazer, Antoni R; Lange, Jos H M; van der Neut, Martina A W; Mulder, Arie; den Boon, Femke S; Werkman, Taco R; Kruse, Chris G; Wadman, Wytse J

    2011-10-01

    The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB(1)/CB(2) dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB(1) over the CB(2) receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission. PMID:21885167

  4. 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...

  5. A robust structure-activity relationship (SAR) model for esters that cause skin irritation in humans.

    PubMed

    Smith, J S; Macina, O T; Sussman, N B; Luster, M I; Karol, M H

    2000-05-01

    A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested. PMID:10788576

  6. 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

  7. 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

  8. Synthesis and structure-activity relationships of a series of increasingly hydrophobic cationic steroid lipofection reagents.

    PubMed

    Gruneich, Jeffrey A; Diamond, Scott L

    2007-05-01

    The use of cholesterol-based cationic lipids and the ability of glucocorticoids to reduce local inflammatory response to lipoplexes motivated an investigation of structure-activity relationships for cationic steroids. A one-step synthetic scheme using iminothiolane was developed to link spermine to the 21-OH position of steroids via an amidine linkage. Five steroids (cortisol, dexamethasone, corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone) with increasing hydrophobicity of the parent steroid (Log P(ster) from 1.51 to 3.01) were conjugated with spermine, formulated with dioleoylphosphatidylethanolamine (DOPE) at DOPE : steroid mole ratios (R) of R = 0.5 to 2, and then complexed with 1 microg enhanced green fluorescent protein (EGFP) plasmid DNA at charge ratios (CR) = 2 to 24 amines per phosphate (0.5 to 6 steroids per phosphate). The resulting 105 different formulations of the cationic steroid series were used to lipofect bovine aortic endothelial cells. Transgene expression data at either 24 or 48 h post-lipofection for all formulations was collapsed onto master curves when plotted against a single empirical dimensionless parameter, the lipofection index (LI) = CR (Log P(liposome))(Log P(ster)/|DeltaLog P|) [R/(R + 1)] where DeltaLog P = Log P(DOPE)- Log P(ster) and Log P(liposome) is a mole-weighted average of the DOPE/cationic steroid liposome hydrophobicity. For 7 < LI < 29, the EGFP expression at 24 or 48 h post-lipofection increased linearly with LI (EGFP approximately 0 for LI < 7), but did not increase further for LI > 29, thus providing a predictive design rule based on Log P of the hydrophobic moiety of the cationic steroid lipid. PMID:17366520

  9. Quantitative structure activities relationships of some 2-mercaptoimidazoles as CCR2 inhibitors using genetic algorithm-artificial neural networks

    PubMed Central

    Saghaie, L; Shahlaei, M; Fassihi, A

    2013-01-01

    Quantitative relationships between structures of twenty six of 2-mercaptoimidazoles as C-C chemokine receptor type 2 (CCR2) inhibitors were assessed. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of genetic algorithm multivariate linear regression (GA-MLR) and genetic algorithm (GA-ANN). The results showed that, the pIC50 values calculated by GA-ANN are in good agreement with the experimental data, and the performance of the artificial neural networks regression model is superior to the multivariate linear regression-based (MLR) model. With respect to the obtained results, it can be deduced that there is a non-linear relationship between the pIC50 s and the calculated structural descriptors of the 2-mercaptoimidazoles. The obtained models were able to describe about 78% and 93% of the variance in the experimental activity of molecules in training set, respectively. The study provided a novel and effective approach for predicting biological activities of 2-mercaptoimidazole derivatives as CCR2 inhibitors and disclosed that combined genetic algorithm and GA-ANN can be used as a powerful chemometric tools for quantitative structure activity relationship (QSAR) studies. PMID:24019819

  10. Relationship between structure and immunological activity of an arabinogalactan from Lycium ruthenicum.

    PubMed

    Peng, Qiang; Liu, Hang; Lei, Hongjie; Wang, Xiaoqin

    2016-03-01

    An immunologically active arabinogalactan (LRGP3) was selectively degraded by acetolysis, mild acid hydrolysis and enzymatic digestion. After exo-?-l-arabinofuranosidase digestion, 56% of the arabinosyl chains were released. The resistant product (LRGP3-AF) had markedly increased complement fixating activities. The acid hydrolysis product (LRGP3-T) contained (1?3)-linked (17.6%), (1?6)-linked (23.1%), (1?3,6)-linked (30.1%) and terminal (29.2%) galactosyl residues, and its complement fixating activity was lower than that of LRGP3-AF. The side chains (Oligo-S) consisted of arabinose, galactose, and rhamnose in the molar ratios 16.8:1.4:1.0. The complement fixating activity of Oligo-S was weak, but Oligo-S had potent macrophage stimulation activity. Degradation of arabinosyl residues in LRGP3 decreased the macrophage stimulation activity, but the galactan backbone still expressed partial activity. The results demonstrated that the galactan backbone of the polymer might be essential for the expression of complement fixating activity and the arabinosyl side chains could be more responsible for the macrophage activation activity. There may be several structurally different active sites involved in the immunological activity of LRGP3. PMID:26471597

  11. Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: a comparative molecular field analysis study.

    PubMed

    Sicsic, S; Serraz, I; Andrieux, J; Brémont, B; Mathé-Allainmat, M; Poncet, A; Shen, S; Langlois, M

    1997-02-28

    A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 molecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrained molecule which contains a tricyclic phenalene structure. This tricyclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning within the receptor site have been suggested previously. CoMFA was tentatively used to discriminate between alternate hypothetical biologically active conformation and between possible positionings. The best 3D quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolute error of prediction of 0.25 log units. These results suggest that the active conformation of the most flexible molecules including melatonin is in a folded form if we consider the spatial position of the ethylamido side chain relative to the aromatic ring. PMID:9057860

  12. In vitro inhibition effect and structure-activity relationships of some saccharin derivatives on erythrocyte carbonic anhydrase I and II.

    PubMed

    Sonmez, Fatih; Bilen, Cigdem; Sumersan, Sinem; Gencer, Nahit; Isik, Semra; Arslan, Oktay; Kucukislamoglu, Mustafa

    2014-02-01

    In this study, in vitro inhibitory effects of some saccharin derivatives on purified carbonic anhydrase I and II were investigated using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among the compounds, 6-(p-tolylthiourenyl) saccharin (6m) was found to be the most active one for hCA I activity (IC50=13.67 ?M) and 6-(m-methoxyphenylurenyl) saccharin (6b) was found to be the most active one for hCA II activity (IC50=6.54 ?M). Structure-activity relationships (SARs) study showed that, generally, thiourea derivatives (6l--v) inhibited more hCA I and hCA II than urea derivatives (6a-k). All compounds (excluding 6c and 6r) have higher inhibitory activity on hCA II than on hCA I. PMID:23339426

  13. 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

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

    PubMed

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

    2015-02-01

    Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia. PMID:25556092

  15. Structure-activity relationship study around guanabenz identifies two derivatives retaining antiprion activity but having lost ?2-adrenergic receptor agonistic activity.

    PubMed

    Nguyen, Phu Hai; Hammoud, Hassan; Halliez, Sophie; Pang, Yanhong; Evrard, Justine; Schmitt, Martine; Oumata, Nassima; Bourguignon, Jean-Jacques; Sanyal, Suparna; Beringue, Vincent; Blondel, Marc; Bihel, Frédéric; Voisset, Cécile

    2014-10-15

    Guanabenz (GA) is an orally active ?2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an ?2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at ?2-adrenergic receptors, we performed a structure-activity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at ?2-adrenergic receptors. Similarly to GA, 6 and 7 were also able to inhibit the protein folding activity of the ribosome (PFAR) which has been suggested to be involved in prion appearance/maintenance. Therefore, these two GA derivatives are worth being considered as drug candidates. PMID:25244284

  16. Quantitative structure-activity relationship (QSAR) of indoloacetamides as inhibitors of human isoprenylcysteine carboxyl methyltransferase.

    PubMed

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

    2007-02-15

    A QSAR is developed for the isoprenylcysteine carboxyl methyltransferase (ICMT) inhibitory activities of a series of indoloacetamides (n=72) that are structurally related to cysmethynil, a selective ICMT inhibitor. Multivariate analytical tools (principal component analysis (PCA) and projection to latent structures (PLS)), multi-linear regression (MLR) 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

  17. 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

  18. Antimicrobial activities of active component isolated from Lawsonia inermis leaves and structure-activity relationships of its analogues against food-borne bacteria.

    PubMed

    Yang, Ji-Yeon; Lee, Hoi-Seon

    2015-04-01

    The antimicrobial activities of Lawsonia inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues against food-borne bacteria. The antimicrobial activities of five fractions derived from the methanol extract of Lawsonia inermis leaves were evaluated against 7 food-borne bacteria. 2-Hydroxy-1,4-naphthoquinone was isolated by chromatographic analyses. 2-Hydroxy-1,4-naphthoquinone showed the strong activities against Bacillus cereus, Listeria monocytogenes, Salmonella enterica, Shigella sonnei, Staphylococcus epidermidis, and S. intermedius, but exerted no growth-inhibitory activities against S. typhimurium. The antimicrobial activities of the 2-hydroxy-1,4-naphthoquinone analogues were tested against 7 food-borne bacteria to establish structure-activity relationships. Hydroxyl (2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone), methoxy (2-methoxy-1,4-naphthoquinone), and methyl (2-methyl-1,4-naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone) functional groups on the 1,4-naphthoquinone skeleton possessed potent activities, whereas bromo (2-bromo-1,4-naphthoquinone and 2,3-dibromo-1,4-naphthoquione) and chloro (2,3-dichloro-1,4-naphthoquinone) exhibited no activity against 7 food-borne bacteria. The L. inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues should be useful as natural antimicrobial agents against food-borne bacteria. PMID:25829631

  19. Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.

    PubMed

    Wright, Lisa; Barril, Xavier; Dymock, Brian; Sheridan, Louisa; Surgenor, Allan; Beswick, Mandy; Drysdale, Martin; Collier, Adam; Massey, Andy; Davies, Nick; Fink, Alex; Fromont, Christophe; Aherne, Wynne; Boxall, Kathy; Sharp, Swee; Workman, Paul; Hubbard, Roderick E

    2004-06-01

    Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties. PMID:15217611

  20. Structure/activity relationship of some natural monoterpenes as acaricides against Psoroptes cuniculi.

    PubMed

    Perrucci, S; Macchioni, G; Cioni, P L; Flamini, G; Morelli, I

    1995-08-01

    The pharmacological activity of many essential oils on a large number of human and animal pathogens, as used in folk medicine, has been confirmed world-wide by several laboratory investigations. Unfortunately, the biological properties of essential oils can be extremely inconsistent because of the variability of their chemical composition. The acaricidal activities of some natural terpenoids, which are the main constitutents of several essential oils, were evaluated in vitro against the mange mite (Psoroptes cuniculi) of the rabbit, by direct contact and by inhalation. Because the test components represent different chemical classes (hydrocarbons, alcohols, and phenols, with free and esterified or etherified functional groups), it was also possible to discern in a preliminary fashion a correlation between chemical structure and acaricidal activity. The results obtained suggest that molecules possessing free alcoholic or phenolic groups showed the most potent acaricidal activity. PMID:7595592

  1. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODELS FOR PREDICTION OF ESTROGEN RECEPTOR BINDING AFFINITY OF STRUCTURALLY DIVERSE CHEMICALS

    EPA Science Inventory

    The demonstrated ability of a variety of structurally diverse chemicals to bind to the estrogen receptor has raised the concern that chemicals in the environment may be causing adverse effects through interference with nuclear receptor pathways. Many structure-activity relationsh...

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

    PubMed

    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. PMID:23747386

  4. AnalogExplorer: a new method for graphical analysis of analog series and associated structure-activity relationship information.

    PubMed

    Zhang, Bijun; Hu, Ye; Bajorath, Jürgen

    2014-11-13

    In recent years, several attempts have been made to develop graphical methods for the analysis of structure-activity relationships (SARs) in increasingly large and heterogeneous compound data sets. Among others, these approaches include extensions of conventional R-group tables and graph representations for the analysis of active analogs. Herein, we introduce AnalogExplorer as a new method for the graphical exploration of analog series. AnalogExplorer consists of three graphical components and is methodologically distinct from previous SAR visualization techniques. It is designed to deconvolute large series of analogs and systematically analyze and compare analog series contained in structurally heterogeneous data sets. In addition, analog subsets forming activity cliffs and R-groups responsible for cliff formation are easily identified in AnalogExplorer graphs. The design of AnalogExplorer is described in detail, and exemplary applications are discussed. In addition, the implementation of AnalogExplorer is made freely available. PMID:25333505

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

    SciTech Connect

    Sadat Hayatshahi, Sayyed Hamed; Khajeh, Khosro

    2005-12-16

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

  6. Rapid preparation of rare ginsenosides by acid transformation and their structure-activity relationships against cancer cells

    PubMed Central

    Quan, Kai; Liu, Qun; Wan, Jin-Yi; Zhao, Yi-Jing; Guo, Ru-Zhou; Alolga, Raphael N.; Li, Ping; Qi, Lian-Wen

    2015-01-01

    The anticancer activities of ginsenosides are widely reported. The structure-activity relationship of ginsenosides against cancer is not well elucidated because of the unavailability of these compounds. In this work, we developed a transformation method to rapidly produce rare dehydroxylated ginsenosides by acid treatment. The optimized temperature, time course, and concentration of formic acid were 120°C, 4?h and 0.01%, respectively. From 100?mg of Rh1, 8.3?mg of Rk3 and 18.7?mg of Rh4 can be produced by acid transformation. Similarly, from 100?mg of Rg3, 7.4?mg of Rk1 and 15.1?mg of Rg5 can be produced. From 100?mg of Rh2, 8.3?mg of Rk2 and 12.7?mg of Rh3 can be generated. Next, the structure-activity relationships of 23 ginsenosides were investigated by comparing their cytotoxic effects on six human cancer cells, including HCT-116, HepG2, MCF-7, Hela, PANC-1, and A549. The results showed that: (1) the cytotoxic effect of ginsenosides is inversely related to the sugar numbers; (2) sugar linkages rank as C-3 > C-6 > C-20; (3) the protopanaxadiol-type has higher activities; (4) having the double bond at the terminal C20-21 exhibits stronger activity than that at C20-22; and (5) 20(S)-ginsenosides show stronger effects than their 20(R)-stereoisomers. PMID:25716943

  7. Computational identification of RNA functional determinants by three-dimensional quantitative structure–activity relationships

    PubMed Central

    Blanchet, Marc-Frédérick; St-Onge, Karine; Lisi, Véronique; Robitaille, Julie; Hamel, Sylvie; Major, François

    2014-01-01

    Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable and lethal mutants and associated structures. However, determining the structure of enough mutants at high resolution is not always possible. Here, we introduce a new computational method, MC-3DQSAR, to determine the vital elements of target RNA structure from mutagenesis and available high-resolution data. We applied the method to further characterize the structural determinants of the bacterial 23S ribosomal RNA sarcin–ricin loop (SRL), as well as those of the lead-activated and hammerhead ribozymes. The method was accurate in confirming experimentally determined essential structural elements and predicting the viability of new SRL variants, which were either observed in bacteria or validated in bacterial growth assays. Our results indicate that MC-3DQSAR could be used systematically to evaluate the drug-target potentials of any RNA sites using current high-resolution structural data. PMID:25200082

  8. 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

  9. Synthesis and structure-activity relationship of Huprine derivatives as human acetylcholinesterase inhibitors.

    PubMed

    Ronco, Cyril; Sorin, Geoffroy; Nachon, Florian; Foucault, Richard; Jean, Ludovic; Romieu, Anthony; Renard, Pierre-Yves

    2009-07-01

    New series of Huprine (12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolines) derivatives have been synthesized and their inhibiting activities toward recombinant human acetylcholinesterase (rh-AChE) are reported. We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group. The second one has been designed in order to evaluate the influence of modification at position 12 where different short linkers have been introduced on the Huprine X, Y skeletons. All these molecules have been prepared from ethyl- or methyl-bicyclo[3.3.1]non-6-en-3-one via Friedländer reaction involving selected o-aminocyano aromatic compounds. The synthesis of two heterodimers based on these Huprines has been also reported. Activities from moderate to same range than the most active Huprines X and Y taken as references have been obtained, the most potent analogue being about three times less active than parent Huprines X and Y. Topologic data have been inferred from molecular dockings and variations of activity between the different linkers suggest future structural modifications for activity improvement. PMID:19473849

  10. Design, Synthesis and Structure-Activity Relationship Optimization of Lycorine Derivatives for HCV Inhibition

    PubMed Central

    Chen, Duozhi; Cai, Jieyun; Cheng, Junjun; Jing, Chenxu; Yin, Junlin; Jiang, Jiandong; Peng, Zonggen; Hao, Xiaojiang

    2015-01-01

    Lycorine is reported to be a multifunctional compound. We previously showed that lycorine is an HCV inhibitor with strong activity. Further research on the antivirus mechanism indicated that lycorine does not affect the enzymes that are indispensable to HCV replication but suppresses the expression of Hsc70 in the host cell to limit HCV replication. However, due to the cytotoxicity and apoptosis induction of lycorine, lycorine is unsafe to be a anti-HCV agent for clinical application. As a result of increasing interest, its structure was optimized for the first time and a novel series of lycorine derivatives was synthesized, all of which lost their cytotoxicity to different degrees. Structure-activity analysis of these compounds revealed that disubstitution on the free hydroxyl groups at C1 and C2 and/or degradation of the benzodioxole group would markedly reduce the cytotoxicity. Furthermore, an ?, ?-unsaturated ketone would improve the HCV inhibitory activity of lycorine. The C3-C4 double bond is crucial to the anti-HCV activity because hydrogenation of this double bond clearly weakened HCV inhibition. PMID:26443922

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

    PubMed

    ?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

    2013-01-01

    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 (1)H, (13)C 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. PMID:22341494

  12. 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

  13. 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 ?g/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 ?g/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

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

    PubMed

    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; Tanaka, S Ken; Levy, Stuart

    2015-11-01

    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 ?g/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 ?g/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

  15. Quantitative structure-activity relationships in a series of endogenous and synthetic steroids exhibiting induction of CYP3A activity and hepatomegaly associated with increased DNA synthesis.

    PubMed

    Lewis, D F; Ioannides, C; Parke, D V; Schulte-Hermann, R

    2000-11-15

    The results of a quantitative structure-activity relationship (QSAR) study on a total of 14 steroids exhibiting induction of a CYP3A-associated activity and increase in liver weight/DNA synthesis is reported. It is found that different, but related, structural descriptors correlate with increase in ethylmorphine N-demethylase activity (r=0.92) and with the increase in liver weight (r=0.78) and DNA synthesis (r=0.78). Although there is a strong correlation between increase in liver weight and DNA content (r=0.999), neither of these correlated with ethylmorphine N-demethylase activity. These findings are discussed in the light of CYP3A induction, substrate specificity and inhibition; a proposed model of human CYP3A4 based on sequence homology with CYP102, a bacterial P450 of known crystal structure, demonstrates the possible mode of interaction between substrates and inhibitors within the putative active site. PMID:11162923

  16. Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin

    PubMed Central

    Cooper, Lisa E.; McClerren, Amanda L; Chary, Anita; van der Donk, Wilfred A.

    2008-01-01

    Summary The lantibiotic haloduracin consists of two post-translationally processed peptides, Hal? and Hal?, that act in synergy to provide bactericidal activity. An in vitro haloduracin production system was utilized to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Hal? B-ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin’s predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine did completely abolish antibacterial activity. This study also established that Hal?-Ser26 and Hal?-Ser22 escape dehydration, requiring revision of the Hal? structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Hal? cystine that is dispensable for bioactivity protects Hal? from further proteolytic degradation. PMID:18940665

  17. Structure-activity relationships in the peptide antibiotic nisin: role of dehydroalanine 5.

    PubMed

    Chan, W C; Dodd, H M; Horn, N; Maclean, K; Lian, L Y; Bycroft, B W; Gasson, M J; Roberts, G C

    1996-08-01

    A mutant of the peptide antibiotic nisin in which the dehydroalanine residue at position 5 has been replaced by an alanine has been produced and structurally characterized. It is shown to have activity very similar to that of wild-type nisin in inhibiting growth of Lactococcus lactis and Micrococcus luteus but is very much less active than nisin as an inhibitor of the outgrowth of spores of Bacillus subtilis. These observations, which parallel those of W. Liu and J. N. Hansen (Appl. Environ. Microbiol. 59:648-651, 1993) on the corresponding mutant of the related antibiotic subtilin, are discussed in terms of the mechanism(s) of action of these antibiotics. PMID:8702290

  18. Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists.

    PubMed

    Ye, Xiang-Yang; Morales, Christian L; Wang, Ying; Rossi, Karen A; Malmstrom, Sarah E; Abousleiman, Mojgan; Sereda, Larisa; Apedo, Atsu; Robl, Jeffrey A; Miller, Keith J; Krupinski, John; Wacker, Dean A

    2014-06-01

    Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles. PMID:24755425

  19. Anti-listerial activity and structure-activity relationships of the six major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus.

    PubMed

    Spathelf, Barbara M; Rautenbach, Marina

    2009-08-01

    Six major tyrocidines, purified from the antibiotic tyrothricin complex produced by Bacillus aneurinolyticus, showed significant lytic and growth inhibitory activity towards the gram+ bacteria, Micrococcus luteus and Listeria monocytogenes, but not against the gram- bacterium, Escherichia coli. The isolated natural tyrocidines were in particular more active against the leucocin A (antimicrobial peptide) resistant strain, L. monocytogenes B73-MR1, than the sensitive L. monocytogenes B73 strain. Remarkably similar structure-activity trends toward the three gram+ bacteria were found between growth inhibition and different physicochemical parameters (solution amphipathicity, theoretical lipophilicity, side-chain surface area and mass-over-charge ratio). PMID:19586775

  20. 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

  1. Bis-phosphonium salts of pyridoxine: the relationship between structure and antibacterial activity.

    PubMed

    Pugachev, Mikhail V; Shtyrlin, Nikita V; Sapozhnikov, Sergey V; Sysoeva, Lubov P; Iksanova, Alfiya G; Nikitina, Elena V; Musin, Rashid Z; Lodochnikova, Olga A; Berdnikov, Eugeny A; Shtyrlin, Yurii G

    2013-12-01

    A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr>Et>Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5 times (MICs=1-1.25 ?g/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1 ?g/ml) and lower cytotoxicity on HEK-293 cells (CC(50)=200 ?g/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin. PMID:24139168

  2. 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 (H?-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) 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

  3. Using quantitative structure-activity relationship modeling to quantitatively predict the developmental toxicity of halogenated azole compounds.

    PubMed

    Craig, Evisabel A; Wang, Nina Ching; Zhao, Q Jay

    2014-07-01

    Developmental toxicity is a relevant endpoint for the comprehensive assessment of human health risk from chemical exposure. However, animal developmental toxicity data remain unavailable for many environmental contaminants due to the complexity and cost of these types of analyses. Here we describe an approach that uses quantitative structure-activity relationship modeling as an alternative methodology to fill data gaps in the developmental toxicity profile of certain halogenated compounds. Chemical information was obtained and curated using the OECD Quantitative Structure-Activity Relationship Toolbox, version 3.0. Data from 35 curated compounds were analyzed via linear regression to build the predictive model, which has an R(2) of 0.79 and a Q(2) of 0.77. The applicability domain (AD) was defined by chemical category and structural similarity. Seven halogenated chemicals that fit the AD but are not part of the training set were employed for external validation purposes. Our model predicted lowest observed adverse effect level values with a maximal threefold deviation from the observed experimental values for all chemicals that fit the AD. The good predictability of our model suggests that this method may be applicable to the analysis of qualifying compounds whenever developmental toxicity information is lacking or incomplete for risk assessment considerations. PMID:24122872

  4. Structure-activity-relationship studies on dihydrofuran-fused perhydrophenanthrenes as an anti-Alzheimer's disease agent.

    PubMed

    Sugimoto, Kenji; Tamura, Kosuke; Tohda, Chihiro; Toyooka, Naoki; Nemoto, Hideo; Matsuya, Yuji

    2013-08-01

    As an extended study on development of anti-Alzheimer's disease agent, we newly synthesized various dihydrofuran-fused perhydrophenanthrenes via o-quinodimethane chemistry. This study revealed that the introduction of carbon side-chain on 8-position or removal of the acetal moiety on 3-position arose a cytotoxicity on rat cortical neurons. On the other hand, the ethereal or thio-ethereal substituent on 8-position enhanced the elongation effect on A?-damaged neurons. The necessity of the cyano group on 10b position was also proved in this structure-activity-relationship study. PMID:23806833

  5. 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

  6. Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers.

    PubMed

    Kers, Inger; Csjernyik, Gabor; Macsari, Istvan; Nylöf, Martin; Sandberg, Lars; Skogholm, Karin; Bueters, Tjerk; Eriksson, Anders B; Oerther, Sandra; Lund, Per-Eric; Venyike, Elisabet; Nyström, Jan-Erik; Besidski, Yevgeni

    2012-09-01

    Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model. PMID:22832315

  7. Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship.

    PubMed

    Kers, Inger; Macsari, Istvan; Csjernyik, Gabor; Nylöf, Martin; Skogholm, Karin; Sandberg, Lars; Minidis, Alexander; Bueters, Tjerk; Malmborg, Jonas; Eriksson, Anders B; Lund, Per-Eric; Venyike, Elisabet; Luo, Lei; Nyström, Jan-Erik; Besidski, Yevgeni

    2012-10-01

    The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile. PMID:22939696

  8. Uncovering structure-activity relationships in manganese-oxide-based heterogeneous catalysts for efficient water oxidation.

    PubMed

    Indra, Arindam; Menezes, Prashanth W; Driess, Matthias

    2015-03-01

    Artificial photosynthesis by harvesting solar light into chemical energy could solve the problems of energy conversion and storage in a sustainable way. In nature, CO2 and H2 O are transformed into carbohydrates by photosynthesis to store the solar energy in chemical bonds and water is oxidized to O2 in the oxygen-evolving center (OEC) of photosystem II (PS II). The OEC contains CaMn4 O5 cluster in which the metals are interconnected through oxido bridges. Inspired by biological systems, manganese-oxide-based catalysts have been synthesized and explored for water oxidation. Structural, functional modeling, and design of the materials have prevailed over the years to achieve an effective and stable catalyst system for water oxidation. Structural flexibility with eg(1) configuration of Mn(III) , mixed valency in manganese, and higher surface area are the main requirements to attain higher efficiency. This Minireview discusses the most recent progress in heterogeneous manganese-oxide-based catalysts for efficient chemical, photochemical, and electrochemical water oxidation as well as the structural requirements for the catalyst to perform actively. PMID:25641823

  9. Cellular uptake of transportan 10 and its analogs in live cells: Selectivity and structure-activity relationship studies.

    PubMed

    Song, Jingjing; Kai, Ming; Zhang, Wei; Zhang, Jindao; Liu, Liwei; Zhang, Bangzhi; Liu, Xin; Wang, Rui

    2011-09-01

    Transportan 10 (TP10) is an amphipathic cell-penetrating peptide with high translocation ability. In order to obtain more details of structure-activity relationship of TP10, we evaluated the effects of structure and charge on its translocation ability. Our results demonstrated that disrupting the helical structure or Arg substitution could remarkably decrease the cellular uptake of TP10. However, increasing the number of positive charge was an effective strategy to enhance translocation ability of TP10. Furthermore, the molecular dynamics simulation supported the results derived from experiments, suggesting that higher membrane disturbance leads to higher cellular uptake of peptides. In addition, our study also demonstrated TP10 and its analogs preferentially entered cancer cells rather than normal cells. The uptake selectivity toward cancer cells makes TP10 and its analogs as potent CPPs for drug delivery. PMID:21827806

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

    PubMed

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

    2015-08-28

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

  11. Structure-Activity Relationships of Antitubercular Salicylanilides Consistent with Disruption of the Proton Gradient via Proton Shuttling

    PubMed Central

    Lee, Ill-Young; Gruber, Todd D.; Samuels, Amanda; Yun, Minhan; Nam, Bora; Kang, Minseo; Crowley, Kathryn; Winterroth, Benjamin; Boshoff, Helena I.; Barry, Clifton E.

    2012-01-01

    A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics. PMID:23211970

  12. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.

    PubMed

    Candice, Soares de Melo; Feng, Tzu-Shean; van der Westhuyzen, Renier; Gessner, Richard K; Street, Leslie J; Morgans, Garreth L; Warner, Digby F; Moosa, Atica; Naran, Krupa; Lawrence, Nina; Boshoff, Helena I M; Barry, Clifton E; Harris, C John; Gordon, Richard; Chibale, Kelly

    2015-11-15

    Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified. PMID:26522089

  13. A Structure-Activity Relationship Study of Naphthoquinone Derivatives as Antitubercular Agents Using Molecular Modeling Techniques.

    PubMed

    Sharma, Mukesh C

    2015-12-01

    Tuberculosis (TB) is one of the major causes of death worldwide. Mycobacterium tuberculosis, the leading causative agent of TB, is responsible for the morbidity and mortality of a large population worldwide. In view of above and as a part of our effort to develop new and potent anti-TB agents, a series of substituted naphthoquinone derivatives were subjected to molecular modeling using various feature selection methods. The statistically significant best 2D-QSAR model having correlation coefficient [Formula: see text] and cross-validated squared correlation coefficient [Formula: see text] with external predictive ability of [Formula: see text] was developed by SA-PLS, and group-based QSAR model having [Formula: see text] and [Formula: see text] with [Formula: see text] was developed by SA-PLS. Further analysis using three-dimensional QSAR technique identifies a suitable model obtained by SA-partial least square method leading to antitubercular activity prediction. k-nearest neighbor molecular field analysis was used to construct the best 3D-QSAR model using SA-PLS method, showing good correlative and predictive capabilities in terms of [Formula: see text] and [Formula: see text]. The pharmacophore analysis results obtained from this study show that the distance between the aromatic/hydrophobic and the naphthoquinone moiety sites to the aliphatic and acceptor groups should be connected with almost the same distance for significant antitubercular activity. The information rendered by QSAR models may lead to a better understanding of structural requirements of antitubercular activity and also can help in the design of novel potent antitubercular activity. PMID:26159131

  14. Use of a (quantitative) structure-activity relationship [(Q)SAR] model to predict the toxicity of naphthenic acids.

    PubMed

    Frank, Richard A; Sanderson, Hans; Kavanagh, Richard; Burnison, B Kent; Headley, John V; Solomon, Keith R

    2010-01-01

    Naphthenic acids (NA) are a complex mixture of carboxylic acids that are natural constituents of oil sand found in north-eastern Alberta, Canada. NA are released and concentrated in the alkaline water used in the extraction of bitumen from oil sand sediment. NA have been identified as the principal toxic components of oil sands process-affected water (OSPW), and microbial degradation of lower molecular weight (MW) NA decreases the toxicity of NA mixtures in OSPW. Analysis by proton nuclear magnetic resonance spectroscopy indicated that larger, more cyclic NA contain greater carboxylic acid content, thereby decreasing their hydrophobicity and acute toxicity in comparison to lower MW NA. The relationship between the acute toxicity of NA and hydrophobicity suggests that narcosis is the probable mode of acute toxic action. The applicability of a (quantitative) structure-activity relationship [(Q)SAR] model to accurately predict the toxicity of NA-like surrogates was investigated. The U.S. Environmental Protection Agency (EPA) ECOSAR model predicted the toxicity of NA-like surrogates with acceptable accuracy in comparison to observed toxicity values from Vibrio fischeri and Daphnia magna assays, indicating that the model has potential to serve as a prioritization tool for identifying NA structures likely to produce an increased toxicity. Investigating NA of equal MW, the ECOSAR model predicted increased toxic potency for NA containing fewer carbon rings. Furthermore, NA structures with a linear grouping of carbon rings had a greater predicted toxic potency than structures containing carbon rings in a clustered grouping. PMID:20077300

  15. 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

  16. Structure-activity relationship of tryptamine analogues on the heart of venus mercenaria

    PubMed Central

    Greenberg, M. J.

    1960-01-01

    A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor. ImagesFIG. 7 PMID:13708259

  17. Analysis of structure-activity relationships in renin substrate analogue inhibitory peptides.

    PubMed

    Hui, K Y; Carlson, W D; Bernatowicz, M S; Haber, E

    1987-08-01

    On the basis of the minimal octapeptide sequence of the renin substrate, a series of peptides was synthesized containing (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine) or (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) at the P1P1' position. Some of these peptides also contained Nin-formyltryptophan at the P5, P3, or P3' position. Renin-inhibitory potency varied over a wide range (from inactive to IC50 = 3 nM). Potency was reduced by at least 10-fold when the peptide was shortened by two residues at either the amino or carboxy terminus. The AHPPA-containing inhibitors were several-fold less potent than the statine-containing inhibitors. Analysis of models for the three-dimensional structure of inhibitors at the active site of human renin suggests that the diminished potency of the AHPPA peptides in comparison with the statine-containing peptides was caused by a shift in the peptide backbone due to a steric conflict between the phenyl ring of the AHPPA residue and the S1 subsite. The importance of the side chain and the 3(S)-hydroxyl group of the statine residue was demonstrated by substituting 5-aminovaleric acid for a dipeptide unit at the P1P1' position, which resulted in a peptide devoid of renin-inhibitory activity. Substitutions of other basic amino acids for histidine at the P2 position caused a great loss in potency, possibly due to disruption of a hydrogen bond as suggested by molecular modeling. Studies on the plasma renins of four nonhuman species suggest that the isoleucine-histidine segment at the P2'P3' position is important to defining the human specificity of the substrate. This work suggests a number of properties important to the design of potent renin inhibitors, and demonstrates the usefulness of three-dimensional models in the interpretation of structure-activity data. PMID:3302256

  18. Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties

    PubMed Central

    Pot??ková, Eliška; Hrušková, Kate?ina; Bureš, Jan; Kova?íková, Petra; Špirková, Iva A.; Pravdíková, Kate?ina; Kolbabová, Lucie; Hergeselová, Tereza; Hašková, Pavlína; Jansová, Hana; Machá?ek, Miloslav; Jirkovská, Anna; Richardson, Vera; Lane, Darius J. R.; Kalinowski, Danuta S.; Richardson, Des R.; Vávrová, Kate?ina; Šim?nek, 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

  19. 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 (H?-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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

    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. Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) showed 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.

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

    PubMed Central

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

    2011-01-01

    While the synthetic utility of asymmetric phase transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product. PMID:21446723

  2. Virulence Factor-activity Relationships: Workshop Summary

    EPA Science Inventory

    The concept or notion of virulence factor–activity relationships (VFAR) is an approach for identifying an analogous process to the use of qualitative structure–activity relationships (QSAR) for identifying new microbial contaminants. In QSAR, it is hypothesized that, for new chem...

  3. Kinetics and quantitative structure-activity relationship study on the degradation reaction from perfluorooctanoic acid to trifluoroacetic acid.

    PubMed

    Gong, Chen; Sun, Xiaomin; Zhang, Chenxi; Zhang, Xue; Niu, Junfeng

    2014-01-01

    Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of 200~500 K. The Arrhenius equations of rate constants of elementary reactions are fitted. The decarboxylation is role step in the degradation mechanism of PFOA. For the perfluorinated carboxylic acids from perfluorooctanoic acid to trifluoroacetic acid, the quantitative structure-activity relationship of the decarboxylation was analyzed with the genetic function approximation method and the structure-activity model was constructed. The main parameters governing rate constants of the decarboxylation reaction from the eight-carbon chain to the two-carbon chain were obtained. As the structure-activity model shows, the bond length and energy of C1-C2 (RC1-C2 and EC1-C2) are positively correlated to rate constants, while the volume (V), the energy difference between EHOMO and ELUMO (?E), and the net atomic charges on atom C2 (QC2) are negatively correlated. PMID:25196516

  4. Kinetics and Quantitative Structure—Activity Relationship Study on the Degradation Reaction from Perfluorooctanoic Acid to Trifluoroacetic Acid

    PubMed Central

    Gong, Chen; Sun, Xiaomin; Zhang, Chenxi; Zhang, Xue; Niu, Junfeng

    2014-01-01

    Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of 200~500 K. The Arrhenius equations of rate constants of elementary reactions are fitted. The decarboxylation is role step in the degradation mechanism of PFOA. For the perfluorinated carboxylic acids from perfluorooctanoic acid to trifluoroacetic acid, the quantitative structure–activity relationship of the decarboxylation was analyzed with the genetic function approximation method and the structure–activity model was constructed. The main parameters governing rate constants of the decarboxylation reaction from the eight-carbon chain to the two-carbon chain were obtained. As the structure–activity model shows, the bond length and energy of C1–C2 (RC1–C2 and EC1–C2) are positively correlated to rate constants, while the volume (V), the energy difference between EHOMO and ELUMO (?E), and the net atomic charges on atom C2 (QC2) are negatively correlated. PMID:25196516

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

    PubMed

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

    2015-01-01

    This chapter describes the main characteristics of olfactory receptor (OR) genes of vertebrates, including generation of this large multigenic family and pseudogenization. OR genes are compared in relation to evolution and among species. OR gene structure and selection of a given gene for expression in an olfactory sensory neuron (OSN) are tackled. The specificities of OR proteins, their expression, and their function are presented. The expression of OR proteins in locations other than the nasal cavity is regulated by different mechanisms, and ORs display various additional functions. A conventional olfactory signal transduction cascade is observed in OSNs, but individual ORs can also mediate different signaling pathways, through the involvement of other molecular partners and depending on the odorant ligand encountered. ORs are engaged in constitutive dimers. Ligand binding induces conformational changes in the ORs that regulate their level of activity depending on odorant dose. When present, odorant binding proteins induce an allosteric modulation of OR activity. Since no 3D structure of an OR has been yet resolved, modeling has to be performed using the closest G-protein-coupled receptor 3D structures available, to facilitate virtual ligand screening using the models. The study of odorant binding modes and affinities may infer best-bet OR ligands, to be subsequently checked experimentally. The relationship between spatial and steric features of odorants and their activity in terms of perceived odor quality are also fields of research that development of computing tools may enhance. PMID:25623335

  6. Lithospheric structure and its relationship to seismic and volcanic activity in southwest China

    NASA Astrophysics Data System (ADS)

    Huang, Jinli; Zhao, Dapeng; Zheng, Sihua

    2002-10-01

    The Sichuan-Yunnan region in southwest China is located in the boundary area between the active Tibetan Plateau to the west and the stable South China platform to the east. This region is characterized by complex Cenozoic structures and active seismotectonics. In this study, we have used over 30,000 arrival times from 1315 local earthquakes recorded by 172 seismic stations to determine a detailed three-dimensional (3-D) P wave velocity structure of the lithosphere down to 85 km depth in this region. We have taken into account the complex morphology of the Moho discontinuity to conduct the tomographic inversions, which leads to a better result than that with a flat Moho as in the previous studies. Our results show that large velocity variations of up to 7% exist in the crust and upper mantle in the Sichuan-Yunnan region. The velocity image of the upper crust correlates with the surface geological features. The Sichuan basin is imaged as a prominent low-velocity zone, while the Panzhihua mining district is imaged as a high-velocity feature. Velocity changes are visible across some of the large fault zones, and the faults and some large crustal earthquakes seem to occur at the boundary areas between slow and fast velocity anomalies. Some of the faults, such as the Red River fault, may have cut through the crust and reached up to the upper mantle. Under the Tengchong volcanic area, strong low-velocity zones are visible down to 85 km depth, with a lateral extent of about 100 km, suggesting the existence of magma chambers under the volcano. It is unclear how the Tengchong intraplate volcanism was generated. It may be related to the collision processes between the Indian plate, Burma microplate and the Eurasian plate, and the possible subduction of the Burma microplate under the Eurasian plate. Another possibility is that it was caused by the extensional fractures of the lithosphere and the upward intrusion of the hot asthenospheric materials. It is also possible that the Tengchong volcanism represents a hot spot with a lower mantle origin.

  7. Quantitative structure-activity relationships for the prediction of relative in vitro potencies (REPs) for chloronaphthalenes.

    PubMed

    Puzyn, Tomasz; Falandysz, Jerzy; Jones, Paul D; Giesy, John P

    2007-04-01

    Chloronaphthalenes (CNs), due to their structural similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the other "dioxin-like" compounds, can bind to the aryl hydrocarbon receptor (AhR) and induce a wide range of pleotrophic effects. Relative potency of individual dioxin analogues can be measured relative to that of TCDD. Relative effects potencies (REP) can be based on many responses, including in vivo and in vitro responses. Both in vivo and in vitro tests, based on either indigenous responses such as the induction of ethoxyresorufin O-deethylase (EROD) or exogenous reporter genes under the control of the AhR such as luciferase can be used to determine REP values. Here we used measured REP values determined for CNs in two assays. Both assays are based on H4IIE rat hepatoma cells. The H4IIE assay is based on expression of the endogenous reporter gene (CYP-1 A) that codes for the expression of EROD and the H4IIE-luc assay which is based on the exogenous reporter gene (luciferase) transfected into the H4IIE cell line. Experimentally determined REP were available for only 17 and 18 of the 75 possible choronaphthalene congeners, for the H4IIE and H4IIE-luc assays, respectively. For this reason computational models were developed to allow prediction of the relative potencies of the other CN congeners. Predictive relationships were based on quantum chemical descriptors obtained from Density Functional Theory (DFT) calculations (B3LYP/6-311++G**). The final models were found by means of a hybrid method combining a genetic algorithm and artificial neural networks. REP values estimated for individual CNs based on the H4IIE assay ranged from 4.3 x 10(- 9) to 3.2 x 10(- 2) while those based on the H4IIE-luc assay ranged from 4.0 x 10(- 8) to 1.8 x 10(- 3). CN congeners nos. 66, 67, 70 and 73 were exhibited the greatest REP values in both assays. The 1,2,3,5,6,8-hexaCN congener (no. 68) had a REP value that was 10-fold less. The remaining congeners had REP values that were less or did not cause sufficient up-regulation of the monitored genes to allow for the calculation of a REP. Interactions of CNs with the AhR could be affected by three possible factors: molecular size, steric interactions and electrostatic interactions. These findings are discussed relative to the use of consensus TCDD equivalency factors' (TEFs) for use in risk assessments of CNs for regulatory purposes. PMID:17454365

  8. Structure–Activity Relationship for the First-in-Class Clinical Steroid Sulfatase Inhibitor Irosustat (STX64, BN83495)

    PubMed Central

    Woo, L W Lawrence; Ganeshapillai, Dharshini; Thomas, Mark P; Sutcliffe, Oliver B; Malini, Bindu; Mahon, Mary F; Purohit, Atul; Potter, Barry V L

    2011-01-01

    Structure–activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nm. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism. PMID:21990014

  9. 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 ?-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 ?M and a KIU of 4.8 ± 0.5 ?M while 1b has a KIC of 0.5 ± 0.07 ?M and a KIU of 1.9 ± 0.2 ?M. 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

  10. Amide-modified prenylcysteine based Icmt inhibitors: Structure-activity relationships, kinetic analysis and cellular characterization.

    PubMed

    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 ?-carboxyl methylation of the C-terminal 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 K(i) values were determined from the IC(50) values. Analog 1a has a K(IC) of 1.4±0.2?M and a K(IU) of 4.8±0.5?M while 1b has a K(IC) of 0.5±0.07?M and a K(IU) of 1.9±0.2?M. 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

  11. 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 ?M 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.

  12. Designing Anti-Influenza Aptamers: Novel Quantitative Structure Activity Relationship Approach Gives Insights into Aptamer – Virus Interaction

    PubMed Central

    Musafia, Boaz; Oren-Banaroya, Rony; Noiman, Silvia

    2014-01-01

    This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus’ infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer’s binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers’ binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2?=?0.702 for the training set, and R2?=?0.66 for the independent test set. Moreover, in the test set the model’s sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer’s binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the influenza virus are discussed. PMID:24846127

  13. Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

    PubMed Central

    2013-01-01

    Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,34 provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells. PMID:23301767

  14. Structure-activity relationship for the addition of OH to (poly)alkenes: site-specific and total rate constants.

    PubMed

    Peeters, J; Boullart, W; Pultau, V; Vandenberk, S; Vereecken, L

    2007-03-01

    A novel site-specific structure-activity relationship was developed for the site-specific addition of OH radicals to (poly)alkenes at 298 K. From a detailed structure-activity analysis of some 65 known OH + alkene and diene reactions, it appears that the total rate constant for this reaction class can be closely approximated by a sum of independent partial rate constants, ki, for addition to the specific (double-bonded) C atoms that depend only on the stability type of the ensuing radical (primary, secondary, etc.), that is, on the number of substituents on the neighboring C atom in the double bond. The (nine) independent partial rate constants, ki, were derived, and the predicted rate constants (kOH,pred = Sigmak(i)) were compared with experimental k(OH,exp) values. For noncyclic (poly)alkenes, including conjugated structures, the agreement is excellent (Delta < 10%). The SAR-predicted rate constants for cyclic (poly)alkenes are in general also within <15% of the experimental value. On the basis of this SAR, it is possible to predict the site-specific rate constants for (poly)alkene + OH reactions accurately, including larger biogenic compounds such as isoprene and terpenes. An important section is devoted to the rigorous experimental validation of the SAR predictions against direct measurements of the site-specific addition contributions within the alkene, for monoalkenes as well as conjugated alkenes. The measured site specificities are within 10-15% of the SAR predictions. PMID:17298042

  15. 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

  16. Synthesis, biological evaluation, and structure-activity relationship study of novel stilbene derivatives as potential fungicidal agents.

    PubMed

    He, Daohang; Jian, Weilin; Liu, Xianping; Shen, Huifang; Song, Shaoyun

    2015-02-11

    A total of 22 novel stilbene derivatives containing the 1,3,4-oxadiazole moiety and trimethoxybenzene were designed and synthesized. Their chemical structures were characterized by (1)H and (13)C nuclear magnetic resonance, infrared, and high-resolution mass spectrometry. Bioassay results revealed that some of the title compounds showed potent in vivo fungicidal activities against three phytopathogenic fungi (Pseudoperonospora cubensis, Colletotrichum lagenarium, and Septoria cucurbitacearum) from cucurbits at 600 ?g/mL. Notably, compounds 4b, 4d, 4i, 4k, and 4l exhibited a broad spectrum and remarkably high activities against those fungi, some of which even showed a comparable control efficacy to that of the commercial fungicides. Three-dimensional quantitative structure-activity relationship based on comparative molecular field analysis with good predictive ability (q(2) = 0.516; r(2) = 0.920) was reasonably discussed. For the first time, the present work suggested that the stilbene derivatives containing the 1,3,4-oxadiazole moiety could be developed as potential fungicides for crop protection. PMID:25594285

  17. 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 the older earthquake, but rather along the edge of the gouge. According to the gouge statistics of the whole fault zone, seismic events have the obvious tendency towards the foot wall, and the thickness of gouge is proportional to the activity of the fault, indicating that the width of fault zone is directly related to the number and evolution history of earthquakes . Repeated earthquakes maybe the main cause for the formation of the Longmenshan Moutains

  18. Drug structure–transport relationships

    PubMed Central

    2010-01-01

    Malcolm Rowland has greatly facilitated an understanding of drug structure–pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm’s work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection–dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm’s special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others. PMID:21107662

  19. Oxoquinoline derivatives: identification and structure-activity relationship (SAR) analysis of new anti-HSV-1 agents.

    PubMed

    Abreu, Paula A; da Silva, Viveca A G G; Santos, Fernanda C; Castro, Helena C; Riscado, Cecília S; de Souza, Mariana T; Ribeiro, Camilly P; Barbosa, Juliana E; dos Santos, Cláudio C C; Rodrigues, Carlos R; Lione, Viviane; Correa, Bianca A M; Cunha, Anna C; Ferreira, Vitor F; de Souza, Maria C B V; Paixão, Izabel C N P

    2011-05-01

    Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis. PMID:21225264

  20. Synthesis and structure-activity relationship studies of peptidomimetic PKB/Akt inhibitors: the significance of backbone interactions.

    PubMed

    Tal-Gan, Yftah; Freeman, Noam S; Klein, Shoshana; Levitzki, Alexander; Gilon, Chaim

    2010-04-15

    Elevated levels of activated Protein Kinase B (PKB/Akt) have been detected in many types of human cancer. In contrast to ATP site inhibitors, substrate-based inhibitors are more likely to be selective because of extensive interactions with the specific substrate binding site. Unfortunately, peptide-based inhibitors lack important pharmacological properties that are required of drug candidates. Chemical modifications of potent peptide inhibitors, such as peptoids and N(alpha)-methylated amino acids, may overcome these drawbacks, while maintaining potency. We present a structure-activity relationship study of a potent, peptide-based PKB/Akt inhibitor, PTR6154. The study was designed to evaluate backbone modifications on the inhibitory activity of PTR6154. Two peptidomimetic libraries, peptoid and N(alpha)-methylation, based on PTR6154, were synthesized and evaluated for in vitro PKB/Akt inhibition efficiency. All the peptoid analogs reduced potency significantly, as well as most of the members of the N-methyl library, suggesting that the backbone conformation and/or hydrogen bond interactions of PTR6154 derivatives are essential for inhibition activity. Two N-terminal members of the N-methyl library did not decrease potency and can be used as future drug leads. PMID:20347317

  1. Structure-Activity Relationship Study of the Neuritogenic Potential of the Glycan of Starfish Ganglioside LLG-3 (‡).

    PubMed

    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

  2. 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 ?M 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

  3. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI.

    PubMed

    Wang, Kai-rong; Zhang, Bang-zhi; Zhang, Wei; Yan, Jie-xi; Li, Jia; Wang, Rui

    2008-06-01

    A novel antimicrobial peptide, polybia-MPI, was purified from the venom of the social wasp Polybia paulista. It has potent antimicrobial activity against both Gram-positive and Gram-negative bacteria, but causing no hemolysis to rat erythrocytes. To date, there is no report about its antitumor effects on any tumor cell lines. In this study we synthesized polybia-MPI and studied its antitumor efficacy and cell selectivity. Our results revealed that polybia-MPI exerts cytotoxic and antiproliferative efficacy by pore formation. It can selectively inhibit the proliferation of prostate and bladder cancer cells, but has lower cytotoxicity to normal murine fibroblasts. In addition, to investigate the structure-activity relationship of polybia-MPI, three analogs in which Leu7, Ala8 or Asp9 replaced by L-Pro were designed and synthesized. L-Pro substitution of Leu7 or Asp9 significantly reduces the content of alpha-helix conformation, and L-Pro substitution of Ala8 can disrupt the alpha-helix conformation thoroughly. The L-Pro substitution induces a significant reduction of antitumor activity, indicating that the alpha-helix conformation of polybia-MPI is important for its antitumor activity. In summary, polybia-MPI may offer a novel therapeutic strategy in the treatment of prostate cancer and bladder cancer, considering its relatively lower cytotoxicity to normal cells. PMID:18328599

  4. Quantitative structure-activity relationship prediction of blood-to-brain partitioning behavior using support vector machine.

    PubMed

    Golmohammadi, Hassan; Dashtbozorgi, Zahra; Acree, William E

    2012-09-29

    In the present study a quantitative structure-activity relationship (QSAR) technique was developed to investigate the blood-to-brain barrier partitioning behavior (log BB) for various drugs and organic compounds. Important descriptors were selected by genetic algorithm-partial least square (GA-PLS) methods. Partial least squares (PLS) and support vector machine (SVM) methods were employed to construct linear and non-linear models, respectively. The results showed that, the log BB values calculated by SVM were in good agreement with the experimental data, and the performance of the SVM model was superior to the PLS model. The study provided a novel and effective method for predicting blood-to-brain barrier penetration of drugs, and disclosed that SVM can be used as a powerful chemometrics tool for QSAR studies. PMID:22771548

  5. Structure-activity relationship studies of sulfonylpiperazine analogs as novel negative allosteric modulators of human neuronal nicotinic receptors

    PubMed Central

    Henderson, Brandon J.; Carper, Daniel J.; Gonzáez-Cestari, Tatiana F.; Yi, Bitna; Mahasenan, Kiran; Pavlovicz, Ryan E.; Dalefield, Martin L.; Coleman, Robert S.; Li, Chenglong; McKay, Dennis B.

    2011-01-01

    Neuronal nicotinic receptors have been implicated in several diseases and disorders such as: autism, Alzheimer’s disease, Parkinson’s disease, epilepsy, and various forms of addiction. To understand the role of nicotinic receptors in these conditions, it would be beneficial to have selective molecules that target specific nicotinic receptors in vitro and in vivo. Our laboratory has previously identified novel negative allosteric modulators of human ?4?2 (H?4?2) and human ?3?4 (H?3?4) nicotinic receptors. In the following studies, the effects of novel sulfonylpiperazine analogs that act as negative allosteric modulators on both H?4?2 nAChRs and H?3?4 nAChRs were investigated. This work, through structure-activity relationship (SAR) studies, describes the chemical features of these molecules that are important for both potency and selectivity on H?4?2 nAChRs. PMID:22060139

  6. Quantitative structure activity relationship (QSAR) of chlorine effects on E(LUMO) of disinfection by-product: Chlorinated alkanes.

    PubMed

    Tang, Walter Z; Wang, Fang

    2010-02-01

    Chlorinated Alkane (CA) is one of the major classes of Disinfection By-Products (DBPs) in chlorinated drinking water. Multi-multivariate regression methods have been used to develop Quantitative Structure-Activity Relationship (QSAR) models between the Energy of the Lowest Unoccupied Molecular Orbital (ELUMO) and three molecular descriptors: namely, number of chlorine (NCl), number of carbon (NC) and the Energy of the Highest Occupied Molecular Orbital (EHOMO). Among different linear QSAR models, the most robust model is ELUMO=-0.1474NCl-0.003766NC+1.9528EHOMO+1.0664 (N=30, R2=0.956, F=188.498, RMSE=0.00762, P=0.000). The model is validated by using internal and external cross validation techniques. The model uncertainties are also quantified through the Bootstrapping and the Taylor methods. Among all the molecular descriptors, number of chlorine (NCl) contributes to the most to the ELUMO of chlorinated alkanes. PMID:20004459

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

    PubMed

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

    2015-06-01

    Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways. Here we present an update on the human SDR superfamily and a ligand identification strategy using differential scanning fluorimetry (DSF) with a focused library of oxidoreductase and metabolic ligands to identify substrate classes and inhibitor chemotypes. This method is applicable to investigate structure-activity relationships of oxidoreductases and ultimately to better understand their physiological roles. PMID:25526675

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

    PubMed

    Jing, Guohua; Zhou, Zuoming; Zhuo, Jing

    2012-01-01

    The acute toxicity of 13 quaternary ammonium compounds (QACs) to Chlorella pyrenoidosa and Scenedesmus quadricauda was investigated in the present study. Significant inhibition on algae biomass was observed and 96 h EC(50)-value of 13 QACs was tested. Sixteen physicochemical and quantum chemical parameters of the QACs were calculated using the semi-empirical MOPAC AMI method. The multiple linear regression (MLR) was employed to derive the quantitative structure-activity relationship (QSAR) models, by which the calculated parameters were correlated to the toxicity of QACs on the two green algaes. Results showed that the alkyl chain lengths (CL) and total connectivity (T(Con)) were the main descriptors in governing the log (1/EC(50)) values of the QACs in the two QSAR models. The two models had high predictive ability and stability, and two parameters were proved to have the general applicability in QSAR study of QACs congeners. PMID:22014469

  9. 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.

  10. Structure-activity relationships of sandalwood odorants: synthesis of a new campholene derivative.

    PubMed

    Stappen, Iris; Höfinghoff, Joris; Buchbauer, Gerhard; Wolschann, Peter

    2010-09-01

    Structural modifications of natural (-)-(Z)-beta-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance. PMID:20922988

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

    E-print Network

    Levin, Lisa

    that seafloor massive sulfide deposits, associated with active and inactive hydrothermal venting, will be mined-cycle microbes at the base of the food chain. In contrast, photosynthesis and sulfide oxidation appear to fuel

  12. Structure Property Relationships for Dirhodium Antitumor Active Compounds: Reactions with Biomolecules and In Cellulo Studies 

    E-print Network

    Aguirre-Flores, Jessica Dafhne

    2011-02-22

    The molecular characteristics that affect the activity of various dirhodium complexes are reported. The importance of the axial position in the action of dirhodium compounds was studied. Three dirhodium complexes with ...

  13. 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.

  14. 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

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

    SciTech Connect

    Bodishbauah, D.F.

    1994-12-31

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

  16. Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts.

    PubMed

    Ponte-Sucre, Alicia; Gulder, Tanja; Wegehaupt, Annemarie; Albert, Christoph; Rikanovi?, Carina; Schaeflein, Leonhard; Frank, Andreas; Schultheis, Martina; Unger, Matthias; Holzgrabe, Ulrike; Bringmann, Gerhard; Moll, Heidrun

    2009-02-12

    Alternative drugs against leishmaniasis are desperately needed. Antimonials, the main chemotherapeutic tool, cause serious side effects and promote chemoresistance. We previously demonstrated that representatives of N,C-linked arylisoquinolines are promising leishmanicidal drug candidates. We now performed structure-activity relationship studies varying the aryl portion of our lead substrate. The new series of compounds show an enhanced selectivity against Leishmania major in comparison to their major host cell, the macrophage. Our results suggest that the arylisoquinolinium salts decrease the macrophage infection rate acting directly on the intracellular parasites. However, the activity of the 4'-i-propyl derivative might also involve the modulation of cytokine and nitric oxide production by host macrophages. Additionally, this isoquinoline acts synergistically with amphotericin B and does not interact with drug-metabolizing cytochrome P450 enzymes involved in the metabolism of antileishmanial drugs. The results demonstrate that the newly synthesized structurally simplified N,C-coupled arylisoquinolinium salts are promising candidates to be considered as leishmanicidal pharmacophores. PMID:19117415

  17. Discovery of a new class of highly potent inhibitors of acid ceramidase: synthesis and structure-activity relationship (SAR).

    PubMed

    Pizzirani, Daniela; Pagliuca, Chiara; Realini, Natalia; Branduardi, Davide; Bottegoni, Giovanni; Mor, Marco; Bertozzi, Fabio; Scarpelli, Rita; Piomelli, Daniele; Bandiera, Tiziano

    2013-05-01

    Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50 = 0.029 ?M). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1-carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC. PMID:23614460

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

    PubMed

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

    2015-04-15

    Our previous results elucidated that the leaves of Eriobotrya japonica possessed the potential to suppress ovariectomy-induced bone mineral density deterioration, and ursolic acid, the major bioactive component in these leaves, suppressed the osteoclast differentiation. The aim of this study was to discover more candidates for development of novel antiosteoclastogenesis agents from the leaves of E. japonica. Phytochemical analysis following a cell-based osteoclastic tartrate-resistant acid phosphatase (TRAP) activity assay revealed 11 more compounds with a potent antiosteoclastogenesis effect. The potency of ursane-type triterpenoids from the leaves of E. japonica prompted us to investigate the structure-activity relationships underlying their antiosteoclastogenesis. The results revealed that both the hydroxyl group at C-3 and the carboxylic group at C-17 played indispensable roles in the antiosteoclastogenesis activity of ursane-type triterpenoids. The configuration at C-3 (a beta-form of the hydroxyl group) was found to be important for this activity. While introducing a hydroxyl group at C-19 increased the inhibitory activity of ursane-type triterpenoids carrying an alpha-form hydroxyl group at C-3. The bioactivity analyses of ursolic acid and oleanolic acid demonstrated that the antiosteoclastogenesis effect of ursolic acid may be related to different positions of the C-29 and C-30 methyl groups on the E-ring, since oleanolic acid showed limited activity. The addition of a hydroxyl group at C-2 would dramatically improve the inhibition of oleanane-type triterpenoids. Collectively, these findings could provide important clues for the improvement of multi-targeted antiosteoclastogenesis agents from the leaves of E. japonica. PMID:25925972

  19. 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...

  20. Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.

    PubMed

    Shivahare, Rahul; Korthikunta, Venkateswarlu; Chandasana, Hardik; Suthar, Manish K; Agnihotri, Pragati; Vishwakarma, Preeti; Chaitanya, Telaprolu K; Kancharla, Papireddy; Khaliq, Tanvir; Gupta, Shweta; Bhatta, Rabi Sankar; Pratap, J Venkatesh; Saxena, Jitendra K; Gupta, Suman; Tadigoppula, Narender

    2014-04-24

    Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis. PMID:24635539

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

    PubMed

    Rawat, S; Bruce, E D

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively. PMID:24738916

  2. 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.

  3. 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 ?M), and sixteen compounds possessed reduced cell-killing efficacy (IC50 > 50 ?M). 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

  4. Biomolecular recognition of antagonists by ?7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    As the key constituent of ligand-gated ion channels in the central nervous system, nicotinic acetylcholine receptors (nAChRs) and neurodegenerative diseases are strongly coupled in the human species. In recently years the developments of selective agonists by using nAChRs as the drug target have made a large progress, but the studies of selective antagonists are severely lacked. Currently these antagonists rest mainly on the extraction of partly natural products from some animals and plants; however, the production of these crude substances is quite restricted, and artificial synthesis of nAChR antagonists is still one of the completely new research fields. In the context of this manuscript, our primary objective was to comprehensively analyze the recognition patterns and the critical interaction descriptors between target ?7 nAChR and a series of the novel compounds with potentially antagonistic activity by means of virtual screening, molecular docking and molecular dynamics simulation, and meanwhile these recognition reactions were also compared with the biointeraction of ?7 nAChR with a commercially natural antagonist - methyllycaconitine. The results suggested clearly that there are relatively obvious differences of molecular structures between synthetic antagonists and methyllycaconitine, while the two systems have similar recognition modes on the whole. The interaction energy and the crucially noncovalent forces of the ?7 nAChR-antagonists are ascertained according to the method of Molecular Mechanics/Generalized Born Surface Area. Several amino acid residues, such as B/Tyr-93, B/Lys-143, B/Trp-147, B/Tyr-188, B/Tyr-195, A/Trp-55 and A/Leu-118 played a major role in the ?7 nAChR-antagonist recognition processes, in particular, residues B/Tyr-93, B/Trp-147 and B/Tyr-188 are the most important. These outcomes tally satisfactorily with the discussions of amino acid mutations. Based on the explorations of three-dimensional quantitative structure-activity relationships, the structure-antagonistic activity relationships of antagonists and the characteristics of ?7 nAChR-ligand recognitions were received a reasonable summary as well. These attempts emerged herein would not only provide helpful guidance for the design of ?7 nAChR antagonists, but shed new light on the subsequent researches in antagonistic mechanism. PMID:25963024

  5. Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

    PubMed Central

    Schmidt, Thomas J.; Borborema, Samanta E. T.; Ferreira, Vitor F.; Rocha, David R.; Tempone, Andre G.

    2014-01-01

    Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. PMID:25171058

  6. RELATIONSHIP BETWEEN STRUCTURE OF BENZIMIDAZOLE DERIVATIVES AND SELECTIVE VIRUS INHIBITORY ACTIVITY

    PubMed Central

    Tamm, Igor; Bablanian, Rostom; Nemes, Marjorie M.; Shunk, Clifford H.; Robinson, Franklin M.; Folkers, Karl

    1961-01-01

    The virus inhibitory activity and selectivity of certain benzimidazole, benzotriazole, and naphthimidazole derivatives were determined with influenza B and polio type 2 viruses. Among the sixty-five compounds examined, several were highly active inhibitors of influenza B virus multiplication in the chorioallantoic membrane in vitro. The following compounds, listed in order of increasing inhibitory activity, were more than 100 times as active as benzimidazole: 5-(4'-toluenesulfonamido)-benzimidazole, 5-hydroxybenzotriazole-4-carboxy-?-naphthylamide, 4,5,6-trichlorobenzotriazole, 5-(3',4'-dichlorobenzenesulfonamido)-benzimidazole, 5-(3',4'-dichlorobenzenesulfonamido) - 1 - (3'',4'' - dichlorobenzenesulfonyl)-benzimidazole, 4-(p-chlorophenylazo)-5-hydroxybenzotriazole, and 4,5,6,7-tetrachlorobenzotriazole. However, none showed high selectivity. Of the sixty-five compounds studied with influenza virus, twenty-five were also examined with poliovirus type 2 in monkey kidney cells in vitro. Included in this group were five of the seven most active inhibitors of influenza virus, listed above. All five were more than 100 times as active in inhibiting poliovirus multiplication as the reference compound. In addition to these, two other compounds were highly active: 2-(?-hydroxybenzyl)-benzimidazole (HBB), and 2-(?-hydroxybenzyl)-5-chlorobenzimidazole, with relative inhibitory activities of 78 and 130, respectively. These two compounds, and the much less active 5,6-dichloro derivative of HBB, were the only ones which showed no, or only slight, toxic effects on cells at concentrations sufficient to cause considerable inhibition of poliovirus multiplication. Furthermore, HBB and the 5-chloro derivative were the only compounds which caused significant inhibition of the cytopathic effects of poliovirus. HBB, and its 5-chloro and 5,6-dichloro derivatives had no effect on the multiplication of influenza B virus in the chorioallantoic membrane. In addition, HBB failed to inhibit influenza B virus multiplication and cytopathic effects in monkey kidney cells. Inhibition of poliovirus-induced cell damage by HBB was characterized by the following features: the curves relating reduction in virus yield or cytopathic effects to concentration of the compound followed an approximately parallel course; somewhat higher concentrations were required to inhibit virus-induced cell damage than to reduce virus yield. HBB suppressed viral cytopathic effects for a period of time which varied directly with the concentration of compound, and inversely with the size of virus inoculum. The development of virus-induced cell damage in treated cultures on prolonged incubation was not due to inactivation of HBB. The inhibitory effect of HBB on virus-induced cell damage was reversible by removal of the compound. HBB inhibited viral cytopathic effects when given during the exponential increase phase in virus multiplication. Inhibition of virus-induced cell damage by HBB was demonstrated by photomicrographs. HBB did not inactivate the infectivity of poliovirus type 2. PMID:13775109

  7. 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.

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

    E-print Network

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

    2007-01-01

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

  9. Quantitative structure-activity relationship studies of HIV-1 integrase inhibition. 1. GETAWAY descriptors.

    PubMed

    Saíz-Urra, Liane; González, Maykel Pérez; Fall, Yagamare; Gómez, Generosa

    2007-01-01

    The GEometry, Topology, and Atom-Weights AssemblY (GETAWAY) approach has been applied to the study of the HIV-1 integrase inhibition of 172 compounds that belong to 11 different chemistry families. A model able to describe more than 68.5% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, none of the five different approaches, including the use of Randi? Molecular Profiles, Geometrical, RDF, 3D-MORSE and WHIM descriptors was able to explain more than 62.4% of the variance in the mentioned property with the same number of variables in the equation. Finally, after extracting five compounds considered by us as outliers the model was able to describe more than 72.5% of the variance in the experimental activity. PMID:17030481

  10. Structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of Apis mellifera.

    PubMed

    Bílikova, Katarina; Huang, Sheng-Chang; Lin, I-Ping; Šimuth, Jozef; Peng, Chi-Chung

    2015-06-01

    Royalisin is a 5.5-kDa antibacterial peptide isolated from the royal jelly of the honeybee (Apis mellifera). The antimicrobial activity of royalisin against fungi, Gram-positive and Gram-negative bacteria has been revealed. Compared with another insect antibacterial peptide, there is an extra stretch of 11 amino acid residues at the C-terminus of royalisin. In this study, a recombinant shortened form of royalisin named as royalisin-D, was constructed without the 11 amino acid residues at the C-terminal of royalisin and linked to the C-terminal of oleosin by an inteinS fragment. The recombinant protein was overexpressed in Escherichia coli, purified by artificial oil body system and subsequently released through self-splicing of inteinS induced by the changes of temperature. The antibacterial activity of royalisin-D was compared with royalisin via minimal inhibitory concentration (MIC) assay, minimal bactericidal concentration (MBC) assay, microbial adhesion to solvents (MATS) methods, and cell membrane permeability. Furthermore, the recombinant royalisin and royalisin-D have also been treated with the reducing agent of disulfide bonds, dithiothreitol (DTT), to investigate the importance of the intra-disulfide bond in royalisin. In our results, royalisin-D exhibited similar antimicrobial activity to royalisin. Royalisin and royalisin D lost their antimicrobial activities when the intra-disulfide bonds were reduced by DDT. The intra-disulfide bond plays a more important role than the extra stretch of 11 amino acid residues at the C-terminus of royalisin in terms of the antimicrobial properties of the native royalisin. PMID:25784287

  11. Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin.

    PubMed

    Chen, Ping; Feng, Dennis; Qian, Xiaoxia; Apgar, James; Wilkening, Robert; Kuethe, Jeffrey T; Gao, Ying-Duo; Scapin, Giovanna; Cox, Jason; Doss, George; Eiermann, George; He, Huaibing; Li, Xiaohua; Lyons, Kathryn A; Metzger, Joseph; Petrov, Aleksandr; Wu, Joseph K; Xu, Shiyao; Weber, Ann E; Yan, Youwei; Roy, Ranabir Sinha; Biftu, Tesfaye

    2015-12-15

    A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan. PMID:26546218

  12. Structure-Activity Relationships of Orotidine-5?-Monophosphate Decarboxylase Inhibitors as Anticancer Agents

    SciTech Connect

    Bello, A.; Konforte, D; Poduch, E; Furlonger, C; Wei, L; Liu, Y; Lewis, M; Pai, E; Paige, C; Kotra, L

    2009-01-01

    A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.

  13. Structure-activity relationships of eighteen somatostatin analogues on gastric secretion.

    PubMed Central

    Brown, M P; Coy, D H; Gomez-Pan, A; Hirst, B H; Hunter, M; Meyers, C; Reed, J D; Schally, A V; Shaw, B

    1978-01-01

    1. The effect of somatostatin and eighteen somatostatin analogues on pentagastrin-stimulated gastric acid and pepsin secretion was investigated in the conscious vagotomized cat prepared with chronic gastric fistulae. The majority of the analogues are peptides where D-amino acids are incorporated into the molecule instead of the natural L-isomers. 2. The ID50 for cyclic-somatostatin inhibition of near-maximal gastric acid secretion stimulated by pentagastrin 8 microgram kg-1 hr-1 was found to be 1.29 +/- 0.13 n-mole kg-1 hr-1. Pentagastrin-stimulated pepsin secretion had a lower threshold to somatostatin inhibition than did acid secretion. 3. D-Phe6, D-Phe7, D-Thr10, D-Thr12 and D-Phe6-D-Trp8 analogues all show low biological activity against the secretion of gastric acid and pepsin, growth hormone, insulin and glucagon. None of these analogues are antagonists of the cyclic-somatostatin inhibition of gastric secretion, suggesting that they have low affinity for this somatostatin receptor. 4. The analogues under investigation show parallel changes in activity against gastric and growth hormone secretion, suggesting a similarity between the gastric and growth hormone receptors for somatostatin. 5. D-Cys14 analogues are equipotent with or have a greater potency than cyclic-simatostatin in inhibiting the secretion of gastric acid, growth hormone and glucagon but show low insulin inhibiting activity. PMID:349135

  14. 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

  15. Synthesis and structure-activity relationships of 1,5-diazaanthraquinones as antitumour compounds.

    PubMed

    Avendaño, Carmen; Pérez, José María; Blanco, Maria del Mar; de la Fuente, Jesús Angel; Manzanaro, Sonia; Vicent, María Jesús; Martín, María Jesús; Salvador-Tormo, Nélida; Menéndez, J Carlos

    2004-08-01

    1,5-Diazaanthraquinone derivatives were synthesized employing single and double hetero Diels-Alder strategies. Their in vitro antitumour activity was assayed using three cell lines. Some of these compounds, specially those bearing methyl or ethyl groups at the C-3,7 positions or chloro at C-4 and methyl at C-7, showed IC(50) values in the 10(-8)M range for human lung carcinoma and human melanoma, which makes them attractive candidates for further development as anticancer agents. PMID:15225700

  16. Structure-activity relationships in the hydrolysis of substrates by the phosphotriesterase from Pseudomonas diminuta

    SciTech Connect

    Donarski, W.J.; Dumas, D.P.; Heitmeyer, D.P.; Lewis, V.E.; Raushel, F.M. )

    1989-05-30

    The mechanism and substrate specificity of the phosphotriesterase from Pseudomonas diminuta have been examined. The enzyme hydrolyzes a large number of phosphotriester substrates in addition to paraoxon (diethyl p-nitrophenyl phosphate) and its thiophosphate analogue, parathion. The two ethyl groups in paraoxon can be changed to propyl and butyl groups, but the maximal velocity and Km values decrease substantially. The enzyme will not hydrolyze phosphomonoesters or -diesters. There is a linear correlation between enzymatic activity and the pKa of the phenolic leaving group for 16 paraoxon analogues. The beta value in the corresponding Bronsted plot is -0.8. No effect on either Vmax or Vmax/Km is observed when sucrose is used to increase the relative solvent viscosity by 3-fold. These results are consistent with rate-limiting phosphorus-oxygen bond cleavage. A plot of log V versus pH for the hydrolysis of paraoxon shows one enzymatic group that must be unprotonated for activity with a pKa of 6.1. The deuterium isotope effect by D2O on Vmax and Vmax/Km is 2.4 and 1.2, respectively, and the proton inventory is linear, which indicates that only one proton is in flight during the transition state. The inhibition patterns by the products are consistent with a random kinetic mechanism.

  17. 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

  18. Further studies regarding the structure activity relationships of beta-adrenoceptor antagonists.

    PubMed

    Bagwell, E E; Williams, E M

    1973-08-01

    1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2. M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.3. Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3.6 times more active in blocking cardiac responses to isoprenaline.4. The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).5. L8429, with a tertiary butyl group in the para position, was a weak beta-adrenoceptor antagonist without cardioselective properties. A longer, less bulky n-butyl group may provide for a more potent and selective antagonist.6. The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of beta-adrenoceptor antagonists. PMID:4150921

  19. Structure-activity relationship for extracellular block of K+ channels by tetraalkylammonium ions.

    PubMed

    Luzhkov, Victor B; Osterberg, Fredrik; Aqvist, Johan

    2003-11-01

    External tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions. PMID:14596932

  20. Synthesis and structure-activity relationship study of organometallic bioconjugates of the cyclic octapeptide octreotate.

    PubMed

    Gross, Annika; Habig, Daniel; Metzler-Nolte, Nils

    2013-12-16

    The chemically stabilized somatostatin-derived cyclic octapeptide octreotate has a number of interesting applications in medicinal chemistry. Here, a number of different organometallic derivatives of octreotate were prepared, and their properties were investigated. Specifically, we report the synthesis and characterization of ruthenocene, ferrocene, and cobaltocenium octreotate derivatives and their fluorophore-labeled conjugates as well as a dicobalt hexacarbonyl alkyne functionalized octreotate. To provide further insights into their characteristics, the log?P values and electrochemical properties of the novel metal conjugates were compared. For biological activity, we determined their toxicity in three different cell lines. Cellular uptake and colocalization of selected compounds were studied by fluorescence microscopy with particular focus on efficiency and specificity of their uptake through the somatostatin receptor SSTR to elucidate the value of the metallocene head group for its potential use as a nontoxic and universal peptide label. PMID:24218362

  1. Quantitative structure-activity relationship analysis of perfluoroiso-propyldinitrobenzene derivatives known as photosystem II electron transfer inhibitors.

    PubMed

    Karacan, Mehmet Say?m; Yakan, Ci?dem; Yakan, Mehmet; Karacan, Nurcan; Zharmukhamedov, Sergey K; Shitov, Alexandr; Los, Dmitry A; Klimov, Vyacheslav V; Allakhverdiev, Suleyman I

    2012-08-01

    Quantitative structure-activity relationship (QSAR) analysis of the twenty-six perfluoroisopropyl-dinitrobenzene (PFIPDNB) derivatives was performed to explain their ability to suppress photochemical activity of the plants photosystem II using chloroplasts and subchloroplast thylakoid membranes enriched in photosystem II, called DT-20. Compounds were optimized by semi-empirical PM3 and DFT/B3LYP/6-31G methods. The Heuristic and the Best Multi-Linear Regression (BMLR) method in CODESSA were used to select the most appropriate molecular descriptors and to develop a linear QSAR model between experimental pI(50) values and the most significant set of the descriptors. The obtained models were validated by cross-validation (R(2)(cv)) and internal validation to confirm the stability and good predictive ability. The obtained eight models with five-parameter show that: (a) coefficient (R(2)) value of the chloroplast samples are slightly higher than that of the DT-20 samples both of Heuristic and BMLR models; (b) the coefficients of the BMLR models are slightly higher than that of Heuristic models both of chloroplasts and DT-20 samples; (c) The YZ shadow parameter and the indicator parameter, for presence of NO(2) substituent in the ring, are the most important descriptor at PM3-based and DFT-based QSAR models, respectively. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID:22306527

  2. 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 ?M), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (Ki 0.328 ?M) and NTPDase3 (Ki 2.22 ?M). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (Ki 1.5 ?M). PMID:18528783

  3. Novel N-2-(Furyl)-2-(chlorobenzyloxyimino) Ethyl Piperazinyl Quinolones: Synthesis, Cytotoxic Evaluation and Structure-Activity Relationship

    PubMed Central

    Mohammadhosseini, Negar; Pordeli, Mahboobeh; Safavi, Maliheh; Firoozpour, Loghman; Amin, Fatame; Kabudanian Ardestani, Sussan; Edraki, Najmeh; Shafiee, Abbas; Foroumadi, Alireza

    2015-01-01

    Quinolone antibacterials are one of the most important classes of pharmacological agents known as potent inhibitors of bacterial DNA gyrase and topoisomerase IV that efficiently inhibit DNA replication and transcription by generating several double-stranded DNA break. Some quinolone derivatives demonstrated inhibitory potential against eukaryote topoismarase II and substantial dose-dependent cytotoxic potential against some cancerous cells. In present study, synthesis and cytotoxic activity evaluation of new series of N-pipearzinyl quinolones containing N-2-(furyl-2 or 3-yl)-2-(chlorobenzyloxyimino) ethyl moiety 7a-i have been studied. Reaction of quinolone, with 2-bromo-1-(furan-2 or 3-yl)ethanone-O-substituted chlorobenzyloxime in DMF in presence of NaHCO3 at room temperature, gave the title compounds N-2-(furan-2 or 3-yl)-2-(chlorobenzyloxyiminoethyl) quinolone 7a-i. Synthesized compounds were further evaluated in-vitro against three human breast tumor cell lines. Preliminary screening indicated that compound 7 g demonstrated significant growth inhibitory potential against all evaluated cell lines. The results of structure-activity relationship study exhibited that quinolone derivatives are superior in cytotoxic potential compared to 1, 8-naphthyridone series. Furthermore, ethyl quinolone derivatives were more potent cytotoxic agents comparing with cyclopropyl quinolones.

  4. Crystallographic insights into the structure-activity relationships of diazaborine enoyl-ACP reductase inhibitors.

    PubMed

    Jordan, Cheryl A; Sandoval, Braddock A; Serobyan, Mkrtich V; Gilling, Damian H; Groziak, Michael P; Xu, H Howard; Vey, Jessica L

    2015-12-01

    Enoyl-ACP reductase, the last enzyme of the fatty-acid biosynthetic pathway, is the molecular target for several successful antibiotics such as the tuberculosis therapeutic isoniazid. It is currently under investigation as a narrow-spectrum antibiotic target for the treatment of several types of bacterial infections. The diazaborine family is a group of boron heterocycle-based synthetic antibacterial inhibitors known to target enoyl-ACP reductase. Development of this class of molecules has thus far focused solely on the sulfonyl-containing versions. Here, the requirement for the sulfonyl group in the diazaborine scaffold was investigated by examining several recently characterized enoyl-ACP reductase inhibitors that lack the sulfonyl group and exhibit additional variability in substitutions, size and flexibility. Biochemical studies are reported showing the inhibition of Escherichia coli enoyl-ACP reductase by four diazaborines, and the crystal structures of two of the inhibitors bound to E. coli enoyl-ACP reductase solved to 2.07 and 2.11?Å resolution are reported. The results show that the sulfonyl group can be replaced with an amide or thioamide without disruption of the mode of inhibition of the molecule. PMID:26625295

  5. 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

  6. Structure-activity relationships of polyphenols to prevent lipid oxidation in pelagic fish muscle.

    PubMed

    Pazos, Manuel; Iglesias, Jacobo; Maestre, Rodrigo; Medina, Isabel

    2010-10-27

    The influence of polymerization (number of monomers) and galloylation (content of esterified gallates) of oligomeric catechins (proanthocyanidins) on their effectiveness to prevent lipid oxidation in pelagic fish muscle was evaluated. Non-galloylated oligomers of catechin with diverse mean polymerization (1.9-3.4 monomeric units) were extracted from pine (Pinus pinaster) bark. Homologous fractions with galloylation ranging from 0.25 to <1 gallate group per molecule were obtained from grape (Vitis vinifera) and witch hazel (Hamamelis virginiana). The results showed the convenience of proanthocyanidins with medium size (2-3 monomeric units) and low galloylation degree (0.15-0.25 gallate group/molecule) to inhibit lipid oxidation in pelagic fish muscle. These optimal structural characteristics of proanthocyanidins were similar to those lately reported in fish oil-in-water emulsions using phosphatidylcholine as emulsifier. This finding suggests that the antioxidant behavior of polyphenols in muscle-based foods can be mimicked in emulsions prepared with phospholipids as emulsifier agents. The present data give relevant information to achieve an optimum use of polyphenols in pelagic fish muscle. PMID:20925315

  7. Structure-activity relationship of carbacephalosporins and cephalosporins: antibacterial activity and interaction with the intestinal proton-dependent dipeptide transport carrier of Caco-2 cells.

    PubMed Central

    Snyder, N J; Tabas, L B; Berry, D M; Duckworth, D C; Spry, D O; Dantzig, A H

    1997-01-01

    An intestinal proton-dependent peptide transporter located on the lumenal surface of the enterocyte is responsible for the uptake of many orally absorbed beta-lactam antibiotics. Both cephalexin and loracarbef are transported by this mechanism into the human intestinal Caco-2 cell line. Forty-seven analogs of the carbacephalosporin loracarbef and the cephalosporin cephalexin were prepared to evaluate the structural features necessary for uptake by this transport carrier. Compounds were evaluated for their antibacterial activities and for their ability to inhibit 1 mM cephalexin uptake and, subsequently, uptake into Caco-2 cells. Three clinically evaluated orally absorbed carbacephems were taken up by Caco-2 cells, consistent with their excellent bioavailability in humans. Although the carrier preferred the L stereoisomer, these compounds lacked antibacterial activity and were hydrolyzed intracellularly in Caco-2 cells. Compounds modified at the 3 position of cephalexin and loracarbef with a cyclopropyl or a trifluoromethyl group inhibited cephalexin uptake. Analogs with lipophilic groups on the primary amine of the side chain inhibited cephalexin uptake, retained activity against gram-positive bacteria but lost activity against gram-negative bacteria. Substitution of the phenylglycl side chain with phenylacetyl side chains gave similar results. Compounds which lacked an aromatic ring in the side chain inhibited cephalexin uptake but lost all antibacterial activity. Thus, the phenylglycl side chain is not absolutely required for uptake. Different structural features are required for antibacterial activity and for being a substrate of the transporter. Competition studies with cephalexin indicate that human intestinal Caco-2 cells may be a useful model system for initially guiding structure-activity relationships for the rational design of new oral agents. PMID:9257735

  8. Investigation of structure-activity relationships of synthetic anti-gonadotropin releasing hormone vaccine candidates.

    PubMed

    Chang, Chenghung; Varamini, Pegah; Giddam, Ashwini Kumar; Mansfeld, Friederike M; D'Occhio, Michael J; Toth, Istvan

    2015-05-01

    The immunoneutralization of gonadotropin-releasing hormone (GnRH) can be used for the treatment of human hormone-dependent male and female cancers or as immunocontraceptives in animals. Vaccine candidates 1 [Th(K-LP)GnRH], 2 [GnRH(K-LP)Th], 3 [GnRH(K-Th)LP], and 4 [Th(K-GnRH)LP] (for which K=lysine, LP=lipopeptide Ser-Ser-C16 -C16 , and Th=T?helper cell epitope influenza HA2), were synthesized by assembling a CD4(+) T?helper cell epitope (Th), GnRH, and an adjuvanting lipid moiety (LP) in various spatial arrangements. All compounds were efficiently taken up by antigen-presenting cells with significant immunogenicity without an external adjuvant. Compounds 2, 3, and 4, in which GnRH is conjugated through its C?terminus, produced higher GnRH-specific antibody responses than construct 1, in which the GnRH moiety is conjugated through its N?terminus. All four constructs induced a significant antiproliferative effect (up to 55?%) on GnRH-receptor-positive LNCaP cells, but showed weaker activity in the GnRH-receptor-negative SKOV-3 cell line. Marked degenerative changes were observed in morphology and follicular development in the ovaries of immunized mice, with approximately 30?% higher degenerative antral and atretic follicles. PMID:25809441

  9. Design, synthesis, and structure--activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists.

    PubMed

    Ma, Haikuo; Lu, Wenfeng; Sun, Zhijian; Luo, Lusong; Geng, Delong; Yang, Zhaohui; Li, Enqin; Zheng, Jiyue; Wang, Meiyu; Zhang, Hongjian; Yang, Shilin; Zhang, Xiaohu

    2015-01-01

    The Smoothened (Smo) receptor is an important component of the hedgehog (Hh) signaling pathway, which plays a critical role during embryonic development. In adults, Hh signaling is curtailed and has limited functions such as stem cell maintenance and tissue repair. However, aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Smo leads to the blockade of Hh signaling, and therefore represents a promising approach toward novel anticancer therapy. Through scaffold morphing of a few known Smo antagonists, a series of novel tetrahydrothiazolopyridine derivatives were developed. Compounds from this new scaffold demonstrated excellent Hh signaling inhibition which was comparable to or better than that of Vismodegib. Further, compound 30 exhibited a lower melting point and a moderately improved solubility compared with those of Vismodegib; compounds 11 and 30 showed good pharmacokinetic profiles with 34% and 77% oral bioavailability in rat, respectively. Collectively, these results strongly support further optimization of this novel scaffold to develop better Smo antagonists. PMID:25462278

  10. 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.

  11. 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 ?- and ?-zearalenol (?ZEL and ?ZEL). These reduced metabolites possess estrogenic properties, ?ZEL 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 ?ZEL and ???L 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 (PPAR?). Our results demonstrated that in spite of structure similarities between ZEN, ?ZEL and ?ZEL, 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.

  12. Structure-activity relationship of mastoparan analogs: Effects of the number and positioning of Lys residues on secondary structure, interaction with membrane-mimetic systems and biological activity.

    PubMed

    Souza, Bibiana Monson de; Cabrera, Marcia Perez Dos Santos; Gomes, Paulo Cesar; Dias, Nathalia Baptista; Stabeli, Rodrigo Guerino; Leite, Natalia Bueno; Neto, João Ruggiero; Palma, Mario Sergio

    2015-10-01

    In this study, a series of mastoparan analogs were engineered based on the strategies of Ala and Lys scanning in relation to the sequences of classical mastoparans. Ten analog mastoparans, presenting from zero to six Lys residues in their sequences were synthesized and assayed for some typical biological activities for this group of peptide: mast cell degranulation, hemolysis, and antibiosis. In relation to mast cell degranulation, the apparent structural requirement to optimize this activity was the existence of one or two Lys residues at positions 8 and/or 9. In relation to hemolysis, one structural feature that strongly correlated with the potency of this activity was the number of amino acid residues from the C-terminus of each peptide continuously embedded into the zwitterionic membrane of erythrocytes-mimicking liposomes, probably due to the contribution of this structural feature to the membrane perturbation. The antibiotic activity of mastoparan analogs was directly dependent on the apparent extension of their hydrophilic surface, i.e., their molecules must have from four to six Lys residues between positions 4 and 11 of the peptide chain to achieve activities comparable to or higher than the reference antibiotic compounds. The optimization of the antibacterial activity of the mastoparans must consider Lys residues at the positions 4, 5, 7, 8, 9, and 11 of the tetradecapeptide chain, with the other positions occupied by hydrophobic residues, and with the C-terminal residue in the amidated form. These requirements resulted in highly active AMPs with greatly reduced (or no) hemolytic and mast cell degranulating activities. PMID:25944744

  13. 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.

  14. 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.

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

    PubMed

    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, R(2) = 0.9502 and variance ratio of regression 122 has been found as the best statistical model. PMID:25709964

  16. 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; Pot??ková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Ma?ecki, Jan G.; Sajewicz, Mieczys?aw; Ratuszna, Alicja; Muchowicz, Angelika; Go??b, Jakub; Šim?nek, 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

  17. 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 designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds. PMID:21269449

  18. 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 ?g/ml to 0.0156 ?g/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 ?g/ml), as well as its high metabolic stability in human liver microsomes. PMID:26310892

  19. 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 (k?, k?, k? 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 ?EHOMO-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

  20. Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study

    PubMed Central

    Satpathy, Raghunath; Guru, R. K.; Behera, R.; Nayak, B.

    2015-01-01

    Context: Boswellic acid consists of a series of pentacyclic triterpene molecules that are produced by the plant Boswellia serrata. The potential applications of Bowsellic acid for treatment of cancer have been focused here. Aims: To predict the property of the bowsellic acid derivatives as anticancer compounds by various computational approaches. Materials and Methods: In this work, all total 65 derivatives of bowsellic acids from the PubChem database were considered for the study. After energy minimization of the ligands various types of molecular descriptors were computed and corresponding two-dimensional quantitative structure activity relationship (QSAR) models were obtained by taking Andrews coefficient as the dependent variable. Statistical Analysis Used: Different types of comparative analysis were used for QSAR study are multiple linear regression, partial least squares, support vector machines and artificial neural network. Results: From the study geometrical descriptors shows the highest correlation coefficient, which indicates the binding factor of the compound. To evaluate the anticancer property molecular docking study of six selected ligands based on Andrews affinity were performed with nuclear factor-kappa protein kinase (Protein Data Bank ID 4G3D), which is an established therapeutic target for cancers. Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. Conclusions: Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. PMID:25709332

  1. Structure-activity relationships of a series of analogues of the RFamide-related peptide 26RFa.

    PubMed

    Le Marec, Olivier; Neveu, Cindy; Lefranc, Benjamin; Dubessy, Christophe; Boutin, Jean A; Do-Régo, Jean-Claude; Costentin, Jean; Tonon, Marie-Christine; Tena-Sempere, Manuel; Vaudry, Hubert; Leprince, Jérôme

    2011-07-14

    26RFa is a new member of the RFamide peptide family that has been identified as the endogenous ligand of the orphan GPCR GPR103. As the C-terminal heptapeptide (26RFa((20-26))) mimics the action of the native peptide on food intake and gonadotropin secretion in rodents, we have synthesized a series of analogues of 26RFa((20-26)) and measured their potency to induce [Ca(2+)](i) mobilization in G?(16)-hGPR103-transfected CHO cells. Systematic replacement of each residue by an alanine (Ala scan) and its D-enantiomer (D scan) showed that the last three C-terminal residues were very sensitive to the substitutions while position 23 tolerated rather well both modifications. Most importantly, replacement of Ser(23) by a norvaline led to an analogue, [Nva(23)]26RFa((20-26)), that was 3-fold more potent than the native heptapeptide. These new pharmacological data, by providing the first information regarding the structure-activity relationships of 26RFa analogues, should prove useful for the rational design of potent GPR103 receptor ligands with potential therapeutic application. PMID:21623631

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

    PubMed

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

    2015-11-15

    Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore. PMID:26507430

  3. Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases

    PubMed Central

    Song, Jiho; Yoo, Jakyung; Kwon, Ara; Kim, Doran; Nguyen, Hong Khanh; Lee, Bong-Yong; Suh, Wonhee; Min, Kyung Hoon

    2015-01-01

    Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold. PMID:26401847

  4. A structure-activity relationship study of the toxicity of ionic liquids using an adapted Ferreira-Kiralj hydrophobicity parameter.

    PubMed

    de Melo, Eduardo Borges

    2015-02-14

    The Ferreira-Kiralj hydrophobicity parameter Wc is a number fraction of hydrophobic carbon atoms and can be regarded as a constitutional descriptor since its calculation depends only on the number of polar and nonpolar carbons in a compound. Hydrophobicity is important to the toxicity of ionic liquids (ILs), which are salts by nature. Herein, a descriptor for this property was calculated using a simple adaptation of the type of polar carbon atoms included (WcAdap) to explore the possibility of its use in quantitative structure-activity relationship (QSAR) studies of ILs. The resulting model was tested using a database of ILs with toxicity against the Leukemia rat cell line IPC-81. Two other models were constructed using Crippen?log?P and Mannhold?log?P descriptors, which are both available in the free program PaDEL. The use of WcAdap led to a better and more indicative model. Thus, WcAdap may be a suitable molecular descriptor for the hydrophobicity of ILs in QSAR studies. PMID:25583131

  5. 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

  6. Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53

    PubMed Central

    Pletsas, Dimitrios; Garelnabi, Elrashied A.E.; Li, Li; Phillips, Roger M.; Wheelhouse, Richard T.

    2014-01-01

    The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed. PMID:23895620

  7. Structure-activity relationship study using peptide arrays to optimize Api137 for an increased antimicrobial activity against Pseudomonas aeruginosa.

    PubMed

    Bluhm, Martina E C; Knappe, Daniel; Hoffmann, Ralf

    2015-10-20

    The opportunistic Gram-negative bacterium Pseudomonas aeruginosa has a low susceptibility to common antibiotics. Additionally, around 15% of all clinical isolates bear acquired resistance genes. Thus, the development of new antibiotics to combat this pathogen in pneumonia, urinary tract infections, and bacteremia, represents an urgent task. The activity spectrum of the proline-rich antimicrobial peptide apidaecin 1b, originally isolated from honeybees (Apis mellifera), was extended in previous studies to further human pathogens including P. aeruginosa. However, the in vitro activity of the optimized peptide Api137 is limited to diluted medium conditions. Thus, we synthesized 323 analogs of Api137 on cellulose membranes using the SPOT strategy by substituting each residue individually by 19 other amino acids or deleting the residue. The peptides were deprotected with trifluoroacetic acid and cleaved with aqueous trimethylamine as C-terminal acids providing around 30 ?g crude peptide per spot. This amount allowed determining the minimal inhibitory concentrations in a microdilution broth assay. The most promising substitutions were selected to synthesize 44 doubly and triply substituted Api137 analogs on the membrane. The 19 best peptides were synthesized at a larger scale and purified. Eight triply substituted Api137 analogs were up to 16-fold more active against P. aeruginosa at high medium concentrations without losing activities against Klebsiella pneumoniae and Acinetobacter baumannii and only slightly against Escherichia coli. The eight most active Api137 analogs were non-hemolytic to human erythrocytes and non-toxic to HeLa cells. PMID:26408816

  8. STRUCTURE-ACTIVITY RELATIONSHIPS FOR INSECT KININS ON EXPRESSED RECEPTORS FROM A TICK (ACARI:IXODIDAE) AND A MOSQUITO (DIPTERA:CULICIDAE)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The systematic analysis of structure-activity relationships of insect kinins on two heterologous receptor-expressing systems is described. Previously, kinin receptors from the southern cattle tick, Boophilus microplus (Canestrini, 1888) [1; 2] and the dengue vector, the mosquito Aedes aegypti (L.) ...

  9. 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...

  10. Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship.

    PubMed

    Domagala, J M; Bridges, A J; Culbertson, T P; Gambino, L; Hagen, S E; Karrick, G; Porter, K; Sanchez, J P; Sesnie, J A; Spense, F G

    1991-03-01

    A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C7 with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C8 (H, F, Cl) and N1 (ethyl, cyclopropyl, difluorophenyl) was also studied. The results showed that several of the structure-activity conclusions regarding side-chain bulk at C7, the effect of halogen at C8, and the effect of the C5-amino group were greatly influenced by the choice of the N1-substituent. Several outstanding broad spectrum quinolones were identified in this work. In particular, the spectrum and potency of the 7-piperazinyl quinolones could be greatly enhanced by the judicious choice of C5-, C8-, and N1-substituents. PMID:1848296

  11. 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 ?-cyclodextrin (?CD) 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 ?CD 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 ?CD series and arginine groups in the CA4 series. Whereas the transfection efficiency relationships remain essentially unchanged within each series, irrespective of the cell type, the optimal platform (?D or CA4) strongly depends on the cell type. The results illustrate the potential of monodisperse vector prototypes and diversity-oriented strategies on identifying the optimal candidates for gene therapy applications. PMID:25474077

  12. 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 ?B 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

  13. Structural characterization and cytotoxic properties of a 4-O-methylglucuronoxylan from castanea sativa. 2. Evidence of a structure-activity relationship.

    PubMed

    Barbat, Aline; Gloaguen, Vincent; Moine, Charlotte; Sainte-Catherine, Odile; Kraemer, Michel; Rogniaux, Hélène; Ropartz, David; Krausz, Pierre

    2008-08-01

    Xylans were purified from delignified holocellulose alkaline extracts of Castanea sativa (Spanish chestnut) and Argania spinosa (Argan tree) and their structures analyzed by means of GC of their per-trimethylsilylated methylglycoside derivatives and (1)H NMR spectroscopy. The structures deduced were characteristic of a 4-O-methylglucuronoxylan (MGX) and a homoxylan (HX), respectively, with degrees of polymerization ranging from 182 to 360. In the case of MGX, the regular or random distribution of 4-O-methylglucuronic acid along the xylosyl backbone--determined by MALDI mass spectrometry after autohydrolysis of the polysaccharide--varied and depended both on the botanical source from which they were extracted and on the xylan extraction procedure. The MGX also inhibited in different ways the proliferation as well as the migration and invasion capability of A431 human epidermoid carcinoma cells. These biological properties could be correlated with structural features including values of the degree of polymerization, 4-O-MeGlcA to xylose ratios, and distribution of 4-O-MeGlcA along the xylosyl backbone, giving evidence of a defined structure-activity relationship. PMID:18646856

  14. Growth-inhibitory and apoptosis-inducing effects of tanshinones on hematological malignancy cells and their structure-activity relationship.

    PubMed

    Li, Hui; Zhang, Qing; Chu, Ting; Shi, Hua-Yue; Fu, Hui-Min; Song, Xiang-Rong; Meng, Wen-Tong; Mao, Sheng-Jun; Jia, Yong-Qian

    2012-09-01

    This study has investigated the growth-inhibitory and apoptosis-inducing effects of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone on hematological malignancy cell lines, aiming to explore their structure-activity relationship. The growth-inhibitory effects of the tanshinones on K562 and Raji cells were assessed using a modified MTT assay; the apoptosis-inducing effects were assessed by fluorescence microscopy and flow cytometry analysis. The changes in cellular morphology were observed using an inverted phase-contrast microscope. MTT results revealed that these tanshinones inhibited cell proliferation in a concentration-dependent and time-dependent manner. The IC50 values of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone for K562 cells were 3.50, 13.52, 19.32, and 47.52 ?mol/l at 24 h; 1.36, 4.70, 5.67, and 22.72 ?mol/l at 48 h; and 1.15, 1.59, 2.82, and 19.53 ?mol/l at 72 h, and the values for Raji cells were 3.30, 4.37, 12.92, and 52.36 ?mol/l at 24 h; 1.55, 1.71, 6.54, and 25.45 ?mol/l at 48 h; and 1.07, 1.38, 1.89, and 18.47 ?mol/l at 72 h. The flow cytometry analysis demonstrated that these tanshinones induced apoptosis of K562 cells in a concentration-dependent manner, and dihydrotanshinone as well as tanshinone I were more potent than tanshinone IIA and cryptotanshinone. Some noticeable apoptotic morphologies could be observed by fluorescence microscopy on tanshinones-treated Raji cells. Collectively, these tanshinones caused growth inhibition and apoptosis in hematological malignancy cell lines, with dihydrotanshinone being the most potent, followed by tanshinone I, tanshinone IIA, and cryptotanshinone. These results suggested that the structure of aromatic ring A enhanced the cytotoxicity and the structure of ring C may have contributed to the cytotoxicity, but the mechanisms need to be further investigated. PMID:22495618

  15. Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study.

    PubMed

    Lau, Qiu Ying; Ng, Fui Mee; Cheong, Jin Wei Darryl; Yap, Yi Yong Alvin; Tan, Yoke Yan Fion; Jureen, Roland; Hill, Jeffrey; Chia, Cheng San Brian

    2015-11-13

    The overuse and misuse of antibiotics has resulted in the emergence of drug-resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections. PMID:26489599

  16. Structure-Activity Relationship of Amino Acid Tunable Lipidated Norspermidine Conjugates: Disrupting Biofilms with Potent Activity against Bacterial Persisters.

    PubMed

    Konai, Mohini M; Adhikary, Utsarga; Samaddar, Sandip; Ghosh, Chandradhish; Haldar, Jayanta

    2015-12-16

    The emergence of bacterial resistance and biofilm associated infections has created a challenging situation in global health. In this present state of affairs where conventional antibiotics are falling short of being able to provide a solution to these problems, development of novel antibacterial compounds possessing the twin prowess of antibacterial and antibiofilm efficacy is imperative. Herein, we report a library of amino acid tunable lipidated norspermidine conjugates that were prepared by conjugating both amino acids and fatty acids with the amine functionalities of norspermidine through amide bond formation. These lipidated conjugates displayed potent antibacterial activity against various planktonic Gram-positive and Gram-negative bacteria including drug-resistant superbugs such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and ?-lactam-resistant Klebsiella pneumoniae. This class of nontoxic and fast-acting antibacterial molecules (capable of killing bacteria within 15 min) did not allow bacteria to develop resistance against them after several passages. Most importantly, an optimized compound in the series was also capable of killing metabolically inactive persisters and stationary phase bacteria. Additionally, this compound was capable of disrupting the preformed biofilms of S. aureus and E. coli. Therefore, this class of antibacterial conjugates have potential in tackling the challenging situation posed by both bacterial resistance as well as drug tolerance due to biofilm formation. PMID:26452096

  17. FISH ACUTE TOXICITY SYNDROMES AND THEIR USE IN THE QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP) APPROACH TO HAZARD ASSESSMENT

    EPA Science Inventory

    Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity re...

  18. Structure-activity relationships for biodistribution, pharmacokinetics, and excretion of atomically precise nanoclusters in a murine model

    NASA Astrophysics Data System (ADS)

    Wong, O. Andrea; Hansen, Ryan J.; Ni, Thomas W.; Heinecke, Christine L.; Compel, W. Scott; Gustafson, Daniel L.; Ackerson, Christopher J.

    2013-10-01

    The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR)44 nanoclusters with different (SR) ligand shells. To rationalize unexpected distribution and excretion properties observed for several clusters in this study and others, we defined a set of atomistic structure-activity relationships (SAR) for nanoparticles, which includes previously investigated parameters such as particle hydrodynamic diameter and net charge, and new parameters such as hydrophobic surface area and surface charge density. Overall we find that small changes in particle formulation can provoke dramatic yet potentially predictable changes in ADME/PK.The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR)44 nanoclusters with different (SR) ligand shells. To rationalize unexpected distribution and excretion properties observed for several clusters in this study and others, we defined a set of atomistic structure-activity relationships (SAR) for nanoparticles, which includes previously investigated parameters such as particle hydrodynamic diameter and net charge, and new parameters such as hydrophobic surface area and surface charge density. Overall we find that small changes in particle formulation can provoke dramatic yet potentially predictable changes in ADME/PK. Electronic supplementary information (ESI) available: The polyacrylamide gel that shows the purity of Au102pMBA44, excretion graphs for compounds 1-5, atomistic models of the Au25 and Au102-based compounds, the zoomed in versions of Fig. 3 and 6, 1H NMR of compound 5, information on the Au102 1 : 1 exchange compound, and blood drug concentration vs. time curves of Au102-based compounds. See DOI: 10.1039/c3nr03121g

  19. Assessment of quantitative structure-activity relationship of toxicity prediction models for Korean chemical substance control legislation

    PubMed Central

    Kim, Kwang-Yon; Shin, Seong Eun; No, Kyoung Tai

    2015-01-01

    Objectives For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. Methods There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. Results We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. Conclusions We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used with predicted toxicity results. Furthermore, by presenting the suitability of individual predicted results, we aimed to provide a foundation that could be used in actual assessments and regulations. PMID:26206368

  20. Structure-activity relationships imply different mechanisms of action for ochratoxin A-mediated cytotoxicity and genotoxicity.

    PubMed

    Hadjeba-Medjdoub, Kheira; Tozlovanu, Mariana; Pfohl-Leszkowicz, Annie; Frenette, Christine; Paugh, Robert J; Manderville, Richard A

    2012-01-13

    Ochratoxin A (OTA) is a fungal toxin that is classified as a possible human carcinogen based on sufficient evidence for carcinogenicity in animal studies. The toxin is known to promote oxidative DNA damage through production of reactive oxygen species (ROS). The toxin also generates covalent DNA adducts, and it has been difficult to separate the biological effects caused by DNA adduction from that of ROS generation. In the current study, we have derived structure-activity relationships (SAR) for the role of the C5 substituent of OTA (C5-X = Cl) by first comparing the ability of OTA, OTBr (C5-X = Br), OTB (C5-X = H), and OTHQ (C5-X = OH) to photochemically react with GSH and 2'-deoxyguanosine (dG). OTA, OTBr, and OTHQ react covalently with GSH and dG following photoirradiation, while the nonchlorinated OTB does not react photochemically with GSH and dG. These findings correlate with their ability to generate covalent DNA adducts (direct genotoxicity) in human bronchial epithelial cells (WI26) and human kidney (HK2) cells, as evidenced by the (32)P-postlabeling technique. OTB lacks direct genotoxicity, while OTA, OTBr, and OTHQ act as direct genotoxins. In contrast, their cytotoxicity in opossum kidney epithelial cells (OK) and WI26 cells did not show a correlation with photoreactivity. In OK and WI26 cells, OTA, OTBr, and OTB are cytotoxic, while the hydroquinone OTHQ failed to exhibit cytotoxicity. Overall, our data show that the C5-Cl atom of OTA is critical for direct genotoxicity but plays a lesser role in OTA-mediated cytotoxicity. These SARs suggest different mechanisms of action (MOA) for OTA genotoxicity and cytotoxicity and are consistent with recent findings showing OTA mutagenicity to stem from direct genotoxicity, while cytotoxicity is derived from oxidative DNA damage. PMID:22126095

  1. Relationship between chemical structure and biological activity of alkali metal o-, m- and p-anisates. FT-IR and microbiological studies

    NASA Astrophysics Data System (ADS)

    Kalinowska, M.; Piekut, J.; Lewandowski, W.

    2011-11-01

    In this work we investigated relationship between molecular structure of alkali metal o-, m-, p-anisate molecules and their antimicrobial activity. For this purpose FT-IR spectra for lithium, sodium, potassium, rubidium and caesium anisates in solid state and solution were recorded, assigned and analysed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Proteus vulgaris. In order to evaluate the dependency between chemical structure and biological activity of alkali metal anisates the statistical analysis (multidimensional regression and principal component) was performed for selected wavenumbers from FT-IR spectra and parameters that describe microbial activity of anisates. The obtained statistical equations show the existence of correlation between molecular structure of anisates and their biological properties.

  2. Relationship between chemical structure and biological activity of alkali metal o-, m- and p-anisates. FT-IR and microbiological studies.

    PubMed

    Kalinowska, M; Piekut, J; Lewandowski, W

    2011-11-01

    In this work we investigated relationship between molecular structure of alkali metal o-, m-, p-anisate molecules and their antimicrobial activity. For this purpose FT-IR spectra for lithium, sodium, potassium, rubidium and caesium anisates in solid state and solution were recorded, assigned and analysed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Proteus vulgaris. In order to evaluate the dependency between chemical structure and biological activity of alkali metal anisates the statistical analysis (multidimensional regression and principal component) was performed for selected wavenumbers from FT-IR spectra and parameters that describe microbial activity of anisates. The obtained statistical equations show the existence of correlation between molecular structure of anisates and their biological properties. PMID:21852187

  3. Structure-Activity Relationship and Substrate-Dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes

    PubMed Central

    Hao, Miao; Zhao, Yuqing; Chen, Peizhan; Huang, He; Liu, Hong; Jiang, Hualiang; Zhang, Ruiwen; Wang, Hui

    2008-01-01

    Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs). Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports. PMID:18628990

  4. Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.

    PubMed

    Wurz, Ryan P; Pettus, Liping H; Henkle, Bradley; Sherman, Lisa; Plant, Matthew; Miner, Kent; McBride, Helen J; Wong, Lu Min; Saris, Christiaan J M; Lee, Matthew R; Chmait, Samer; Mohr, Christopher; Hsieh, Faye; Tasker, Andrew S

    2010-03-01

    A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg. PMID:20138761

  5. STRUCTURE-GENOTOXIC ACTIVITY RELATIONSHIPS OF PESTICIDES: COMPARISON OF THE RESULTS FROM SEVERAL SHORT-TERM ASSAYS

    EPA Science Inventory

    The Computer-Automated Structure Evaluation (CASE) program has been applied to the analysis of the genotoxic activity of 54 pesticides (31 insecticides, 15 herbicides and 8 fungicides), in 5 different short-term test systems measuring point-gene mutation and DNA damage. The datab...

  6. Structure-plant phytotoxic activity relationship of 7,7'-epoxylignanes, (+)- and (-)-verrucosin: simplification on the aromatic ring substituents.

    PubMed

    Yamauchi, Satoshi; Nakayama, Kumiko; Nishiwaki, Hisashi; Shuto, Yoshihiro

    2014-10-15

    The synthesized 7-aryl derivatives of (7R,7'S,8S,8'S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (-95%) and the shoot (-60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7'R,8R,8'R)-(-)-verrucosin at 1mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (-)-verrucosin against the root (-95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (-80%) than that of (-)-verrucosin (-60%). As the next step, (7S,7'R,8R,8'R)-7-(3-hydroxyphenyl)-7'-aryl-(-)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7'-(2-hydroxyphenyl) derivative 37 and 7'-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7'-aryl structures of 7,7'-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7'-aryl structures were simplified to show comparable activity to or higher activity than that of (-)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C3b, was estimated as -80% inhibition at 1mM against ryegrass roots. PMID:25248684

  7. Synthesis and Structure-Activity Relationships of Small Molecule Inhibitors of the Simian Virus 40 T Antigen Oncoprotein, an Anti-Polyomaviral Target

    PubMed Central

    Gupta, Tushar; Seguin, Sandlin P.; Liang, Mary; Resnick, Lynn; Goldberg, Margot T.; Manos-Turvey, Alexandra; Pipas, James M.; Wipf, Peter; Brodsky, Jeffrey L.

    2014-01-01

    Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirus-associated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone-peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50?M). To improve upon this scaffold and to develop a structure-activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded analogs with modestly improved IC50s (~15 ?M), which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of ~5 ?M. We suggest that the knowledge gained from the structure-activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases. PMID:25440730

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

    PubMed

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

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

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

    PubMed Central

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

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

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

    PubMed

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

    2003-07-17

    The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure-activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the general role of lipophilicity for activity, also highlighted the relevance of the substitution pattern at the positions 2, 3, and 5, suggesting the involvement of this fragment in binding. The most powerful compound of the series, euphodendroidin D (4), outperformed cyclosporin by a factor of 2 to inhibit Pgp-mediated daunomycin transport. PMID:12852769

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

    SciTech Connect

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

    2012-04-24

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18{_}V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 {angstrom} resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3{beta} (HsGSK-3{beta}) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

  12. Structure Determination of Glycogen Synthase Kinase-3 from Leishmania major and Comparative Inhibitor Structure-Activity Relationships with Trypanosoma brucei GSK-3

    PubMed Central

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

    2011-01-01

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3? (HsGSK-3?) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found. PMID:21195115

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

    PubMed

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

    2011-04-01

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 ? resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3? (HsGSK-3?) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found. PMID:21195115

  14. Synthesis, structure-activity relationship and biological evaluation of novel nitrogen mustard sophoridinic acid derivatives as potential anticancer agents.

    PubMed

    Li, Dong-Dong; Dai, Lin-Lin; Zhang, Na; Tao, Zun-Wei

    2015-10-01

    A series of novel nitrogen mustard sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. Of the newly synthesized compounds, compound 6 exhibited a potent effect against hepatocellular carcinoma in vitro and in vivo. SAR analysis indicated that introduction of a nitrogen mustard group to the structure of sophoridinic acid significantly enhance the antitumor activity. Moreover, molecular docking study exhibited benzyl group introduced to the nitrogen atom at the 12-position and aryl nitrogen mustard group at the 4'-carboxyl region for compound 6 were beneficial for the higher anticancer activity. This work provides useful information for further structural modifications of these compounds and for the synthesis of new, potent antitumor agents. PMID:26299348

  15. Molecular dynamics investigation of psalmopeotoxin I. Probing the relationship between 3D structure, anti-malarial activity and thermal stability.

    PubMed

    Gleeson, Matthew Paul; Deechongkit, Songpon; Ruchirawat, Somsak

    2011-04-01

    PcFK1 is a member of the cysteine knot inhibitor family that displays anti-malarial properties. The naturally occurring molecule is ? 40 amino acids in length and forms a highly constrained 3D structure due to the presence of 3 disulfide and multiple intra-molecular H-bonds. Recent experimental studies on PcFK1 wild-type and mutants, where the cystiene residues of each disulfide bond were mutated into serine residues, suggest that alterations to these structural constraints can give rise to sizeable differences in SAR. To better understand the relationship between the dynamic inhibitor 3D structure, biophysical and biological properties we have performed solution based molecular dynamics calculations over 150 ns using the CHARMM forcefield. We have analyzed the theoretical trajectory in a systematic way using principal components analysis, which allows us to identify the correlated nature of the protein loop, turn and sheet movements. We have identified the key molecular motions that give rise to the differing SAR which has helped to more precisely direct our ongoing SAR studies in this important therapeutic area. PMID:20544240

  16. Interspecies quantitative structure-activity relationships (QSARs) for eco-toxicity screening of chemicals: the role of physicochemical properties.

    PubMed

    Furuhama, A; Hasunuma, K; Aoki, Y

    2015-10-01

    In addition to molecular structure profiles, descriptors based on physicochemical properties are useful for explaining the eco-toxicities of chemicals. In a previous study we reported that a criterion based on the difference between the partition coefficient (log POW) and distribution coefficient (log D) values of chemicals enabled us to identify aromatic amines and phenols for which interspecies relationships with strong correlations could be developed for fish-daphnid and algal-daphnid toxicities. The chemicals that met the log D-based criterion were expected to have similar toxicity mechanisms (related to membrane penetration). Here, we investigated the applicability of log D-based criteria to the eco-toxicity of other kinds of chemicals, including aliphatic compounds. At pH 10, use of a log POW - log D > 0 criterion and omission of outliers resulted in the selection of more than 100 chemicals whose acute fish toxicities or algal growth inhibition toxicities were almost equal to their acute daphnid toxicities. The advantage of log D-based criteria is that they allow for simple, rapid screening and prioritizing of chemicals. However, inorganic molecules and chemicals containing certain structural elements cannot be evaluated, because calculated log D values are unavailable. PMID:26540445

  17. Phenyl-imidazolo-cytidine analogues: structure-photophysical activity relationship and ability to detect single DNA mismatch.

    PubMed

    Kovaliov, Marina; Weitman, Michal; Major, Dan Thomas; Fischer, Bilha

    2014-08-01

    To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine ((Ph)ImC) analogues 5a-g and established a relationship between their structure and fluorescence properties. These analogues were more emissive than cytidine (?em 398-420 nm, ? 0.009-0.687), and excellent correlation was found between ? of 5a-g and ?p(-) of the substituent on the phenyl-imidazolo moiety (R(2) = 0.94). Calculations suggested that the dominant tautomer of (Ph)ImC in methanol solution is identical to that of cytidine. DFT calculations of the stable tautomer of selected (Ph)ImC analogues suggested a relationship between the HOMO-LUMO gap and ? and explained the loss of fluorescence in the nitro analogue. Incorporation of the CF3-(Ph)ImdC analogue into a DNA probe resulted in 6-fold fluorescence quenching of the former. A 17-fold reduction of fluorescence was observed for the G-matched duplex vs ODN(CF3-(Ph)ImdC), while for A-mismatched duplex, only a 2-fold decrease was observed. Furthermore, since the quantum yield of ODN(CF3-(Ph)ImdC):ODN(G) was reduced 17-fold vs that of a single strand, whereas that of ODN(CF3-(Ph)ImdC):ORN(G) was reduced only 3.8-fold, ODN(CF3-(Ph)ImdC) appears to be a DNA-selective probe. We conclude that the ODN(CF3-(Ph)ImdC) probe, exhibiting emission sensitivity upon single nucleotide replacement, may be potentially useful for DNA single nucleotide polymorphism (SNP) typing. PMID:24992467

  18. Quantitative Structure Inter-Activity Relationship (QSInAR). Cytotoxicity Study of Some Hemisynthetic and Isolated Natural Steroids and Precursors on Human Fibrosarcoma Cells HT1080.

    PubMed

    Putz, Mihai V; Lazea, Marius; Sandjo, Louis P

    2011-01-01

    Combined experimental and quantitative structure inter-activity relationship (QSIAR) computation methods were advanced in order to establish the structural and mechanistic influences that steroids and triterpenes, either as newly synthesized or naturally isolated products, have on human HT1080 mammalian cancer cells. The main Hansch structural indicators such as hydrophobicity (LogP), polarizability (POL) and total energy (Etot) were considered and both the structure-projected as well as globally computed correlations were reported; while the inter-activity correlation of the global activity with those projected on structural information was revealed as equal to the direct structural-activity one for the trial sets of compounds, the prediction for the testing set of molecules reported even superior performances respecting those characteristic for the calibration set, validating therefore the present QSInAR models; accordingly, it follows that the LogP carries the most part of the cytotoxic signal, while POL has little influence on inhibiting tumor growth-A complementary behavior with their earlier known influence on genotoxic carcinogenesis. Regarding the newly hemisynthetic compounds it was found that stigmasta-4,22-dien-3-one is not adapted for cell membrane diffusion; it is recommended that aminocinnamyl chlorohydrate be further modified in order to acquire better steric influence, while aminocinnamyl-2,3,4,6-O-tétraacétyl-?-D-glucopyranoside was identified as being inhibited in the tumor cell by other molecular mechanisms-here not revealed-although it has a moderate-high anti-cancer structurally predicted activity. PMID:25134765

  19. Inhibition of human Cytochrome P450 2E1 and 2A6 by aldehydes: Structure and activity relationships

    PubMed Central

    Kandagatla, Suneel K.; Mack, Todd; Simpson, Sean; Sollenberger, Jill; Helton, Eric; Raner, Gregory M.

    2014-01-01

    The purpose of this study was to probe active site structure and dynamics of human cytochrome P4502E1 and P4502A6 using a series of related short chain fatty aldehydes. Binding efficiency of the aldehydes was monitored via their ability to inhibit the binding and activation of the probe substrates p-nitrophenol (2E1) and coumarin (2A6). Oxidation of the aldehydes was observed in reactions with individually expressed 2E1, but not 2A6, suggesting alternate binding modes. For saturated aldehydes the optimum chain length for inhibition of 2E1 was 9 carbons (KI=7.8 ±0.3 ?M), whereas for 2A6 heptanal was most potent (KI=15.8 ±1.1 ?M). A double bond in the 2-position of the aldehyde significantly decreased the observed KI relative to the corresponding saturated compound in most cases. A clear difference in the effect of the double bond was observed between the two isoforms. With 2E1, the double bond appeared to remove steric constraints on aldehyde binding with KI values for the 5–12 carbon compounds ranging between 2.6 ± 0.1 ?M and 12.8± 0.5 ?M, whereas steric effects remained the dominant factor in the binding of the unsaturated aldehydes to 2A6 (observed KI values between 7.0± 0.5 ?M and >1000 ?M). The aldehyde function was essential for effective inhibition, as the corresponding carboxylic acids had very little effect on enzyme activity over the same range of concentrations, and branching at the 3-position of the aldehydes increased the corresponding KI value in all cases examined. The results suggest that a conjugated ?-system may be a key structural determinant in the binding of these compounds to both enzymes, and may also be an important feature for the expansion of the active site volume in 2E1. PMID:24924949

  20. Inhibition of human cytochrome P450 2E1 and 2A6 by aldehydes: structure and activity relationships.

    PubMed

    Kandagatla, Suneel K; Mack, Todd; Simpson, Sean; Sollenberger, Jill; Helton, Eric; Raner, Gregory M

    2014-08-01

    The purpose of this study was to probe active site structure and dynamics of human cytochrome P4502E1 and P4502A6 using a series of related short chain fatty aldehydes. Binding efficiency of the aldehydes was monitored via their ability to inhibit the binding and activation of the probe substrates p-nitrophenol (2E1) and coumarin (2A6). Oxidation of the aldehydes was observed in reactions with individually expressed 2E1, but not 2A6, suggesting alternate binding modes. For saturated aldehydes the optimum chain length for inhibition of 2E1 was 9 carbons (KI=7.8 ± 0.3 ?M), whereas for 2A6 heptanal was most potent (KI=15.8 ± 1.1 ?M). A double bond in the 2-position of the aldehyde significantly decreased the observed KI relative to the corresponding saturated compound in most cases. A clear difference in the effect of the double bond was observed between the two isoforms. With 2E1, the double bond appeared to remove steric constraints on aldehyde binding with KI values for the 5-12 carbon compounds ranging between 2.6 ± 0.1 ?M and 12.8 ± 0.5 ?M, whereas steric effects remained the dominant factor in the binding of the unsaturated aldehydes to 2A6 (observed KI values between 7.0 ± 0.5 ?M and >1000 ?M). The aldehyde function was essential for effective inhibition, as the corresponding carboxylic acids had very little effect on enzyme activity over the same range of concentrations, and branching at the 3-position of the aldehydes increased the corresponding KI value in all cases examined. The results suggest that a conjugated ?-system may be a key structural determinant in the binding of these compounds to both enzymes, and may also be an important feature for the expansion of the active site volume in 2E1. PMID:24924949

  1. Structure-antioxidant efficiency relationships of phenolic compounds and their contribution to the antioxidant activity of sea buckthorn juice.

    PubMed

    Rösch, Daniel; Bergmann, Meike; Knorr, Dietrich; Kroh, Lothar W

    2003-07-16

    The phenolic composition of juice derived from fruits of sea buckthorn (Hippophae rhamnoides) was investigated by high-performance liquid chromatography (HPLC) with diode array and electrochemical detection. Flavonols were found to be the predominating polyphenols while phenolic acids and catechins represent minor components. Of the seven flavonols identified, isorhamnetin 3-O-glycosides were the most important representatives quantitatively. However, because of their structural properties, they were poor radical scavengers as shown by electron spin resonance spectroscopy. Phenolic compounds such as quercetin 3-O-glycosides, catechins, and hydroxybenzoic acids with a catechol structure exhibited good antioxidant capacities, but their concentration in sea buckthorn juice was small. These phenolic compounds, determined by HPLC, accounted for less than 5% of the total antioxidant activity of the filtered juice. Ascorbic acid was shown to be the major antioxidant in sea buckthorn juice. Because of its high concentration of 1.22 g/L, it contributes approximately 75% to total antioxidant activity. The remaining difference can be attributed to higher molecular weight flavan-3-ols (proanthocyanidins), which were determined photometrically after acid depolymerization to colored anthocyanidins. PMID:12848490

  2. Mode of action and the assessment of chemical hazards in the presence of limited data: use of structure-activity relationships (SAR) under TSCA, Section 5.

    PubMed Central

    Auer, C M; Nabholz, J V; Baetcke, K P

    1990-01-01

    Section 5 of the Toxic Substances Control Act (TSCA) requires that manufacturers and importers of new chemicals must submit a Premanufacture Notification (PMN) to the U.S. Environmental Protection Agency 90 days before they intend to commence manufacture or import. Certain information such as chemical identity, uses, etc., must be included in the notification. The submission of test data on the new substance, however, is not required, although any available health and environmental information must be provided. Nonetheless, over half of all PMNs submitted to the agency do not contain any test data; because PMN chemicals are new, no test data is generally available in the scientific literature. Given this situation, EPA has had to develop techniques for hazard assessment that can be used in the presence of limited test data. EPA's approach has been termed "structure-activity relationships" (SAR) and involves three major components: the first is critical evaluation and interpretation of available toxicity data on the chemical; the second component involves evaluation of test data available on analogous substances and/or potential metabolites; and the third component involves the use of mathematical expressions for biological activity known as "quantitative structure-activity relationships" (QSARs). At present, the use of QSARs is limited to estimating physical chemical properties, environmental toxicity, and bioconcentration factors. An important overarching element in EPA's approach is the experience and judgment of scientific assessors in interpreting and integrating the available data and information. Examples are provided that illustrate EPA's approach to hazard assessment for PMN chemicals. PMID:2269224

  3. Developing structure-activity relationships from an HTS hit for inhibition of the Cks1-Skp2 protein-protein interaction.

    PubMed

    Singh, Rajinder; Sran, Arvinder; Carroll, David C; Huang, Jianing; Tsvetkov, Lyuben; Zhou, Xiulan; Sheung, Julie; McLaughlin, John; Issakani, Sarkiz D; Payan, Donald G; Shaw, Simon J

    2015-11-15

    Structure-activity relationships have been developed around 5-bromo-8-toluylsulfonamidoquinoline 1 a hit compound in an assay for the interaction of the E3 ligase Skp2 with Cks1, part of the SCF ligase complex. Disruption of this protein-protein interaction results in higher levels of CDK inhibitor p27, which can act as a tumor suppressor. The results of the SAR developed highlight the relationship between the sulfonamide and quinoline nitrogen, while also suggesting that an aryl substituent at the 5-position of the quinoline ring contributes to the potency in the interaction assay. Compounds showing potency in the interaction assay result in greater levels of p27 and have been shown to inhibit cell growth of two p27 sensitive tumor cell lines. PMID:26463131

  4. Structure–Activity Relationship of Adenosine 5?-diphosphoribose at the Transient Receptor Potential Melastatin 2 (TRPM2) Channel: Rational Design of Antagonists

    PubMed Central

    2013-01-01

    Adenosine 5?-diphosphoribose (ADPR) activates TRPM2, a Ca2+, Na+, and K+ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure–activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2?-deoxy-ADPR (86, IC50 = 3 ?M), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca2+ signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2. PMID:24304219

  5. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study.

    PubMed

    Pérez, Sheila; Vale, Carmen; Alonso, Eva; Fuwa, Haruhiko; Sasaki, Makoto; Konno, Yu; Goto, Tomomi; Suga, Yuto; Vieytes, Mercedes R; Botana, Luis M

    2012-09-17

    The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 ?g/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases. PMID:22894724

  6. Structure-Activity Relationship of Au/ZrO2 Catalyst on Formation of Hydroxyl Groups and Its Influence on CO Oxidation

    SciTech Connect

    Karwacki, Christopher J; Ganesh, Panchapakesan; Gordon, Wesley O; Peterson, Gregory W; Niu, Jun Jie; Gogotsi, Yury G.

    2013-01-01

    The effect of changes in morphology and surface hydroxyl species upon thermal treatment of zirconia on the oxidation activity of Au/ZrO2 catalyst was studied. We observed using transmission fourier transform infrared (FTIR) spectroscopy progressive changes in the presence of monodentate (type I), bidentate (type II) and hydrogen bridged species (type III) for each of the thermally treated (85 to 500 C) supports consisting of bare zirconia and Au/ZrO2 catalysts. Furthermore, structural changes in zirconia were accompanied by an increase in crystal size (7 to 58 nm) and contraction of the supports porosity (SSA 532 to 7 m2/g) with increasing thermal treatment. Deposition of gold nanoparticles under similar preparation conditions on different thermally treated zirconia resulted in changes in the mean gold cluster size, ranging from 3.7 to 5.6 nm. Changes in the surface hydroxyl species, support structure and size of the gold centers are important parameters responsible for the observed decrease (> 90 %) in CO conversion activity for the Au/ZrO2 catalysts. Density functional theory calculations provide evidence of increased CO binding to Au nanoclusters in the presence of surface hydroxyls on zirconia, which increases charge transfer at the perimeter of the gold nanocluster on zirconia support. This further helps in reducing a model CO-oxidation reaction barrier in the presence of surface hydroxyls. This work demonstrates the need to understand the structure-activity relationship of both the support and active particles for the design of catalytic materials.

  7. Structure-activity relationship of Au-ZrO2 catalyst on formation of hydroxyl groups and its influence on CO oxidation

    SciTech Connect

    Karwacki, Christopher J; Ganesh, Panchapakesan; Kent, P. R. C.; Gordon, Wesley O; Peterson, Gregory W; Niu, Jun Jie; Gogotsi, Yury G.

    2013-01-01

    The effect of changes in morphology and surface hydroxyl species upon thermal treatment of zirconia on the oxidation activity of Au/ZrO2 catalyst was studied. We observed using transmission Fourier transform infrared (FTIR) spectroscopy progressive changes in the presence of monodentate (type I), bidentate (type II) and hydrogen bridged species (type III) for each of the thermally treated (85 to 500 C) supports consisting of bare zirconia and Au/ZrO2 catalysts. Furthermore, structural changes in zirconia were accompanied by an increase in crystal size (7 to 58 nm) and contraction of the supports porosity (SSA 532 to 7 m2 g 1) with increasing thermal treatment. Deposition of gold nanoparticles under similar preparation conditions on different thermally treated zirconia resulted in changes in the mean gold cluster size, ranging from 3.7 to 5.6 nm. Changes in the surface hydroxyl species, support structure and size of the gold centers are important parameters responsible for the observed decrease (>90%) in CO conversion activity for the Au/ZrO2 catalysts. Density functional theory calculations provide evidence of increased CO binding to Au nanoclusters in the presence of surface hydroxyls on zirconia, which increases charge transfer at the perimeter of the gold nanocluster on zirconia support. This further helps in reducing a model CO-oxidation reaction barrier in the presence of surface hydroxyls. This work demonstrates the need to understand the structure activity relationship of both the support and active particles for the design of catalytic materials.

  8. Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi.

    PubMed

    Keenan, Martine; Alexander, Paul W; Diao, Hugo; Best, Wayne M; Khong, Andrea; Kerfoot, Maria; Thompson, R C Andrew; White, Karen L; Shackleford, David M; Ryan, Eileen; Gregg, Alison D; Charman, Susan A; von Geldern, Thomas W; Scandale, Ivan; Chatelain, Eric

    2013-04-01

    A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days. PMID:23462713

  9. Structure-Activity Relationships of Bifunctional Cyclic Disulfide Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

    PubMed Central

    Agnes, Richard S.; Ying, Jinfa; Kövér, Katalin E.; Lee, Yeon Sun; Davis, Peg; Ma, Shou-wu; Badghisi, Hamid; Porreca, Frank; Lai, Josephine; Hruby, Victor J.

    2008-01-01

    Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[D-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at ? and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands. PMID:18502541

  10. Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials.

    PubMed

    Lai, David Y

    2015-11-01

    With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials. PMID:26111809

  11. Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties

    PubMed Central

    Xiao, Min; Wang, Jin; Lin, Zongtao; Lu, Yan; Li, Zhenmei; White, Stephen W.; Miller, Duane D.; Li, Wei

    2015-01-01

    The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 ?M for UC-112 vs. 0.5 ?M for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents. PMID:26070194

  12. Synthesis and structure-activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists.

    PubMed

    Negoro, Kenji; Yonetoku, Yasuhiro; Moritomo, Ayako; Hayakawa, Masahiko; Iikubo, Kazuhiko; Yoshida, Shigeru; Takeuchi, Makoto; Ohta, Mitsuaki

    2012-11-01

    A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus. PMID:23010456

  13. Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

    PubMed Central

    2015-01-01

    Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing “heuristics” to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity. PMID:25192394

  14. Structure-activity relationship study of anticancer thymidine-quinoxaline conjugates under the low radiance of long wavelength ultraviolet light for photodynamic therapy.

    PubMed

    Zhang, Dejun; Liu, Huaming; Wei, Qiong; Zhou, Qibing

    2016-01-01

    Thymidine quinoxaline conjugate (dT-QX) is a thymidine analog with selective cytotoxicity against different cancer cells. In this study, the structure activity relationship study of dT-QX analogs was carried out under the low radiance of black fluorescent (UVA-1) light. Significantly enhanced cytotoxicity was observed under UVA-1 activation among analogs containing both thymidine and quinoxaline moieties with different length of the linker, stereochemical configuration and halogenated substituents. Among these analogs, the thymidine dichloroquinoxaline conjugate exhibited potent activity under UVA-1 activation as the best candidate with EC50 at 0.67 ?M and 1.3 ?M against liver and pancreatic cancer cells, respectively. In contrast, the replacement of thymidine moiety with a galactosyl residue or the replacement of quinoxaline moiety with a fluorescent pyrenyl residue or a simplified diketone structure resulted in the full loss of activity. Furthermore, it was revealed that the low radiance of UVA-1 at 3 mW/cm(2) for 20 min was sufficient enough to induce the full cytotoxicity of thymidine dichloroquinoxaline conjugate and that the cytotoxic mechanism was achieved through a rapid and steady production of reactive oxygen species. PMID:26584085

  15. Peroxidase activity-structure relationship of the intermolecular four-stranded G-quadruplex-hemin complexes and their application in Hg2+ ion detection.

    PubMed

    Kong, De-Ming; Wu, Jing; Wang, Na; Yang, Wei; Shen, Han-Xi

    2009-12-15

    The peroxidase activities of the complexes of hemin and intermolecular four-stranded G-quadruplexes formed by short-stranded X(n)G(m)X(p) sequences (X=A, T or C), especially T(n)G(m)T(p) sequences, were compared. The results, combining with those of circular dichroism (CD) spectra and acid-base transition study for DNA-hemin complexes, provide some important information about DNAzymes based on G-quadruplex-hemin complexes, such as the formation of a G-quadruplex structure is an important factor for determining whether a DNA sequence can enhance the catalytic activity of hemin; both intramolecular parallel G-quadruplexes and intermolecular four-stranded parallel G-quadruplexes can enhance the catalytic activity of hemin; the addition of T nucleotides to the 5'-end of a G-tract confers corresponding G-quadruplex greatly enhanced catalytic activity, whereas the addition of T nucleotides to the 3'-end of the G-tract has little effect; the high catalytic activity of hemin in the presence of some short-stranded G-rich sequences may be a result of the reduction of the acidity of the bound hemin cofactor. These studies provide more information for the DNA-hemin peroxidase model system, may help to elucidate the structure-function relationship of peroxidase enzymes and to develop novel, highly efficient peroxidase-liking DNAzymes. As a sequence of such an investigation, a new Hg(2+) detection method was developed. PMID:19836504

  16. Quantitative Structure-Activity Relationship Analysis of the Effect of Metoclopramide and Related Compounds on the Surface Ionization of Fumed Silica.

    PubMed

    Buyuktimkin, Tuba; Wurster, Dale Eric

    2015-08-01

    Potentiometric titration curves were generated for fumed silica with various concentrations of dissolved metoclopramide. The effects of various benzamide analogs of metoclopramide, which are positively charged in the titration medium and differ solely by their aromatic substituents, as well as lidocaine, which is also structurally analogous but is mainly in the unionized form, were also studied. At sufficiently high pH, pH 7.0 and above, the silica surface charge was independent of the metoclopramide concentration. A reasonable linear relationship with a positive slope was found between the logarithmic octanol-water partition coefficient (log P) values of the compounds and the negative surface charge determined at pH 7.0 and 7.2. These results can be attributed to specific adsorbate-surface interactions rather than concentration effects. The carbonyl oxygens of the benzamide structures most likely form hydrogen bonds with the neutral silanols. The use of positively charged triethylamine and ephedrine resulted in surface charge values that were the least negative in the aforementioned quantitative structure-activity relationship analyses. These results are consistent with ionic interactions between the positively charged aliphatic amine groups and the negatively charged surface silanols occurring simultaneously with the nonionic interactions. PMID:26097011

  17. Using quantitative structure activity relationship models to predict an appropriate solvent system from a common solvent system family for countercurrent chromatography separation.

    PubMed

    Marsden-Jones, Siân; Colclough, Nicola; Garrard, Ian; Sumner, Neil; Ignatova, Svetlana

    2015-06-12

    Countercurrent chromatography (CCC) is a form of liquid-liquid chromatography. It works by running one immiscible solvent (mobile phase) over another solvent (stationary phase) being held in a CCC column using centrifugal force. The concentration of compound in each phase is characterised by the partition coefficient (Kd), which is the concentration in the stationary phase divided by the concentration in the mobile phase. When Kd is between approximately 0.2 and 2, it is most likely that optimal separation will be achieved. Having the Kd in this range allows the compound enough time in the column to be separated without resulting in a broad peak and long run time. In this paper we report the development of quantitative structure activity relationship (QSAR) models to predict logKd. The QSAR models use only the molecule's 2D structure to predict the molecular property logKd. PMID:25931379

  18. Benzaldehyde Schiff bases regulation to the metabolism, hemolysis, and virulence genes expression in vitro and their structure-microbicidal activity relationship.

    PubMed

    Xia, Lei; Xia, Yu-Fen; Huang, Li-Rong; Xiao, Xiao; Lou, Hua-Yong; Liu, Tang-Jingjun; Pan, Wei-Dong; Luo, Heng

    2015-06-01

    There is an urgent need to develop new antibacterial agents because of multidrug resistance by bacteria and fungi. Schiff bases (aldehyde or ketone-like compounds) exhibit intense antibacterial characteristics, and are therefore, promising candidates as antibacterial agents. To investigate the mechanism of action of newly designed benzaldehyde Schiff bases, a series of high-yielding benzaldehyde Schiff bases were synthesized, and their structures were determined by NMR and MS spectra data. The structure-microbicidal activity relationship of derivatives was investigated, and the antibacterial mechanisms were investigated by gene assays for the expression of functional genes in vitro using Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The active compounds were selective for certain active groups. The polar substitution of the R2 group of the amino acids in the Schiff bases, affected the antibacterial activity against E. coli and S. aureus; specific active group at the R3 or R4 groups of the acylhydrazone Schiff bases could improve their inhibitory activity against these three tested organisms. The antibacterial mechanism of the active benzaldehyde Schiff bases appeared to regulate the expression of metabolism-associated genes in E. coli, hemolysis-associated genes in B. subtilis, and key virulence genes in S. aureus. Some benzaldehyde Schiff bases were bactericidal to all the three strains and appeared to regulate gene expression associated with metabolism, hemolysis, and virulence, in vitro. The newly designed benzaldehyde Schiff bases possessed unique antibacterial activity and might be potentially useful for prophylactic or therapeutic intervention of bacterial infections. PMID:25982329

  19. Large-scale structure-activity relationship study of hepatitis C virus NS5B polymerase inhibition using SMILES-based descriptors.

    PubMed

    Worachartcheewan, Apilak; Prachayasittikul, Virapong; Toropova, Alla P; Toropov, Andrey A; Nantasenamat, Chanin

    2015-11-01

    Hepatitis C virus (HCV) is composed of structural and non-structural proteins involved in viral transcription and propagation. In particular, NS5B is an RNA-dependent RNA polymerase for viral transcription and genome replication and is a target for designing anti-viral agents. In this study, classification and quantitative structure-activity relationship (QSAR) models of HCV NS5B inhibitors were constructed using the Correlation and Logic software. Molecular descriptors for a set of 970 HCV NS5B inhibitors were encoded using the simplified molecular input line entry system notation, and predictive models were built via the Monte Carlo method. The QSAR models provided acceptable correlation coefficients of [Formula: see text] and [Formula: see text] in the ranges of 0.6038-0.7344 and 0.6171-0.7294, respectively, while the classification models displayed sensitivity, specificity, and accuracy in ranges of 88.24-98.84, 83.87-93.94, and 86.50-94.41 %, respectively. Furthermore, molecular fragments as substructures involved in increased and decreased inhibitory activities were explored. The results provide information on QSAR and classification models for high-throughput screening and mechanistic insights into the inhibitory activity of HCV NS5B polymerase. PMID:26164590

  20. Dietary protection against free radicals: a case for multiple testing to establish structure-activity relationships for antioxidant potential of anthocyanic plant species.

    PubMed

    Philpott, Martin; Lim, Chiara Cheng; Ferguson, Lynnette R

    2009-03-01

    DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0 degrees C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37 degrees C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays. PMID:19399239

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

    PubMed Central

    Philpott, Martin; Lim, Chiara Cheng; Ferguson, Lynnette R.

    2009-01-01

    DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0°C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37°C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays. PMID:19399239

  2. Loratadine and analogues: discovery and preliminary structure-activity relationship of inhibitors of the amino acid transporter B(0)AT2.

    PubMed

    Cuboni, Serena; Devigny, Christian; Hoogeland, Bastiaan; Strasser, Andrea; Pomplun, Sebastian; Hauger, Barbara; Höfner, Georg; Wanner, Klaus T; Eder, Matthias; Buschauer, Armin; Holsboer, Florian; Hausch, Felix

    2014-11-26

    B(0)AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain, but little is otherwise known about its function. To identify inhibitors for this transporter, we screened a library of 3133 different bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B(0)AT2 with an IC50 of 4 ?M while being less active or inactive against several other members of the SLC6 family. Reversible inhibition of B(0)AT2 was confirmed by electrophysiology. A series of loratadine analogues were synthesized to gain insight into the structure-activity relationships. Our studies provide the first chemical tool for B(0)AT2. PMID:25318072

  3. Evaluation of Phytocannabinoids from High Potency Cannabis sativa using In Vitro Bioassays to Determine Structure-Activity Relationships for Cannabinoid Receptor 1 and Cannabinoid Receptor 2.

    PubMed

    Husni, Afeef S; McCurdy, Christopher R; Radwan, Mohamed M; Ahmed, Safwat A; Slade, Desmond; Ross, Samir A; ElSohly, Mahmoud A; Cutler, Stephen J

    2014-09-01

    Cannabis has been around for thousands of years and has been used recreationally, medicinally, and for fiber. Over 500 compounds have been isolated from Cannabis sativa with approximately 105 being cannabinoids. Of those 105 compounds, ?(9)-tetrahydrocannabinol has been determined as the primary constituent, which is also responsible for the psychoactivity associated with Cannabis. Cannabinoid receptors belong to the large superfamily of G protein-coupled receptors. Targeting the cannabinoid receptors has the potential to treat a variety of conditions such as pain, neurodegeneration, appetite, immune function, anxiety, cancer, and others. Developing in vitro bioassays to determine binding and functional activity of compounds has the ability to lead researchers to develop a safe and effective drug that may target the cannabinoid receptors. Using radioligand binding and functional bioassays, a structure-activity relationship for major and minor cannabinoids was developed. PMID:25419092

  4. Synthesis and Structure-Activity Relationships of 5,6,7-substituted Pyrazolopyrimidines: Discovery of a novel TSPO PET Ligand for Cancer Imaging

    PubMed Central

    Tang, Dewei; McKinley, Eliot T.; Hight, Matthew R.; Uddin, Md. Imam; Harp, Joel M.; Fu, Allie; Nickels, Michael L.; Buck, Jason R.; Manning, H. Charles

    2013-01-01

    Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (18F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18F-6b) in high radiochemical yield and specific activity. In vivo studies of 18F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers. PMID:23521048

  5. Evaluation of Phytocannabinoids from High Potency Cannabis sativa using In Vitro Bioassays to Determine Structure-Activity Relationships for Cannabinoid Receptor 1 and Cannabinoid Receptor 2

    PubMed Central

    Husni, Afeef S.; McCurdy, Christopher R.; Radwan, Mohamed M.; Ahmed, Safwat A.; Slade, Desmond; Ross, Samir A.; ElSohly, Mahmoud A.; Cutler, Stephen J.

    2014-01-01

    Cannabis has been around for thousands of years and has been used recreationally, medicinally, and for fiber. Over 500 compounds have been isolated from Cannabis sativa with approximately 105 being cannabinoids. Of those 105 compounds, ?9-tetrahydrocannabinol has been determined as the primary constituent, which is also responsible for the psychoactivity associated with Cannabis. Cannabinoid receptors belong to the large superfamily of G protein-coupled receptors. Targeting the cannabinoid receptors has the potential to treat a variety of conditions such as pain, neurodegeneration, appetite, immune function, anxiety, cancer, and others. Developing in vitro bioassays to determine binding and functional activity of compounds has the ability to lead researchers to develop a safe and effective drug that may target the cannabinoid receptors. Using radioligand binding and functional bioassays, a structure-activity relationship for major and minor cannabinoids was developed. PMID:25419092

  6. Structure-activity relationship refinement and further assessment of 4-phenylquinazoline-2-carboxamide translocator protein ligands as antiproliferative agents in human glioblastoma tumors.

    PubMed

    Castellano, Sabrina; Taliani, Sabrina; Viviano, Monica; Milite, Ciro; Da Pozzo, Eleonora; Costa, Barbara; Barresi, Elisabetta; Bruno, Agostino; Cosconati, Sandro; Marinelli, Luciana; Greco, Giovanni; Novellino, Ettore; Sbardella, Gianluca; Da Settimo, Federico; Martini, Claudia

    2014-03-27

    Structure-activity relationships (SARs) within the 4-phenylquinazoline-2-carboxamide series of translocator protein (TSPO) ligands have been explored further by the synthesis and TSPO binding affinity evaluation of N-benzyl-N-ethyl/methyl derivatives variously decorated at the 6-, 2'-, 4'-, and 4?-positions. Most of the compounds showed high affinity with K(i) values in the nanomolar/subnanomolar range. A pharmacophore model was developed and employed to better address SAR data presented by the new TSPO ligands. A subset of the new compounds (5, 8, 12, and 19) were tested for their ability to inhibit the viability of human glioblastoma cell line U343. The observed antiproliferative effect was demonstrated to be specific for compound 19, endowed with the best combination of binding affinity and efficacy. Furthermore, the ability of 19 to induce mitochondrial membrane dissipation (??(m)) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO. PMID:24580635

  7. Navigating structure-activity landscapes.

    PubMed

    Bajorath, Jürgen; Peltason, Lisa; Wawer, Mathias; Guha, Rajarshi; Lajiness, Michael S; Van Drie, John H

    2009-07-01

    The problem of how to explore structure-activity relationships (SARs) systematically is still largely unsolved in medicinal chemistry. Recently, data analysis tools have been introduced to navigate activity landscapes and to assess SARs on a large scale. Initial investigations reveal a surprising heterogeneity among SARs and shed light on the relationship between 'global' and 'local' SAR features. Moreover, insights are provided into the fundamental issue of why modeling tools work well in some cases, but not in others. PMID:19410012

  8. Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure–Activity Relationships of the Nucleobase Domain of 5?-O-[N-(Salicyl)sulfamoyl]adenosine

    PubMed Central

    Neres, João; Labello, Nicholas P.; Somu, Ravindranadh V.; Boshoff, Helena I.; Wilson, Daniel J.; Vannada, Jagadeshwar; Chen, Liqiang; Barry, Clifton E.; Bennett, Eric M.; Aldrich, Courtney C.

    2009-01-01

    5?-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure–activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 µM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence. PMID:18690677

  9. Structure-Activity Relationship of Cinnamaldehyde Analogs as Inhibitors of AI-2 Based Quorum Sensing and Their Effect on Virulence of Vibrio spp

    PubMed Central

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

    2011-01-01

    Background Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. Methodology/Principal Findings By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an ?,? unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. Conclusions/Significance Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands. PMID:21249192

  10. Synthesis and Structure–Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

    PubMed Central

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

    2010-01-01

    The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-?, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a a series of ?-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo. PMID:20604568

  11. Structure-activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X7 receptor antagonists.

    PubMed

    Park, Jin-Hee; Lee, Ga-Eun; Lee, So-Deok; Ko, Hyojin; Kim, Yong-Chul

    2015-12-01

    As an optimization strategy, the flexible structure of KN-62, a known P2X7 receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X7 receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X7 receptor (EtBr uptake assay) and in THP-1 cells (IL-1? ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18m and adamantyl carbonyl derivatives 19g-19i and 19k showed potent antagonistic effects, with IC50 values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X7 receptor antagonists for the development of anti-inflammatory drugs. PMID:26547056

  12. Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure-activity relationship study.

    PubMed

    Ho, Si-Han Sherman; Sim, Mei-Yi; Yee, Wei-Loong Sherman; Yang, Tianming; Yuen, Shyi-Peng John; Go, Mei-Lin

    2015-11-01

    The anticancer agent YM155 is widely investigated as a specific survivin suppressant. More recently, YM155 was found to induce DNA damage and this has raised doubts as to whether survivin is its primary target. In an effort to assess the contribution of DNA damage to the anticancer activity of YM155, several analogs were prepared and evaluated for antiproliferative activity on malignant cells, participation in DNA intercalation and free radical generation by redox cycling. The intact positively charged scaffold was found to be essential for antiproliferative activity and intercalation but was less critical for redox cycling where the minimal requirement was a pared down bicyclic quinone. Side chain requirements at the N(1) and N(3) positions of the scaffold were more alike for redox cycling and intercalation than antiproliferative activity, underscoring yet again, the limited structural overlaps for these activities. Furthermore, antiproliferative activities were poorly correlated to DNA intercalation and redox cycling. Potent antiproliferative activity (IC50 9-23 nM), exceeding that of YM155, was found for a minimally substituted methyl analog AB7. Like YM155 and other dioxonaphthoimidazoliums, AB7 was a modest DNA intercalator but with weak redox cycling activity. Thus, the capacity of this scaffold to inflict direct DNA damage leading to cell death may not be significant and YM155 should not be routinely classified as a DNA damaging agent. PMID:26433618

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

    PubMed

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

    2013-06-19

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

  14. Species-Specific Differences and Structure-Activity Relationships in the Debromination of PBDE Congeners in Three Fish Species

    PubMed Central

    Roberts, Simon C.; Noyes, Pamela D.; Gallagher, Evan P.

    2011-01-01

    Previous studies have suggested that there may be species-specific differences in the metabolism of polybrominated diphenyl ethers (PBDEs) among different fish species. In this study, we investigated the in vitro hepatic metabolism of eleven individual PBDE congeners (tri- through decaBDEs) in three different fish species: rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and Chinook salmon (O. tschwatcha). In addition, we evaluated the influence of PBDE structural characteristics (i.e., bromine substitution patterns) on metabolism. Six of the eleven congeners we evaluated, BDEs 99, 153, 183, 203, 208, and 209, were metabolically debrominated to lower brominated congeners. All of the congeners that were metabolized contained at least one meta-substituted bromine. Metabolites were not detected for congeners without one meta-substituted bromine (e.g., BDEs 28, 47, and 100). Metabolite formation rates were generally 10–100 times faster in carp than in trout and salmon. BDEs 47, 49, 101, 154, and 183 were the major metabolites observed in all three species with the exception of BDE 47, which was only detected in carp. Carp demonstrated a preference towards meta-debromination, while trout and salmon debrominated meta- and para- bromine atoms to an equal extent. We compared glutathione-S-transferase (GST) and deiodinase (DI) activity among all three species as these enzyme systems have been hypothesized to play a role in PBDE debromination among teleosts. Carp exhibited a preference for meta-deiodination of the thyroid hormone thyroxine, which was consistent with the preference for meta-debromination of PBDEs observed in carp. PMID:21291240

  15. 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: structure activity relationships of the 2-oxy pyridine C-region.

    PubMed

    Thorat, Shivaji A; Kang, Dong Wook; Ryu, HyungChul; Kim, Myeong Seop; Kim, Ho Shin; Ann, Jihyae; Ha, Taehwan; Kim, Sung-Eun; Son, Karam; Choi, Sun; Blumberg, Peter M; Frank, Robert; Bahrenberg, Gregor; Schiene, Klaus; Christoph, Thomas; Lee, Jeewoo

    2013-06-01

    The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively. PMID:23685943

  16. Synthesis and structure-activity relationship (SAR) of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters, a class of potent N-acylethanolamine acid amidase (NAAA) inhibitors.

    PubMed

    Ponzano, Stefano; Bertozzi, Fabio; Mengatto, Luisa; Dionisi, Mauro; Armirotti, Andrea; Romeo, Elisa; Berteotti, Anna; Fiorelli, Claudio; Tarozzo, Glauco; Reggiani, Angelo; Duranti, Andrea; Tarzia, Giorgio; Mor, Marco; Cavalli, Andrea; Piomelli, Daniele; Bandiera, Tiziano

    2013-09-12

    N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-?, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The ?-lactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure-activity relationship (SAR) of threonine-derived ?-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of ?-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC50 = 7 nM on both rat NAAA and human NAAA). PMID:23991897

  17. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines.

    PubMed

    Le Manach, Claire; Paquet, Tanya; Brunschwig, Christel; Njoroge, Mathew; Han, Ze; Gonzàlez Cabrera, Diego; Bashyam, Sridevi; Dhinakaran, Rajkumar; Taylor, Dale; Reader, Janette; Botha, Mariette; Churchyard, Alisje; Lauterbach, Sonja; Coetzer, Theresa L; Birkholtz, Lyn-Marie; Meister, Stephan; Winzeler, Elizabeth A; Waterson, David; Witty, Michael J; Wittlin, Sergio; Jiménez-Díaz, María-Belén; Santos Martínez, María; Ferrer, Santiago; Angulo-Barturen, Iñigo; Street, Leslie J; Chibale, Kelly

    2015-11-12

    Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest. PMID:26502160

  18. Peptide Dendrimer/Lipid Hybrid Systems Are Efficient DNA Transfection Reagents: Structure–Activity Relationships Highlight the Role of Charge Distribution Across Dendrimer Generations

    PubMed Central

    2013-01-01

    Efficient DNA delivery into cells is the prerequisite of the genetic manipulation of organisms in molecular and cellular biology as well as, ultimately, in nonviral gene therapy. Current reagents, however, are relatively inefficient, and structure–activity relationships to guide their improvement are hard to come by. We now explore peptide dendrimers as a new type of transfection reagent and provide a quantitative framework for their evaluation. A collection of dendrimers with cationic and hydrophobic amino acid motifs (such as KK, KA, KH, KL, and LL) distributed across three dendrimer generations was synthesized by a solid-phase protocol that provides ready access to dendrimers in milligram quantities. In conjunction with a lipid component (DOTMA/DOPE), the best reagent, G1,2,3-KL ((LysLeu)8(LysLysLeu)4(LysLysLeu)2LysGlySerCys-NH2), improves transfection by 6–10-fold over commercial reagents under their respective optimal conditions. Emerging structure–activity relationships show that dendrimers with cationic and hydrophobic residues distributed in each generation are transfecting most efficiently. The trigenerational dendritic structure has an advantage over a linear analogue worth up to an order of magnitude. The success of placing the decisive cationic charge patterns in inner shells rather than previously on the surface of macromolecules suggests that this class of dendrimers significantly differs from existing transfection reagents. In the future, this platform may be tuned further and coupled to cell-targeting moieties to enhance transfection and cell specificity. PMID:23682947

  19. Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: Pharmacophore modeling and structure-activity relationship studies

    PubMed Central

    Yi, Bitna; Long, Sihui; González-Cestari, Tatiana F.; Henderson, Brandon J.; Pavlovicz, Ryan E.; Werbovetz, Karl; Li, Chenglong; McKay, Dennis B.

    2015-01-01

    The present study describes our ongoing efforts toward the discovery of drugs that selectively target nAChR subtypes. We exploited knowledge on nAChR ligands and their binding site that were previously identified by our laboratory through virtual screenings and identified benzamide analogs as a novel chemical class of neuronal nicotinic receptor (nAChR) ligands. The lead molecule, compound 1 (4-(allyloxy)-N-(6-methylpyridin-2-yl)benzamide) inhibits nAChR activity with an IC50 value of 6.0 (3.4–10.6) µM on human ?4?2 nAChRs with a ~5-fold preference against human ?3?4 nAChRs. Twenty-six analogs of compound 1 were also either synthesized or purchased for structure-activity relationship (SAR) studies and provided information relating the chemical/structural properties of the molecules to their ability to inhibit nAChR activity. The discovery of subtype-selective ligands of nAChRs described here should contribute significantly to our understanding of the involvement of specific nAChR subtypes in normal and pathophysiological states. PMID:23757208

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

    PubMed

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

    2013-12-23

    There are thousands of environmental chemicals subject to regulatory decisions for endocrine disrupting potential. The ToxCast and Tox21 programs have tested ?8200 chemicals in a broad screening panel of in vitro high-throughput screening (HTS) assays for estrogen receptor (ER) agonist and antagonist activity. The present work uses this large data set to develop in silico quantitative structure-activity relationship (QSAR) models using machine learning (ML) methods and a novel approach to manage the imbalanced data distribution. Training compounds from the ToxCast project were categorized as active or inactive (binding or nonbinding) classes based on a composite ER Interaction Score derived from a collection of 13 ER in vitro assays. A total of 1537 chemicals from ToxCast were used to derive and optimize the binary classification models while 5073 additional chemicals from the Tox21 project, evaluated in 2 of the 13 in vitro assays, were used to externally validate the model performance. In order to handle the imbalanced distribution of active and inactive chemicals, we developed a cluster-selection strategy to minimize information loss and increase predictive performance and compared this strategy to three currently popular techniques: cost-sensitive learning, oversampling of the minority class, and undersampling of the majority class. QSAR classification models were built to relate the molecular structures of chemicals to their ER activities using linear discriminant analysis (LDA), classification and regression trees (CART), and support vector machines (SVM) with 51 molecular descriptors from QikProp and 4328 bits of structural fingerprints as explanatory variables. A random forest (RF) feature selection method was employed to extract the structural features most relevant to the ER activity. The best model was obtained using SVM in combination with a subset of descriptors identified from a large set via the RF algorithm, which recognized the active and inactive compounds at the accuracies of 76.1% and 82.8% with a total accuracy of 81.6% on the internal test set and 70.8% on the external test set. These results demonstrate that a combination of high-quality experimental data and ML methods can lead to robust models that achieve excellent predictive accuracy, which are potentially useful for facilitating the virtual screening of chemicals for environmental risk assessment. PMID:24279462

  1. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.

    PubMed

    Mohedas, Agustin H; Wang, You; Sanvitale, Caroline E; Canning, Peter; Choi, Sungwoon; Xing, Xuechao; Bullock, Alex N; Cuny, Gregory D; Yu, Paul B

    2014-10-01

    There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-? type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-? inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG. PMID:25101911

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

    PubMed

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

    2015-11-01

    Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor activity via an episulfonium ion-mediated DNA alkylation upon reductive activation in the presence of cellular thiols. We recently isolated leinamycin E1 (LNM E1, 2) from an engineered strain S. atroolivaceus SB3033, which lacks the 1,3-dioxo-1,2-dithiolane moiety. Here we report the chemical synthesis of 8,4'-dideshydroxy-LNM (5) from 2 and determination of the cytotoxicity of 5 against selected cancer cell lines in comparison with 1; 5 exhibits comparable activity as 1 with the EC50 values between 8.21 and 275nM. This work reveals new insight into the structure-activity relationship of LNM and highlights the synergy between metabolic pathway engineering and medicinal chemistry for natural product drug discovery. PMID:26071634

  3. Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants

    PubMed Central

    2015-01-01

    There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-? type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-? inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG. PMID:25101911

  4. Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents.

    PubMed

    Chen, Hao; Ma, Yun-Bao; Huang, Xiao-Yan; Geng, Chang-An; Zhao, Yong; Wang, Li-Jun; Guo, Rui-Hua; Liang, Wen-Juan; Zhang, Xue-Mei; Chen, Ji-Jun

    2014-05-15

    Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07?M and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal logP value of 1.78 and logD values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs. PMID:24731274

  5. Synthesis, Biological Evaluation and Structure-Activity Relationships of N-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania

    PubMed Central

    Stec, Jozef; Huang, Qingqing; Pieroni, Marco; Kaiser, Marcel; Fomovska, Alina; Mui, Ernest; Witola, William H.; Bettis, Samuel; McLeod, Rima; Brun, Reto; Kozikowski, Alan P.

    2012-01-01

    In our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against T. gondii tachyzoites with activity discovered for N-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against T. gondii as described elsewhere.1 Synthesis of a compound set was guided by T. gondii SAR with 1r found to be superior for T. gondii, also active against Thai and Sierra Leone strains of P. falciparum, and with superior ADMET properties as described elsewhere.1 Herein, synthesis methods and details of the chemical analysis of the compounds in this series are described. Further, this series of N-benzoyl-2-hydroxybenzamides was re-purposed for testing against four other protozoan parasites: T. b. rhodesiense, T. cruzi, L. donovani, and P. falciparum (K1 isolate). Structure-activity analyses led to the identification of compounds in this set with excellent anti-leishmanial activity (compound 1d). Overall, compound 1r was the best and had activity 21-fold superior to that of the standard anti-malarial drug chloroquine against the K1 P. falciparum isolate. PMID:22352841

  6. Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors.

    PubMed

    Moreno-Sanz, Guillermo; Duranti, Andrea; Melzig, Laurin; Fiorelli, Claudio; Ruda, Gian Filippo; Colombano, Giampiero; Mestichelli, Paola; Sanchini, Silvano; Tontini, Andrea; Mor, Marco; Bandiera, Tiziano; Scarpelli, Rita; Tarzia, Giorgio; Piomelli, Daniele

    2013-07-25

    The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3'-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date. PMID:23822179

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

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

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

  8. Structural analysis of Canavalia maritima and Canavalia gladiata lectins complexed with different dimannosides: new insights into the understanding of the structure-biological activity relationship in legume lectins.

    PubMed

    Bezerra, Gustavo Arruda; Oliveira, Taianá Maia; Moreno, Frederico Bruno Mendes Batista; de Souza, Emmanuel Prata; da Rocha, Bruno Anderson Matias; Benevides, Raquel Guimarães; Delatorre, Plínio; de Azevedo, Walter Filgueira; Cavada, Benildo Sousa

    2007-11-01

    Plant lectins, especially those purified from species of the Leguminosae family, represent the best studied group of carbohydrate-binding proteins. The legume lectins from Diocleinae subtribe are highly similar proteins that present significant differences in the potency/efficacy of their biological activities. The structural studies of the interactions between lectins and sugars may clarify the origin of the distinct biological activities observed in this high similar class of proteins. In this way, this work presents a crystallographic study of the ConM and CGL (agglutinins from Canavalia maritima and Canavalia gladiata, respectively) in the following complexes: ConM/CGL:Man(alpha1-2)Man(alpha1-O)Me, ConM/CGL:Man(alpha1-3)Man(alpha1-O)Me and ConM/CGL:Man(alpha1-4)Man(alpha1-O)Me, which crystallized in different conditions and space group from the native proteins. The structures were solved by molecular replacement, presenting satisfactory values for R(factor) and R(free). Comparisons between ConM, CGL and ConA (Canavalia ensiformis lectin) binding mode with the dimannosides in subject, presented different interactions patterns, which may account for a structural explanation of the distincts biological properties observed in the lectins of Diocleinae subtribe. PMID:17881248

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

    PubMed

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

    2016-03-01

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

  10. Organosolv ethanol lignin from hybrid poplar as a radical scavenger: relationship between lignin structure, extraction conditions, and antioxidant activity.

    PubMed

    Pan, Xuejun; Kadla, John F; Ehara, Katsunobu; Gilkes, Neil; Saddler, Jack N

    2006-08-01

    Twenty-one organosolv ethanol lignin samples were prepared from hybrid poplar (Populus nigra xP. maximowiczii) under varied conditions with an experimental matrix designed using response surface methodology (RSM). The lignin preparations were evaluated as potential antioxidants. Results indicated that the lignins with more phenolic hydroxyl groups, less aliphatic hydroxyl groups, low molecular weight, and narrow polydispersity showed high antioxidant activity. Processing conditions affected the functional groups and molecular weight of the extracted organosolv ethanol lignins, and consequently influenced the antioxidant activity of the lignins. In general, the lignins prepared at elevated temperature, longer reaction time, increased catalyst, and diluted ethanol showed high antioxidant activity. Regression models were developed to enable the quantitative prediction of lignin characteristics and antioxidant activity based on the processing conditions. PMID:16881681

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

    PubMed

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

    2014-10-01

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

  12. Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

    PubMed Central

    Woo, Yin-Tak; Lai, David; McLain, Jennifer L; Manibusan, Mary Ko; Dellarco, Vicki

    2002-01-01

    Disinfection by-products (DBPs) are formed when disinfectants such as chlorine, chloramine, and ozone react with organic and inorganic matter in water. The observations that some DBPs such as trihalomethanes (THMs), di-/trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) are carcinogenic in animal studies have raised public concern over the possible adverse health effects of DBPs. To date, several hundred DBPs have been identified. To prioritize research efforts, an in-depth, mechanism-based structure-activity relationship analysis, supplemented by extensive literature search for genotoxicity and other data, was conducted for ranking the carcinogenic potential of DBPs that met the following criteria: a) detected in actual drinking water samples, b) have insufficient cancer bioassay data for risk assessment, and c) have structural features/alerts or short-term predictive assays indicative of carcinogenic potential. A semiquantitative concern rating scale of low, marginal, low-moderate, moderate, high-moderate, and high was used along with delineation of scientific rationale. Of the 209 DBPs analyzed, 20 were of priority concern with a moderate or high-moderate rating. Of these, four were structural analogs of MX and five were haloalkanes that presumably will be controlled by existing and future THM regulations. The other eleven DBPs, which included halonitriles (6), haloketones (2), haloaldehyde (1), halonitroalkane (1), and dialdehyde (1), are suitable priority candidates for future carcinogenicity testing and/or mechanistic studies. PMID:11834465

  13. Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors.

    PubMed

    Mostofi, Manizheh; Mohammadi Ziarani, Ghodsi; Mahdavi, Mohammad; Moradi, Alireza; Nadri, Hamid; Emami, Saeed; Alinezhad, Heshmatollah; Foroumadi, Alireza; Shafiee, Abbas

    2015-10-20

    A series of benzofuran-based chalconoids 6a-v were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6a-v showed that most compounds had significant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3-pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC50 value of 0.027 ?M was as potent as standard drug donepezil. PMID:26363872

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

    PubMed

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

    2015-10-01

    Acute-to-chronic ratios (ACRs) and quantitative structure-activity relationships (QSARs) are of particular interest in chemical risk assessment. Previous studies focusing on the relationship between the size or variation of ACRs to substance classes and QSAR models were often based on data for standard test organisms, such as daphnids and fish. In the present study, acute and chronic toxicity tests were performed with the nematode Caenorhabditis elegans for a total of 11 chemicals covering 3 substance classes (nonpolar narcotics: 1-propanol, ethanol, methanol, 2-butoxyethanol; metals: copper, cadmium, zinc; and carbamates: methomyl, oxamyl, aldicarb, dioxacarb). The ACRs were variable, especially for the carbamates and metals, although there was a trend toward small and less variable ACRs for nonpolar narcotic substances. The octanol-water partition coefficient was a good predictor for explaining acute and chronic toxicity of nonpolar narcotic substances to C. elegans, but not for carbamates. Metal toxicity could be related to the covalent index ?m2r. Overall, the results support earlier results from ACR and QSAR studies with standard freshwater test animals. As such C. elegans as a representative of small soil/sediment invertebrates would probably be protected by risk assessment strategies already in use. To increase the predictive power of ACRs and QSARs, further research should be expanded to other species and compounds and should also consider the target sites and toxicokinetics of chemicals. PMID:25994998

  15. DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (QSARS) TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

    EPA Science Inventory

    A web accessible software tool is being developed to predict the toxicity of unknown chemicals for a wide variety of endpoints. The tool will enable a user to easily predict the toxicity of a query compound by simply entering its structure in a 2-dimensional (2-D) chemical sketc...

  16. Structure-Activity Relationship Studies of Strigolactone-Related Molecules for Branching Inhibition in Garden Pea: Molecule Design for Shoot Branching1[W

    PubMed Central

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

    2012-01-01

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

  17. Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

    PubMed Central

    2011-01-01

    Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on ?-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships. PMID:21604746

  18. Synthesis and structure--activity relationships of substituted cinnamic acids and amide analogues: a new class of herbicides.

    PubMed

    Vishnoi, Shipra; Agrawal, Vikash; Kasana, Virendra K

    2009-04-22

    In the present investigation, substituted cinnamic acids (3-hydroxy, 4-hydroxy, 2-nitro, 3-nitro, 4-nitro, 3-chloro, and 4-methoxy) and their amide analogues with four different types of substituted anilines have been synthesized. The synthesized compounds have been screened for their germination inhibition activity on radish (Raphanus sativus L. var. Japanese White) seeds at 50, 100, and 200 ppm concentrations, and the activity was compared with standard herbicide, metribuzin formulation (sencor). Significant activity was exhibited by all of the compounds. It was observed that with the increase in concentration of the test solution, the activity also increased. All of the compounds showed more than 70% inhibition at 100 ppm concentration except 4-hydroxy cinnamanilide. The compound, 2-chloro (4'-hydroxy) cinnamanilide was the best among the tested compounds, and it was found to be at par with the standard, metribuzin at all concentrations. Thus, it can be concluded that substituted cinnamic acids and their amide analogues may be developed as potential herbicides. PMID:19368353

  19. QUANTITATIVE STRUCTURE—PROPERTY RELATIONSHIPS FOR ENHANCING PREDICTIONS OF SYNTHETIC ORGANIC CHEMICAL REMOVAL FROM DRINKING WATER BY GRANULAR ACTIVATED CARBON

    EPA Science Inventory


    A number of mathematical models have been developed to predict activated carbon column performance using single-solute isotherm data as inputs. Many assumptions are built into these models to account for kinetics of adsorption and competition for adsorption sites. This work...

  20. Total Synthesis and Structure-Activity Relationship Study of the Potent cAMP Signaling Agonist (-)-Alotaketal A

    PubMed Central

    Huang, Jinhua; Yang, Jessica R.

    2013-01-01

    A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (-)-alotaketal A and allows verification of alotaketal A’s effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A’s unique activity in selectively targeting nuclear PKA signaling in living cells. PMID:23584129

  1. Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.

    PubMed

    Zhou, Zhong-Zhen; Ge, Bing-Chen; Chen, Yu-Fang; Shi, Xiu-Dong; Yang, Xue-Mei; Xu, Jiang-Ping

    2015-11-15

    In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8j with a short amide linker (CONHCH2) displayed comparable PDE4CAT inhibitory activity (IC50=410nM) with rolipram. More interestingly, compound 8g, a potent and selective PDE4D inhibitor (IC50=94nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8g forms three extra H-bonds with the NH of residue Asn487 and two water molecules. PMID:26526739

  2. Structure-activity relationship in the toxicity of some naturally occurring coumarins-chalepin, imperatorin and oxypeucedanine.

    PubMed

    Emerole, G; Thabrew, M I; Anosa, V; Okorie, D A

    1981-01-01

    Imperatorin, oxypeucedanine and chalepin are furanocoumarins isolated from Clausena anisata a medicinal plant common in West Africa. Only chalepin is found to have anticoagulant activity when administered to rats at a single dose. Aniline hydroxylase activity was appreciably depressed by each of the substances. Ethylmorphine demethylase, hepatic DNA, reduced glutathione and glucose-6-phosphatase were unaffected by these compounds when administered at a dose of 50 mg/kg for 3 days prior to sacrifice. Under similar conditions only chalepin treatment resulted in alpha-1-globulin increase and a decrease in beta-globulin content of the serum. Intraperitoneal treatment with chalepin (100 mg/kg) for 2 days resulted in the death of 4 rats out of 10 within a 48 h of treatment. Livers of dead rats showed generalized necrosis of hepatocytes. No deaths were recorded for imperatorin and oxypeucedanine. Rats surviving after 8 weeks showed no changes in hepatic enzyme activity, reduced glutathione and DNA concentrations. However, chalepin and imperatorin induced alterations in the serum protein pattern within this period. Liver lesions were observed in chalepin treated animals and were characterized by very mild necrosis of hepatocytes. No lesions were observed in the livers of rats treated with imperatorin and oxypeucedanine. PMID:7268793

  3. Stereospecific recognition and quantitative structure-activity relationship between antibodies and enantiomers: ofloxacin as a model hapten.

    PubMed

    Mu, Hongtao; Wang, Baoling; Xu, Zhenlin; Sun, Yuanming; Huang, Xinan; Shen, Yudong; Eremin, Sergei A; Zherdev, Anatoly V; Dzantiev, Boris B; Lei, Hongtao

    2015-02-21

    In this study, ofloxacin stereoisomers were chosen as a simple model to investigate the stereospecific recognition of chiral haptens and antibodies. Three polyclonal antibodies were studied and showed a relatively high enantioselectivity and an excellent sensitivity. Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to investigate the chiral recognition between the antibody and the ofloxacin enantiomer, and all the models yielded high correlation and predictive ability. It was found that the chiral discrimination was probably caused by steric hindrance; the antibody stereospecificity could be ascribed to the variation of the R1 and R3 groups of quinolones; the common structure of the quinolones is also essential in the hapten-antibody recognition. The recognition between the chiral haptens and the antibodies was co-affected by multiple interaction forces, and those forces were defined explicitly at the sub-structural level. An illustrative enhanced model with good simplicity and universality was also developed for a better understanding of the stereospecific recognition of ofloxacin enantiomers and antibodies for the first time. This work provides insights into the stereospecific recognition of chiral haptens and antibodies. PMID:25553733

  4. Structure-Activity Relationships of FMRF-NH2 Peptides Demonstrate A Role for the Conserved C Terminus and Unique N-Terminal Extension in Modulating Cardiac Contractility

    PubMed Central

    Katanski, Chris; Thakur, Kiran; Manoogian, Beth; Leander, Megan; Nichols, Ruthann

    2013-01-01

    FMRF-NH2 peptides which contain a conserved, identical C-terminal tetrapeptide but unique N terminus modulate cardiac contractility; yet, little is known about the mechanisms involved in signaling. Here, the structure-activity relationships (SARs) of the Drosophila melanogaster FMRF-NH2 peptides, PDNFMRF-NH2, SDNFMRF-NH2, DPKQDFMRF-NH2, SPKQDFMRF-NH2, and TPAEDFMRF-NH2, which bind FMRFa-R, were investigated. The hypothesis tested was the C-terminal tetrapeptide FMRF-NH2, particularly F1, makes extensive, strong ligand-receptor contacts, yet the unique N terminus influences docking and activity. To test this hypothesis, docking, binding, and bioactivity of the C-terminal tetrapeptide and analogs, and the FMRF-NH2 peptides were compared. Results for FMRF-NH2 and analogs were consistent with the hypothesis; F1 made extensive, strong ligand-receptor contacts with FMRFa-R; Y?F (YMRF-NH2) retained binding, yet A?F (AMRF-NH2) did not. These findings reflected amino acid physicochemical properties; the bulky, aromatic residues F and Y formed strong pi-stacking and hydrophobic contacts to anchor the ligand, interactions which could not be maintained in diversity or number by the small, aliphatic A. The FMRF-NH2 peptides modulated heart rate in larva, pupa, and adult distinctly, representative of the contact sites influenced by their unique N-terminal structures. Based on physicochemical properties, the peptides each docked to FMRFa-R with one best pose, except FMRF-NH2 which docked with two equally favorable poses, consistent with the N terminus influencing docking to define specific ligand-receptor contacts. Furthermore, SDNAMRF-NH2 was designed and, despite lacking the aromatic properties of one F, it binds FMRFa-R and demonstrated a unique SAR, consistent with the N terminus influencing docking and conferring binding and activity; thus, supporting our hypothesis. PMID:24069424

  5. Electronic-topological and neural network approaches to the structure- antimycobacterial activity relationships study on hydrazones derivatives.

    PubMed

    Kandemirli, Fatma; Vurdu, Can Dogan; Basaran, Murat Alper; Sayiner, Hakan Sezgin; Shvets, Nathaly; Dimoglo, Anatholy; Kovalish, Vasyl; Polat, Turgay

    2014-01-01

    That the implementation of Electronic-Topological Method and a variant of Feed Forward Neural Network (FFNN) called as the Associative Neural Network are applied to the compounds of Hydrazones derivatives have been employed in order to construct model which can be used in the prediction of antituberculosis activity. The supervised learning has been performed using (ASNN) and categorized correctly 84.4% of them, namely, 38 out of 45. Ph1 pharmacophore and Ph2 pharmacophore consisting of 6 and 7 atoms, respectively were found. Anti-pharmacophore features socalled "break of activity" have also been revealed, which means that APh1 is found in 22 inactive molecules. Statistical analyses have been carried out by using the descriptors, such as EHOMO, ELUMO, ?E, hardness, softness, chemical potential, electrophilicity index, exact polarizibility, total of electronic and zero point energies, dipole moment as independent variables in order to account for the dependent variable called inhibition efficiency. Observing several complexities, namely, linearity, nonlinearity and multi-co linearity at the same time leads data to be modeled using two different techniques called multiple regression and Artificial Neural Networks (ANNs) after computing correlations among descriptors in order to compute QSAR. Computations resulting in determining some compounds with relatively high values of inhibition are presented. PMID:24773351

  6. Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells.

    PubMed

    Wada, Koji; Hazawa, Masaharu; Takahashi, Kenji; Mori, Takao; Kawahara, Norio; Kashiwakura, Ikuo

    2011-01-01

    The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C(20)-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC(50) values against A549 cells ranged from 1.72 to 5.44 ?M. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest. PMID:20706796

  7. Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

    PubMed Central

    Hazawa, Masaharu; Takahashi, Kenji; Mori, Takao; Kawahara, Norio; Kashiwakura, Ikuo

    2010-01-01

    The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C20-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC50 values against A549 cells ranged from 1.72 to 5.44 ?M. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest. PMID:20706796

  8. Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against Plasmodium falciparum.

    PubMed

    Milner, Erin; Gardner, Sean; Moon, Jay; Grauer, Kristina; Auschwitz, Jennifer; Bathurst, Ian; Caridha, Diana; Gerena, Lucia; Gettayacamin, Montip; Johnson, Jacob; Kozar, Michael; Lee, Patricia; Leed, Susan; Li, Qigui; McCalmont, William; Melendez, Victor; Roncal, Norma; Sciotti, Richard; Smith, Bryan; Sousa, Jason; Tungtaeng, Anchalee; Wipf, Peter; Dow, Geoffrey

    2011-09-22

    A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine. PMID:21854078

  9. Vaulted Biaryls in Catalysis: A Structure-Activity Relationship Guided Tour of the Immanent Domain of the VANOL Ligand

    PubMed Central

    Guan, Yong; Ding, Zhensheng

    2013-01-01

    The active site in the BOROX catalyst is a chiral polyborate anion (boroxinate) that is assembled in-situ from three equivalents of B(OPh)3 and one of the VANOL ligand by a molecule of substrate. The substrates are bound to the boroxinate by H-bonds to oxygens O1-O3. The effects of introducing substituents at each position of the naphthalene core of the VANOL ligand are systematically investigated in an aziridination reaction. Substituents in the 4,4?- and 8,8?-positions have a negative effect on catalyst performance, whereas, substituents in the 7- and 7?-positions have the biggest impact in a positive direction. PMID:24123264

  10. Effects of flavonoids on the release of reactive oxygen species by stimulated human neutrophils. Multivariate analysis of structure-activity relationships (SAR).

    PubMed

    Limasset, B; le Doucen, C; Dore, J C; Ojasoo, T; Damon, M; Crastes de Paulet, A

    1993-10-01

    In the present study we measured the inhibition by 34 compounds, either flavonoids or related substances, of the release of reactive oxygen species by human neutrophils after stimulation by three agents: the bacterial peptide N-fMetLeuPhe (FMLP), the protein kinase C activator phorbol myristate acetate (PMA) or opsonized zymosan (OZ), using two chemiluminescent probes, lucigenin or luminol in the presence or absence of horseradish peroxidase (HRP). The data matrix (34 x 7) was submitted to multivariate analysis: first, a correspondence factorial analysis to uncover levels of correlation among the biochemical parameters and the specificity of action of the test-compounds and second, a minimum spanning tree analysis that classified the chemical structures into a network describing both specificity and amplitude of the inhibition of the chemiluminescence response. The major conclusions of the analyses were: (a) opposition between inhibition of poly-morphonuclear leukocytes (PMNs) stimulated by FMLP and of PMNs stimulated by PMA or OZ implying that, for the molecules under study, there was a fundamental difference in the manner in which this inhibition occurred and, conversely, a difference in the nature of the stimulatory action of these activators. Molecules lacking hydroxyl groups on ring B, i.e. chrysin, chalcone, flavone and galangin, molecules glycosylated in position 7, i.e. hesperidin and naringin and ring B mono-hydroxylated molecules were, for the most part, at the origin of this dichotomy and might interfere with the membrane FMLP receptor; (b) a marked difference in chemiluminescence inhibition in the presence or absence of HRP that can be explained by the differential action of catechins compared to flavone and flavonol derivatives; (c) a similarity in biological profile between non-flavonoids such as chalcone and phloretin and low mean-activity flavonoids such as chrysin and galangin and between the non-flavonoid curcumin and the highly active flavonoid isorhamnetin; (d) a reaffirmation of the importance of ring A (C5,7) and ring B (C3',4') dihydroxylation, ring C (C3) hydroxylation, but also of the presence of a methoxy group on ring B in engendering high potency. This potency is generally decreased by C2-C3 saturation and by glycosylation. The most active molecules identified in this study provide valuable information for the selection of simpler molecules (e.g. metabolites accounting for the potency of orally administered flavonoids) for further structure-activity relationship (SAR) studies that could lead to the design of novel drugs or prodrugs. PMID:8216378

  11. Structure-activity relationship of HP (2-20) analog peptide: enhanced antimicrobial activity by N-terminal random coil region deletion.

    PubMed

    Park, Yoonkyung; Park, Seong-Cheol; Park, Hae-Kyun; Shin, Song Yub; Kim, Yangmee; Hahm, Kyung-Soo

    2007-01-01

    HP (2-20) (AKKVFKRLEKLFSKIQNDK) is a 19-aa antimicrobial peptide derived from N-terminus of Helicobacter pylori Ribosomal protein L1 (RpL1). In the previous study, several analogs with amino acid substitutions were designed to increase or decrease only the net hydrophobicity. In particular, substitutions of Gln(16) and Asp(18) with Trp (Anal 3) for hydrophobic amino acid caused a dramatic increase in antibiotic activity without a hemolytic effect. HP-A3 is a potent antimicrobial peptide that forms, in a hydrophobic medium, an amphipathic structure consisting of an N-terminal random coil region (residues 2-5) and extended C-terminal regular alpha-helical region (residues 6-20). To obtain the short and potent alpha-helical antimicrobial peptide, we synthesized a N-terminal random coil deleted HP-A3 (A3-NT) and examined their antimicrobial activity and mechanism of action. The resulting 15mer peptide showed increased antibacterial and antifungal activity to 2- and 4-fold, respectively, without hemolysis. Confocal fluorescence microscopy studies showed that A3-NT was accumulated in the plasma membrane. Flow cytometric analysis revealed that A3-NT acted in salt- and energy-independent manner. Furthermore, A3-NT causes significant morphological alterations of the bacterial surfaces as shown by scanning electron microscopy. Circular dichroism (CD) analysis revealed that A3-NT showed higher alpha-helical contents than the HP-A3 peptide in 50% TFE solution. Therefore, the cell-lytic efficiency of HP-A3, which depended on the alpha-helical content of peptide, correlated linearly with their antimicrobial potency. PMID:17216635

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

    PubMed

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

    2015-05-01

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

  13. Relative toxicity of para-substituted phenols: log K/sub ow/ and pKa-dependent structure-activity relationships

    SciTech Connect

    Schultz, T.W.

    1987-06-01

    The toxic response of the majority of industrial chemicals which are nonreactive and non -ionic can be quantitatively modeled by the 1-octanol/water partition coefficient (K/sub ow/) in a linear fashion following a log-log transformation of the data. The toxicity of phenols, however does not model by these same quantitative structure-activity relationships (QSAR). Earlier studies have shown that the addition of pKa as a second molecular descriptor improves the predictive capability of log K/sub ow/ QSAR. The predicted toxicity of phenol derivatives, which ionize poorly under the test conditions, is not significantly altered by using models in which pKa is not included. In an effort to systematically explore the extent to which such log K/sub ow/ and, log K/sub ow/ and pKa-dependent QSAR can be used to predict the biological activity of phenols, the first in a series of investigations was conducted using the rapid and inexpensive Tetrahymena population growth impairment assay to determine relative toxicity of 30 para-substituted derivatives.

  14. Synthesis of a Sugar-Based Thiosemicarbazone Series and Structure-Activity Relationship versus the Parasite Cysteine Proteases Rhodesain, Cruzain, and Schistosoma mansoni Cathepsin B1

    PubMed Central

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

    2015-01-01

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

  15. The Discovery of Geranylgeranyltransferase-I Inhibitors with Novel Scaffolds by the Means of Quantitative Structure-Activity Relationship Modeling, Virtual Screening, and Experimental Validation

    PubMed Central

    Peterson, Yuri K.; Wang, Xiang S.; Casey, Patrick J.; Tropsha, Alexander

    2009-01-01

    Geranylgeranylation is critical to the function of several proteins including Rho, Rap1, Rac, Cdc42, and G-protein gamma subunits. Geranylgeranyltransferase type I (GGTase-I) inhibitors (GGTIs) have therapeutic potential to treat inflammation, multiple sclerosis, atherosclerosis, and many other diseases. Following our standard QSAR modeling workflow, we have developed and rigorously validated Quantitative Structure Activity Relationship (QSAR) models for 48 GGTIs using variable selection k nearest neighbor (kNN), automated lazy learning (ALL), and partial least square (PLS) methods. The QSAR models were employed for virtual screening of 9.5 million commercially available chemicals yielding 47 diverse computational hits. Seven of these compounds with novel scaffolds and high predicted GGTase-I inhibitory activities were tested in vitro, and all were found to be bona fide and selective micromolar inhibitors. Notably, these novel hits could not be identified using traditional similarity search. These data demonstrate that rigorously developed QSAR models can serve as reliable virtual screening tools. PMID:19537691

  16. Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).

    PubMed

    Singh, Sheo B; Kaelin, David E; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Meinke, Peter T; Olsen, David B; Lagrutta, Armando; Wei, Changqing; Liao, Yonggang; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Yajima, Masanobu; Shibue, Taku; Shibata, Takeshi; Ohata, Kohei; Nishimura, Akinori; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 ?M) profile. PMID:26141771

  17. First Y-type actinomycins from Streptomyces with divergent structure-activity relationships for antibacterial and cytotoxic properties.

    PubMed

    Bitzer, Jens; Streibel, Martin; Langer, Hans-Jörg; Grond, Stephanie

    2009-02-01

    Streptomyces sp. strain Gö-GS12 was found to produce five novel actinomycins Y(1)-Y(5) (). Their amino acid pattern discloses them as members of a new family of this important class of antibiotics. Compounds differ from Z-type actinomycins in their beta-peptidolactone rings which here contain trans-4-hydroxyproline (Hyp) or 4-oxoproline (OPro) amino acids, and from the X-congeners by containing methylalanine (MeAla). Within the new Y-type actinomycins variations are not only in the rare chlorinated or hydroxylated threonine residue. Furthermore, the beta-ring can undergo rearrangement by a two-fold acyl shift (compounds and ) or show a unique additional ring closure with the chromophore (compound ), resulting in metabolites with yet unknown structural motifs, altered conformations and distinct bioactivities. The strongest bioactivity was found for the chlorine containing actinomycin Y(1) (), the most surprising for Y(5) () with cytotoxic and antibacterial effects losing their coherence, which has been observed for the first time here. PMID:19156308

  18. BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536.

    PubMed

    Chen, Lijia; Yap, Jeremy L; Yoshioka, Makoto; Lanning, Maryanna E; Fountain, Rachel N; Raje, Mithun; Scheenstra, Jacob A; Strovel, Jeffrey W; Fletcher, Steven

    2015-07-01

    A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal. PMID:26191363

  19. Redesigning the DNA-Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

    PubMed Central

    Pickard, Amanda J.; Liu, Fang; Bartenstein, Thomas F.; Haines, Laura G.; Levine, Keith E.; Kucera, Gregory L.; Bierbach, Ulrich

    2014-01-01

    Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1. PMID:25302716

  20. Structure–Activity Relationships of Cyclic Lactam Analogues of ?-Melanocyte-Stimulating Hormone (?-MSH) Targeting the Human Melanocortin-3 Receptor

    PubMed Central

    Mayorov, Alexander V.; Cai, Minying; Palmer, Erin S.; Dedek, Matthew M.; Cain, James P.; Van Scoy, April R.; Tan, Bahar; Vagner, Josef; Trivedi, Dev; Hruby, Victor J.

    2008-01-01

    A variety of dicarboxylic acid linkers introduced between the ?-amino group of Pro6 and the ?-amino group of Lys10 of the cyclic lactam ?-melanocyte-stimulating hormone (?-MSH)-derived Pro6-D-Phe7/D-Nal(2?)7-Arg8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2?)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a ?-turn-like structure with the D-Phe/D-Nal(2?) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D-Nal(2?)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic ?-melanocyte-stimulating hormone (?-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor. PMID:18088090

  1. 266 Bull. Korean Chem. Soc. 2006, Vol. 27, No. 2 Nagakumar Bharatham et al. Quantitative Structure-Activity Relationships and Molecular

    E-print Network

    Lee, Keun Woo

    diseases, rheumatoid arthritis, multiple sclerosis, lupus, as well as inflammatory diseases, prevention structure of P56 LCK. Good correlation between predicted fitness scores versus observed activities

  2. Structure-function relationships of immunostimulatory polysaccharides: A review.

    PubMed

    Ferreira, Sónia S; Passos, Cláudia P; Madureira, Pedro; Vilanova, Manuel; Coimbra, Manuel A

    2015-11-01

    Immunostimulatory polysaccharides are compounds capable of interacting with the immune system and enhance specific mechanisms of the host response. Glucans, mannans, pectic polysaccharides, arabinogalactans, fucoidans, galactans, hyaluronans, fructans, and xylans are polysaccharides with reported immunostimulatory activity. The structural features that have been related with such activity are the monosaccharide and glycosidic-linkage composition, conformation, molecular weight, functional groups, and branching characteristics. However, the establishment of structure-function relationships is possible only if purified and characterized polysaccharides are used and selective structural modifications performed. Aiming at contributing to the definition of the structure-function relationships necessary to design immunostimulatory polysaccharides with potential for preventive or therapeutical purposes or to be recognized as health-improving ingredients in functional foods, this review introduces basic immunological concepts required to understand the mechanisms that rule the potential claimed immunostimulatory activity of polysaccharides and critically presents a literature survey on the structural features of the polysaccharides and reported immunostimulatory activity. PMID:26256362

  3. Quantitative Structure-Cytotoxicity Relationship of Oleoylamides.

    PubMed

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

    2015-10-01

    Eighteen oleoylamides were subjected to quantitative structure-activity relationship analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to assess their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and five human oral normal cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell, oral keratinocyte, primary gingival epithelial cells) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-selectivity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal human oral cells to that against OSCC cell lines. Potency-selectivity expression (PSE) was determined by the ratio of TS to CC50 against OSCC. Anti-HIV activity was evaluated by the ratio of CC50 to the concentration leading to 50% cytoprotection from HIV infection (EC50). Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. Among 18 derivatives, compounds 8: with a catechol group) and 18: with a (2-pyridyl)amino group) had the highest TS. On the other hand, doxorubicin and 5-fluorouracil (5-FU) were more highly cytotoxic to normal epithelial cells, displaying unexpectedly lower TS and PSE values. None of the compounds had anti-HIV activity. Among 330 chemical descriptors, 75, 73 and 19 descriptors significantly correlated to the cytotoxicity to normal and tumor cells, and TS, respectively. Multivariate statistics with chemical descriptors for molecular polarization and hydrophobicity may be useful for the evaluation of cytotoxicity and TS of oleoylamides. PMID:26408695

  4. Structure-activity relationship studies of melanin-concentrating hormone (MCH)-related peptide ligands at SLC-1, the human MCH receptor.

    PubMed

    Audinot, V; Beauverger, P; Lahaye, C; Suply, T; Rodriguez, M; Ouvry, C; Lamamy, V; Imbert, J; Rique, H; Nahon, J L; Galizzi, J P; Canet, E; Levens, N; Fauchere, J L; Boutin, J A

    2001-04-27

    Melanin-concentrating hormone (MCH) is a cyclic nonadecapeptide involved in the regulation of feeding behavior, which acts through a G protein-coupled receptor (SLC-1) inhibiting adenylcyclase activity. In this study, 57 analogues of MCH were investigated on the recently cloned human MCH receptor stably expressed in HEK293 cells, on both the inhibition of forskolin-stimulated cAMP production and guanosine-5'-O-(3-[(35)S]thiotriphosphate ([(35)S]- GTPgammaS) binding. The dodecapeptide MCH-(6-17) (MCH ring between Cys(7) and Cys(16), with a single extra amino acid at the N terminus (Arg(6)) and at the C terminus (Trp(17))) was found to be the minimal sequence required for a full and potent agonistic response on cAMP formation and [(35)S]- GTPgammaS binding. We Ala-scanned this dodecapeptide and found that only 3 of 8 amino acids of the ring, namely Met(8), Arg(11), and Tyr(13), were essential to elicit full and potent responses in both tests. Deletions inside the ring led either to inactivity or to poor antagonists with potencies in the micromolar range. Cys(7) and Cys(16) were substituted by Asp and Lys or one of their analogues, in an attempt to replace the disulfide bridge by an amide bond. However, those modifications were deleterious for agonistic activity. In [(35)S]- GTPgammaS binding, these compounds behaved as weak antagonists (K(B) 1-4 microm). Finally, substitution in MCH-(6-17) of 6 out of 12 amino acids by non-natural residues and concomitant replacement of the disulfide bond by an amide bond led to three compounds with potent antagonistic properties (K(B) = 0.1-0.2 microm). Exploitation of these structure-activity relationships should open the way to the design of short and stable MCH peptide antagonists. PMID:11278733

  5. Cardiac Contractility Structure-Activity Relationship and Ligand-Receptor Interactions; the Discovery Of Unique and Novel Molecular Switches in Myosuppressin Signaling

    PubMed Central

    Leander, Megan; Bass, Chloe; Marchetti, Kathryn; Maynard, Benjamin F.; Wulff, Juan Pedro; Ons, Sheila; Nichols, Ruthann

    2015-01-01

    Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3–6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3–6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3–6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology. PMID:25793503

  6. Structure-activity relationships of the antimicrobial peptide gramicidin S and its analogs: aqueous solubility, self-association, conformation, antimicrobial activity and interaction with model lipid membranes.

    PubMed

    Abraham, Thomas; Prenner, Elmar J; Lewis, Ruthven N A H; Mant, Colin T; Keller, Sandro; Hodges, Robert S; McElhaney, Ronald N

    2014-05-01

    GS10 [cyclo-(VKLdYPVKLdYP)] is a synthetic analog of the naturally occurring antimicrobial peptide gramicidin (GS) in which the two positively charged ornithine (Orn) residues are replaced by two positively charged lysine (Lys) residues and the two less polar aromatic phenylalanine (Phe) residues are replaced by the more polar tyrosine (Tyr) residues. In this study, we examine the effects of these seemingly conservative modifications to the parent GS molecule on the physical properties of the peptide, and on its interactions with lipid bilayer model and biological membranes, by a variety of biophysical techniques. We show that although GS10 retains the largely ?-sheet conformation characteristic of GS, it is less structured in both water and membrane-mimetic solvents. GS10 is also more water soluble and less hydrophobic than GS, as predicted, and also exhibits a reduced tendency for self-association in aqueous solution. Surprisingly, GS10 associates more strongly with zwitterionic and anionic phospholipid bilayer model membranes than does GS, despite its greater water solubility, and the presence of anionic phospholipids and cholesterol (Chol) modestly reduces the association of both GS10 and GS to these model membranes. The strong partitioning of both peptides into lipid bilayers is driven by a large favorable entropy change opposed by a much smaller unfavorable enthalpy change. However, GS10 is also less potent than GS at inducing inverted cubic phases in phospholipid bilayer model membranes and at inhibiting the growth of the cell wall-less bacterium Acholeplasma laidlawii B. These results are discussed in terms of the comparative antibiotic and hemolytic activities of these peptides. PMID:24388950

  7. Physicochemical explanation of peptide binding to HLA-A*0201 major histocompatibility complex: a three-dimensional quantitative structure-activity relationship study.

    PubMed

    Doytchinova, Irini A; Flower, Darren R

    2002-08-15

    A three-dimensional quantitative structure-activity relationship method for the prediction of peptide binding affinities to the MHC class I molecule HLA-A*0201 was developed by applying the CoMSIA technique on a set of 266 peptides. To increase the self consistency of the initial CoMSIA model, the poorly predicted peptides were excluded from the training set in a stepwise manner and then included in the study as a test set. The final model, based on 236 peptides and considering the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields, had q2 = 0.683 and r2 = 0.891. The stability of this model was proven by cross-validations in two and five groups and by a bootstrap analysis of the non-cross-validated model. The residuals between the experimental pIC50 (-logIC50) values and those calculated by "leave-one-out" cross-validation were analyzed. According to the best model, 63.2% of the peptides were predicted with /residuals/ < or = 0.5 log unit; 29.3% with 1.0 < or = /residuals/ < 0.5; and 7.5% with /residuals/ > 1.0 log unit. The mean /residual/ value was 0.489. The coefficient contour maps identify the physicochemical property requirements at each position in the peptide molecule and suggest amino acid sequences for high-affinity binding to the HLA-A*0201 molecule. PMID:12112675

  8. Quantum chemistry based quantitative structure-activity relationships for modeling the (sub)acute toxicity of substituted mononitrobenzenes in aquatic systems.

    PubMed

    Zvinavashe, Elton; Murk, Albertinka J; Vervoort, Jacques; Soffers, Ans E M E; Freidig, Andreas; Rietjens, Ivonne M C M

    2006-09-01

    Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to algae (Scenedesmus obliquus, Chlorella pyrenoidosa, C. vulgaris), daphnids (Daphnia magna, D. carinata), fish (Cyprinus carpio, Poecilia reticulata), protozoa (Tetrahymena pyriformis), bacteria (Phosphobacterium phosphoreum), and yeast (Saccharomyces cerevisiae) were used to establish quantum chemistry based quantitative structure-activity relationships (QSARs). The logarithm of the octanol/water partition coefficient, log Kow, and the energy of the lowest unoccupied molecular orbital, Elumo, were used as descriptors. Suitable QSAR models (0.65 < r2 < 0.98) to predict acute toxicity of substituted mononitrobenzenes to protozoa, fish, daphnids, yeast, and algae have been derived. The log Kow was a sufficient descriptor for all cases, with the additional Elumo descriptor being required only for algae. The QSARs were found to be valid for neutral substituted mononitrobenzenes with no -OH, -COOH, or -CN substituents attached directly to the ring. From the 100,196 European Inventory of Existing Commercial Substances (EINECS), 497 chemicals were identified that fit the selection criteria for the established QSARs. Based on these results, an advisory tool has been developed that directs users to the appropriate QSAR model to apply for various types of organisms within specified log Kow ranges. Using this tool, it is possible to obtain a good indication of the toxicity of a large set of EINECS chemicals and newly developed substituted mononitrobenzenes to five different organisms without the need for additional experimental testing. PMID:16986785

  9. Structure-Activity Relationship (SAR) and Preliminary Mode of Action Studies of 3-Substituted Benzylthioquinolinium Iodide as Anti-opportunistic Infection Agents

    PubMed Central

    Bolden, Sidney; Zhu, Xue Y.; Etukala, Jagan R; Boateng, Comfort; Mazu, Tryphon; Flores-Rozas, Hernan; Jacob, Melissa R.; Khan, Shabana I; Walker, Larry A.; Ablordeppey, Seth Y.

    2013-01-01

    Opportunistic infections are devastating to immunocompromised patients. And in especially sub-Saharan Africa where the AIDS epidemic is still raging, the mortality rate was recently as high as 70%. The paucity of anti-opportunistic drugs, the decreasing efficacy and the development of resistance against the azoles and even amphotericin B have stimulated the search for new drugs with new mechanisms of action. In a previous work, we showed that a new chemotype derived from the natural product cryptolepine displayed selective toxicity against opportunistic pathogens with minimal cytotoxicity to normal cells. In this manuscript, we report the design and synthesis of substituted benzylthioquinolinium iodides, evaluated their anti-infective properties and formulated some initial structure-activity relationships around phenyl ring A from the original natural product. The sensitivity of the most potent analog 10l, to selected strains of C. cerevisiae was also evaluated leading to the observation that this scaffold may have a different mode of action from its predecessor, cryptolepine. PMID:24141203

  10. Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells.

    PubMed

    Chang, Chi-Fen; Ke, Ci-Yi; Wu, Yang-Chang; Chuang, Ta-Hsien

    2015-01-01

    In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 ?M against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity. PMID:26492346

  11. Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells

    PubMed Central

    Chang, Chi-Fen; Ke, Ci-Yi; Wu, Yang-Chang; Chuang, Ta-Hsien

    2015-01-01

    In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 ?M against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity. PMID:26492346

  12. Structure-Activity Relationship Study on Isothiocyanates: Comparison of TRPA1-Activating Ability between Allyl Isothiocyanate and Specific Flavor Components of Wasabi, Horseradish, and White Mustard.

    PubMed

    Terada, Yuko; Masuda, Hideki; Watanabe, Tatsuo

    2015-08-28

    Allyl isothiocyanate (ITC) (4) is the main pungent component in wasabi, and it generates an acrid sensation by activating TRPA1. The flavor and pungency of ITCs vary depending on the compound. However, the differences in activity to activate TRPA1 between ITCs are not known except for a few compounds. To investigate the effect of carbon chain length and substituents of ITCs, the TRPA1-activiting ability of 16 ITCs was measured. Since most of the ITCs showed nearly equal TRPA1-activiting potency, the ITC moiety is likely the predominant contributor to their TRPA1-activating abilities, and contributions of other functional groups to their activities to activate TRPA1 are comparatively small. PMID:26263397

  13. Inhibition of Protein Kinase C-Driven Nuclear Factor-?B Activation: Synthesis, Structure?Activity Relationship, and Pharmacological Profiling of Pathway Specific Benzimidazole Probe Molecules

    PubMed Central

    2010-01-01

    A unique series of biologically active chemical probes that selectively inhibit NF-?B activation induced by protein kinase C (PKC) pathway activators have been identified through a cell-based phenotypic reporter gene assay. These 2-aminobenzimidazoles represent initial chemical tools to be used in gaining further understanding on the cellular mechanisms driven by B and T cell antigen receptors. Starting from the founding member of this chemical series 1a (notated in PubChem as CID-2858522), we report the chemical synthesis, SAR studies, and pharmacological profiling of this pathway-selective inhibitor of NF-?B activation. PMID:20481485

  14. Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure-Activity Relationship Study.

    PubMed

    Yellol, Jyoti; Pérez, Sergio A; Buceta, Alicia; Yellol, Gorakh; Donaire, Antonio; Szumlas, Piotr; Bednarski, Patrick J; Makhloufi, Gamall; Janiak, Christoph; Espinosa, Arturo; Ruiz, José

    2015-09-24

    A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(?(6)-p-cymene)RuCl(?(2)-N,C-L)] and [(?(5)-C5Me5)IrCl(?(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 ?M, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent. PMID:26313136

  15. Social Relationships, Leisure Activity, and Health in Older Adults

    PubMed Central

    Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

    2015-01-01

    Objective Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Methods Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modelling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. Results The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. Discussion & Conclusions The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PMID:24884905

  16. Categorization of fragrance contact allergens for prioritization of preventive measures: clinical and experimental data and consideration of structure-activity relationships.

    PubMed

    Uter, Wolfgang; Johansen, Jeanne D; Börje, Anna; Karlberg, Ann-Therese; Lidén, Carola; Rastogi, Suresh; Roberts, David; White, Ian R

    2013-10-01

    Contact allergy to fragrances is still relatively common, affecting ? 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization of substances as contact allergens. A total of 54 individual chemicals and 28 natural extracts (essential oils) can be categorized as established contact allergens in humans, including all 26 substances previously identified as contact allergens (SCCNFP/0017/98). Twelve of the 54 individual chemicals are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (>100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration of 11 substances of special concern should be limited to 100 ppm. The substance hydroxyisohexyl 3-cyclohexene carboxaldehyde and the two ingredients chloroatranol and atranol in the natural extracts Evernia prunastri and Evernia furfuracea should not be present in cosmetic products. PMID:23889298

  17. Structure-Activity Relationships of Cyanoquinolines with Corrector-Potentiator Activity in delta-F508-Cystic Fibrosis Transmembrane Conductance Regulator Protein

    PubMed Central

    Knapp, John M.; Wood, Alex B.; Phuan, Puay-Wah; Lodewyk, Michael W.; Tantillo, Dean J.; Verkman, A. S.; Kurth, Mark J.

    2012-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ?F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified, cyanoquinolines with both corrector (“Co”; normalizing ?F508-CFTR targeting) and potentiator (“Po”; normalizing ?F508-CFTR channel gating) activities. Here, we synthesized and characterized twenty-four targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ? force-field lowest energy assessment ? geometry optimization] suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and aryl amide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo’s should adopt two distinct ?-stacking conformations to elicit corrector and potentiator activities. PMID:22214395

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

    PubMed

    Tomioka, Haruaki

    2014-01-01

    Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is promoting the elucidation of the molecular structures of drug targets in MTB, and are consequently markedly useful for the design of new, promising antituberculous drugs using QSAR techniques. In this issue, we review the following areas. Firstly, Dr. Li M. Fu reviews the perspective that combines machine learning and genomics for drug discovery in tuberculosis, in relation to the problem that the exhaustive search for useful drug targets over the entire MTB genome would not be as productive as expected in practice [1]. Secondly, the review article by Drs. R. S. Chauhan. S. K. Chanumolu, C. Rout, and R. Shrivastava focuses on analysis of the current state of MTB genomic resources, host-pathogen interaction studies in the context of mycobacterial persistence, and drug target discovery based on the utilization of computational tools and metabolic network analyses [2]. Thirdly, Drs. Daria Bottai, Agnese Serafini, Alessandro Cascioferro, Roland Brosch, and Riccardo Manganelli review the current knowledge on MTB T7SS/ESX secretion systems and their impact on MTB physiology and virulence, and the possible approaches to develop T7SS/ESX inhibitors [3]. Fourthly, Drs. E. Jeffrey North, Mary Jackson, and Richard E. Lee review and analyze new and emerging inhibitors of the mycolic acid biosynthetic pathway, including mycobacterial enzymes for fatty acid synthesis, mycolic acid-modifying enzymes, fatty acid-activating and -condensing enzymes, transporters, and transferases, that have been discovered in the post-genomic era of tuberculosis drug discovery [4]. Fifthly, Drs. Katarina Mikusova, Vadim Makarov, and Joao Neres review the mycobacterial enzyme DprE1, which catalyzes a unique epimerization reaction in the biosynthesis of decaprenylphosphoryl arabinose, a single donor of the arabinosyl residue for the build-up of arabinans, one of the mycobacterial cell wall components, as an important drug target especially for the development of benzothiazinones [5]. Sixthly, I review the present status of global research on novel drug targets related to the Toll-like receptor in t

  19. Odor qualities and thresholds of physiological metabolites of 1,8-cineole as an example for structure-activity relationships considering chirality aspects.

    PubMed

    Kirsch, Frauke; Buettner, Andrea

    2013-09-01

    The present study aimed at analyzing the odor properties of a group of physiological human metabolites of the odorant 1,8-cineole: 2,3-dehydro-, ?2,3-epoxy-, ?/?2-hydroxy-, ?3-hydroxy-, 4-hydroxy-, 7-hydroxy-, 9-hydroxy-, 2-oxo-, and 3-oxo-1,8-cineole. These metabolites constitute a group of structurally closely related molecules, which differ mainly in nature and position of O-containing functional groups. They thus offer the possibility to correlate odor properties with molecular structure, i.e., to establish structure-odor relationships of compounds that are biologically generated from a potent odorant as parent substance. Generally, the metabolites preserved the eucalyptus-like odor quality of 1,8-cineole but showed additional odor notes such as sweet, citrus-like, plastic-like, earthy, musty, and faecal, which made them distinguishable. The individual enantiomers of chiral molecules also exhibited different odors. With the exception of 2,3-dehydro-1,8-cineole, all metabolites showed a highly decreased odor threshold in comparison to 1,8-cineole. The determination of odor qualities and odor thresholds was accomplished by gas chromatography/olfactometry (GC/O) on achiral and chiral GC capillaries. The results were correlated with common theories on structure-odor relationships. PMID:24078601

  20. Using Structural Relationships to Facilitate API Learning

    E-print Network

    Robillard, Martin

    Using Structural Relationships to Facilitate API Learning by Ekwa Duala-Ekoko Doctor of Philosophy for having both of you in my life. iv #12;ABSTRACT Application Programming Interfaces (APIs) allow software functionalities from scratch. The benefits of reusing source code or services through APIs have encouraged

  1. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling.

    PubMed

    Eterovi?, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A; El Sayed, Khalid A; Ferchmin, Pedro A

    2013-08-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the ?7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisynthetic, or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 ?M. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  2. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling

    PubMed Central

    Eterovi?, Vesna A.; Valle-Rodriguez, Angelie Del; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.

    2013-01-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the ?7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 ?M. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  3. Kinetics of OH-initiated oxidation of oxygenated organic compounds in the aqueous phase: new rate constants, structure-activity relationships and atmospheric implications

    NASA Astrophysics Data System (ADS)

    Monod, A.; Poulain, L.; Grubert, S.; Voisin, D.; Wortham, H.

    The kinetics of OH oxidation of several organic compounds of atmospheric relevance were measured in the aqueous phase. Relative kinetics were performed using various organic references and OH sources. After validation of the protocol, temperature-dependent rate constants for the reactions of OH radical with ethyl ter-butyl ether ( k297=1.5(±1.7)×109Ms, E/R=580 (±560) K), n-butyl acetate ( k297=1.8 (±0.4)×10 9 M -1 s -1, E/R=1000 (±200) K), acetone ( k298=0.11 (±0.05)×10 9 M -1 s -1, E/R=1400 (±500) K), methyl ethyl ketone ( k298=0.81(±0.18)×109Ms, E/R=1200 (±200) K), methyl iso-butyl ketone ( k298=2.1(±0.5)×109Ms, E/R=1200 (±300) K) and methylglyoxal ( k298=0.53(±0.04)×109Ms, E/R=1100 (±300) K) were determined. A non-Arrhenius behavior was found for phenol, in good agreement with the contribution of an OH addition to the mechanism, which also includes H-abstraction by OH radicals. Global rate constants of acetaldehyde, propionaldehyde, butyraldehyde and valeraldehyde were studied at 298 K only, as these compounds partly hydrate in the aqueous phase. All the obtained data (except those of phenol) complemented by literature data were used to investigate three methods to estimate rate constants for H-abstraction reactions of OH radicals in aqueous solutions when measured data were not available: Evans-Polanyi-type correlations, comparisons with gas-phase data, structure activity relationships (SAR). The results show that the SAR method is promising; however, the data set is currently too small to extend this method to temperatures other than 298 K. The atmospheric impact of aqueous phase OH oxidation of water-soluble organic compounds is discussed with the determination of their global atmospheric lifetimes, taking into account both gas- and aqueous-phase reactivities. The results show that atmospheric droplets can act as powerful photoreactors to eliminate soluble organic compounds from the atmosphere.

  4. Structure-function relationship of gonadotropins

    SciTech Connect

    Bellet, D.; Bidart, J.M.

    1989-01-01

    In this book, investigators highlight progress recently made in research on the structure-function relationship of gonadotropins. The contributors provide coverage of major breakthroughs such as the cloning of the ovarian receptor for lutropin and choriogonadotropin, the elucidation of the structure of this receptor, and the first crystallographic studies of human chorionic gonadotropin. The book also describes significant advances in the epitope mapping of gonadotropins, the immunochemical and biochemical study of their structure, the examination of regulatory processes involved in subunit association, and the elucidation of the complex mechanisms responsible for regulation and expression of gonadotropin genes.

  5. Design and structure-activity relationship of thrombin inhibitors with an azaphenylalanine scaffold: potency and selectivity enhancements via P2 optimization.

    PubMed

    Zega, A; Mlinsek, G; Sepic, P; Golic Grdadolnik, S; Solmajer, T; Tschopp, T B; Steiner, B; Kikelj, D; Urleb, U

    2001-10-01

    Theoretical and structural studies followed by the directed synthesis and in vitro biological tests lead us to novel noncovalent thrombin pseudopeptide inhibitors. We have incorporated an azapeptide scaffold into the central part of the classical tripeptide D-Phe-Pro-Arg inhibitor structure thus eliminating one stereogenic center from the molecule. A series of compounds has been designed to optimize the occupancy of the S2 pocket of thrombin. Increased hydrophobicity at P2 provides an enhanced fit into this active site S2 pocket. In the present paper, we also report on the structure of these inhibitors in solution and conformational analysis of inhibitors in the active site in order to asses the consequences of the replacement of the central alpha-CH by a nitrogen functionality. In vitro biological testing of the designed inhibitors shows that elimination of R, S stereoisomerism and restriction of conformational freedom influences the binding of inhibitors in a favorable fashion. PMID:11557360

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

    NASA Astrophysics Data System (ADS)

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

    2010-12-01

    The nitrate radical (NO3) has long been recognized as the dominant night-time oxidant of organic species, in particular of unsaturated compounds. More recently, it has been shown that it can contribute significantly to the oxidation of very reactive VOC (e.g. terpenes) even during the day[1]. Volatile organic compounds are widely emitted into the atmosphere by both anthropogenic and biogenic sources. When released into the troposphere, they can undergo either photolysis or oxidation by OH and NO3 radicals and by ozone. These chemical processes are known to be responsible for the formation of photooxidants and SOA which are involved in photochemical smog events. Hence, to estimate their impact on the tropospheric chemistry, it is necessary to know their reactivity towards the atmospheric oxidants. But because of huge number of VOCs, it is impossible to perform kinetic experiments for all of them. For this reason, estimation methods have been developed to predict rate constants. A number of methods for the estimation of rate constants have been proposed. Many of them utilize the physical or chemical properties of the organic compounds such as the ionization energy[2] or the energy of molecular orbital[3]. However, these methods are restricted in their use because of the limited database concerning molecular properties and the discrepancies between the different molecular models used to calculate these parameters. For this reason, a structure-activity relationship has been developed by Atkinson[4] to predict rate constants of the OH-oxidation of VOCs. This kind of SAR is very easy to use and has been successfully integrated in chemical models[5, 6]. Concerning the reactivity of organic compounds with NO3 radicals, it has long been considered that the number of experimental data was not sufficient to use the approach proposed by Atkinson. But during the last decade, many experimental studies, in particular on the unsaturated oxygenated compounds, have enhanced the kinetic database on NO3-oxidation rate constants. This allowed us to develop a new SAR for the gas-phase reactions of NO3 with organic compounds which is based exclusively on correlations between the molecular structures and the rate constants. This new SAR is based on experimental rate constants of 150 molecules and has been developed for alkanes, alkenes (simple and cyclic alkenes, dienes and terpenes) and saturated and unsaturated oxygenated species (alcohols, carbonyls, ethers and esters). Results and performances of this SAR will be discussed here. References [1] Geyer, A., et al., J. Geophys. Res., 108 (2003), 4368. [2] Grosjean, D. and E.L. Williams, Atmospheric Environment. Part A. General Topics, 26 (1992), 1395-1405. [3] Pfrang, C., et al., Atmospheric Environment, 40 (2006), 1180-1186. [4] Kwok, E.S.C. and R. Atkinson, Atmospheric Environment, 29 (1995), 1685-1695. [5] Jenkin, M.E., S.M. Saunders, and M.J. Pilling, Atmospheric Environment, 31(1997), 81-104. [6] Aumont, B., S. Szopa, and S. Madronich, Atmospheric Chemistry and Physics, 5 (2005), 2497-2517.

  7. 17(R),18(S)-Epoxyeicosatetraenoic Acid, A Potent Eicosapentaenoic Acid (EPA)-Derived Regulator of Cardiomyocyte Contraction: Structure-Activity Relationships and Stable Analogs

    PubMed Central

    Falck, John R.; Wallukat, Gerd; Puli, Narender; Goli, Mohan; Arnold, Cosima; Konkel, Anne; Rothe, Michael; Fischer, Robert; Müller, Dominik N.; Schunck, Wolf-Hagen

    2011-01-01

    17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca2+-overload with an EC50 ~1–2 nM. Structure-activity studies revealed a cis-?11,12- or ?14,15-olefin and a 17(R),18(S)-epoxide are minimal structural elements for anti-arrhythmic activity whereas antagonist activity was often associated with the combination of a ?14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogs are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates. PMID:21591683

  8. Application of "Hydrogen-Bonding Interaction" in Drug Design. Part 2: Design, Synthesis, and Structure-Activity Relationships of Thiophosphoramide Derivatives as Novel Antiviral and Antifungal Agents.

    PubMed

    Lu, Aidang; Ma, Yuanyuan; Wang, Ziwen; Zhou, Zhenghong; Wang, Qingmin

    2015-11-01

    On the basis of the structure of natural product harmine, lead compound 18, and the structure of compounds in part 1, a series of thiophosphoramide derivatives 1-17 were designed and synthesized from various amines in one step. Their antiviral and antifungal activities were evaluated. Most of the compounds showed significantly higher antiviral activity against tobacco mosaic virus (TMV) than commercial virucide ribavirin. Compound (R,R)-17 showed the best anti-TMV activity in vitro (70%/500 ?g/mL and 33%/100 ?g/mL) and in vivo (inactivation effect, 68%/500 ?g/mL and 30%/100 ?g/mL; curative effect, 64%/500 ?g/mL and 31%/100 ?g/mL; protection effect, 66%/500 ?g/mL and 31%/100 ?g/mL), which is higher than that of ningnanmycin and lead compound 18. The antiviral activity of (R,R)-17·HCl is about similar to that of (R,R)-17. However, the antifungal activity of (R,R)-17·HCl against Puccinia sorghi is slightly lower than that of (R,R)-17. The systematic study provides compelling evidence that these simple thiophosphoramide compounds could become efficient antiviral and antifungal agents. PMID:26485246

  9. Quantitative structure-activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella typhimurium TA100

    SciTech Connect

    Debnath, A.K.; Hansch, C. ); Shusterman, A.J. ); Lopez de Compadre, R.L. )

    1992-01-01

    A quantitative structure-activity relationship (QSAR) has been derived for the mutagenic activity of 117 aromatic and heteroaromatic nitro compounds acting on Salmonella typhimurium TA100. Relative mutagenic activity is bilinearly dependent on hydrophobicity, with an optimal log P of 5.44, and is linearly dependent on the energy of the lowest unoccupied molecular orbital of the nitro compound. The dependence of mutagenic activity on hydrophobicity and electronic effects is very similar for TA98 and TA100. Mutagenic activity in TA100 does not depend on the size of the aromatic ring system, as it does in TA98. The effect of the choice of assay organism, TA98 versus TA100, on nitroarene QSAR is seen to be similar to the effect previously found for aminoarenes. Lateral verification of QSARs is presented as a tool for establishing the significance of a new QSAR.

  10. Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.

    PubMed

    Li, Zheng; Wang, Xuekun; Xu, Xue; Yang, Jianyong; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai

    2015-10-15

    The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice. PMID:26420383

  11. Design, synthesis, and structure-activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists.

    PubMed

    Hasui, Tomoaki; Ohra, Taiichi; Ohyabu, Norio; Asano, Kouhei; Matsui, Hideki; Mizukami, Atsushi; Habuka, Noriyuki; Sogabe, Satoshi; Endo, Satoshi; Siedem, Christopher S; Tang, Tony P; Gauthier, Cassandra; De Meese, Lisa A; Boyd, Steven A; Fukumoto, Shoji

    2013-10-01

    Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR). PMID:23958516

  12. Relationship between potential platelet activation and LCS

    NASA Astrophysics Data System (ADS)

    Shadden, Shawn

    2010-11-01

    In the study of blood flow, emphasis is often directed at understanding shear stress at the vessel wall due to its potentially disruptive influence on the endothelium. However, it is also known that shear stress has a potent effect on platelet activation. Platelet activation is a precursor for blood clotting, which in turn is the cause of most forms of death. Since most platelets are contained in the flow domain, it is important to consider stresses acting on the platelet as they are convected. Locations of high stress can correspond to boundaries between different dynamic regions and locations of hyperbolic points in the Eulerian sense. In the computation of LCS, strain in typically considered in the Lagrangian sense. In this talk we discuss the relationship between locations of potential platelet activation due to increased stress and locations of LCS marking increase Lagrangian deformation.

  13. Structure-toxicity relationships for phenols

    SciTech Connect

    Bearden, A.P.; Schultz, T.W.; Jaworska, J.S.

    1995-12-31

    Toxicity values for 45 phenols tested in the 2-d static population growth inhibition assay with the ciliate Tetrahymena pyriformis were tabulated. Each chemical was selected so the series formed uniform coverage of the hydrophobicity/ionization surface. A high quality hydrophobicity-dependent (log K{sub ow}) structure-toxicity relationship (log IGC{sub 50}{sup {minus}1} = 0.737 (log K{sub ow}) {minus} 1.440; n = 15, r{sup 2} = 0.093, s = 0.103, F = 758.29, Pr > F = 0.0001) was developed for phenols with pK{sub a} values > 9.4. Similarly, separate hydrophobicity-dependent relationships were developed for phenols with pK{sub a} values of 4.0, 5.1, 6.4, 7.5, and 8.7. Comparisons of intercepts and slopes, respectively, revealed phenols with pK{sub a},, values of 6.4 to be the most toxic and the least influenced by hydrophobicity. These relationships are reversed for the more acidic and basic phenols. Plots of toxicity versus pK{sub a} for nitro-substituted phenols and phenols with log K{sub ow} values of either 1.75 or 2.50 further demonstrated the parabolic relationship between toxicity and ionization constant. In an effort to more accurately model the parabolic-like relationship between toxicity and ionization, the bilinear function {vert_bar} 6.4 {minus} pK{sub a} {vert_bar} was used to model ionization effects for derivatives with pK{sub a} values of between 3.4 and 9.4. For derivatives with pK{sub a}, values < 3.4 and > 9.4, a value of 3.00 was used to quantitate ionization effects. The use of log K{sub ow} in conjunction with this modified pK{sub a} ({Delta} pK{sub a}) resulted in the structure-toxicity relationship (log IGC{sub 50}{sup {minus}1} = 0.574 (log K{sub ow}) {minus} 0.273 ({Delta} pK{sub a}) + 0.078; n = 45, r{sup 2}=0.902, s = 0.264, F = 193.06, Pr > F = 0.0001).

  14. Structure–activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme

    SciTech Connect

    Charton, Julie; Dumont, Julie; Liang, Wenguang G.; Leroux, Florence; Deprez, Benoit

    2015-10-30

    Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.

  15. Structure-function relationship of monocot mannose-binding lectins.

    PubMed Central

    Barre, A; Van Damme, E J; Peumans, W J; Rougé, P

    1996-01-01

    The monocot mannose-binding lectins are an extended superfamily of structurally and evolutionarily related proteins, which until now have been isolated from species of the Amaryllidaceae, Alliaceae, Araceae, Orchidaceae, and Liliaceae. To explain the obvious differences in biological activities, the structure-function relationships of the monocot mannose-binding lectins were studied by a combination of glycan-binding studies and molecular modeling using the deduced amino acid sequences of the currently known lectins. Molecular modeling indicated that the number of active mannose-binding sites per monomer varies between three and zero. Since the number of binding sites is fairly well correlated with the binding activity measured by surface plasmon resonance, and is also in good agreement with the results of previous studies of the biological activities of the mannose-binding lectins, molecular modeling is of great value for predicting which lectins are best suited for a particular application. PMID:8972598

  16. Structure-function relationships in dendrimer-encapsulated metal nanoparticles 

    E-print Network

    Wilson, Orla Mary

    2006-04-12

    The synthesis, characterization and structure-function relationships of mono- and bimetallic dendrimerencapsulated nanoparticles (DENs) are described. Control over the factors influencing the structure of bimetallic DENs ...

  17. Structure-Activity Relationship and Mode of Action of a Frog Secreted Antibacterial Peptide B1CTcu5 Using Synthetically and Modularly Modified or Deleted (SMMD) Peptides

    PubMed Central

    Abraham, Parvin; Sundaram, Anand; R, Asha; V, Reshmy; George, Sanil; Kumar, K. Santhosh

    2015-01-01

    All life forms are equipped with rapidly acting, evolutionally conserved components of an innate immune defense system that consists of a group of unique and diverse molecules known as host defense peptides (HDPs). A Systematic and Modular Modification and Deletion (SMMD) approach was followed to analyse the structural requirement of B1CTcu5, a brevinin antibacterial peptide amide identified from the skin secretion of frog Clinotarsus curtipes, India, to show antibacterial activity and to explore the active core region. Seventeen SMMD-B1CTcu5 analogs were designed and synthesised by C and N-terminal amino acid substitution or deletion. Enhancement in cationicity by N-terminal Lys/Arg substitution or hydrophobicity by Trp substitution produced no drastic change in bactericidal nature against selected bacterial strains except S. aureus. But the sequential removal of N-terminal amino acids had a negative effect on bactericidal potency. Analog B1CTcu5-LIAG obtained by the removal of four N-terminal amino acids displayed bactericidal effect comparable to, or in excess of, the parent peptide with reduced hemolytic character. Its higher activity was well correlated with the improved inner membrane permeabilisation capacity. This region may act as the active core of B1CTcu5. Presence of C-terminal disulphide bond was not a necessary condition to display antibacterial activity but helped to promote hemolytic nature. Removal of the C-terminal rana box region drastically reduced antibacterial and hemolytic activity of the peptide, showing that this region is important for membrane targeting. The bactericidal potency of the D-peptide (DB1CTcu5) helped to rule out the stereospecific interaction with the bacterial membrane. Our data suggests that both the C and N-terminal regions are necessary for bactericidal activity, even though the active core region is located near the N-terminal of B1CTcu5. A judicious modification at the N-terminal region may produce a short SMMD analog with enhanced bactericidal activity and low toxicity against eukaryotic cells. PMID:25997127

  18. Structure-Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents.

    PubMed

    Wang, Rubing; Chen, Chengsheng; Zhang, Xiaojie; Zhang, Changde; Zhong, Qiu; Chen, Guanglin; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2015-06-11

    Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner-Wadsworth-Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure-activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles. PMID:25961334

  19. Familial Identification: Population Structure and Relationship Distinguishability

    PubMed Central

    Rohlfs, Rori V.; Fullerton, Stephanie Malia; Weir, Bruce S.

    2012-01-01

    With the expansion of offender/arrestee DNA profile databases, genetic forensic identification has become commonplace in the United States criminal justice system. Implementation of familial searching has been proposed to extend forensic identification to family members of individuals with profiles in offender/arrestee DNA databases. In familial searching, a partial genetic profile match between a database entrant and a crime scene sample is used to implicate genetic relatives of the database entrant as potential sources of the crime scene sample. In addition to concerns regarding civil liberties, familial searching poses unanswered statistical questions. In this study, we define confidence intervals on estimated likelihood ratios for familial identification. Using these confidence intervals, we consider familial searching in a structured population. We show that relatives and unrelated individuals from population samples with lower gene diversity over the loci considered are less distinguishable. We also consider cases where the most appropriate population sample for individuals considered is unknown. We find that as a less appropriate population sample, and thus allele frequency distribution, is assumed, relatives and unrelated individuals become more difficult to distinguish. In addition, we show that relationship distinguishability increases with the number of markers considered, but decreases for more distant genetic familial relationships. All of these results indicate that caution is warranted in the application of familial searching in structured populations, such as in the United States. PMID:22346758

  20. Synthesis and structure-activity relationships of 1-aralkyl-4-benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent sigma ligands.

    PubMed

    Costantino, Luca; Gandolfi, Francesca; Sorbi, Claudia; Franchini, Silvia; Prezzavento, Orazio; Vittorio, Franco; Ronsisvalle, Giuseppe; Leonardi, Amedeo; Poggesi, Elena; Brasili, Livio

    2005-01-13

    In the attempt to define more accurately structure-affinity relationships for sigma(1) and sigma(2) ligands, we synthesized and tested on sigma subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a sigma(2)/sigma(1) selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to sigma(1) receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for sigma vs serotonin 5-HT(1A) and dopamine D(2) receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both sigma and 5-HT(1A) receptors, with K(i) in the nanomolar range, and are selective with respect to D(2) receptors. They displayed also a partial agonist profile in a human 5-HT(1A) [(35)S]GTP gamma S binding assay, suggesting their potential use as atypical antipsychotic agents. PMID:15634021

  1. What do sexually active adolescent females say about relationship issues?

    PubMed

    Bralock, Anita; Koniak-Griffin, Deborah

    2009-04-01

    Many sexually active teenagers face risk for contracting sexually transmitted infections (STIs) including HIV. The purpose of our study was to gain an understanding about influences on condom use among sexually active adolescents in relationships. Data were collected through semi-structured openended interviews. The findings of this study suggest that many adolescents desired the love of a male partner, and were willing to concede to his request of practicing unprotected sex. Findings support the urgent need for interventions that will promote skill-building techniques to negotiate safer sex behaviors among youth who are most likely to be exposed to STIs through risky behaviors. PMID:19268234

  2. Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate

    PubMed Central

    Woo, L W Lawrence; Wood, Paul M; Bubert, Christian; Thomas, Mark P; Purohit, Atul; Potter, Barry V L

    2013-01-01

    4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nm, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nm in the same assay. PMID:23495205

  3. Structure-antioxidant relationship of flavonoids from fermented rooibos.

    PubMed

    Krafczyk, Nicole; Woyand, Franziska; Glomb, Marcus A

    2009-05-01

    Rooibos tea (Aspalathus linearis) contains different bioactive phenolic compounds such as dihydrochalcones, flavonols, flavanones, flavones, and flavanols. Flavonoids isolated from rooibos were subjected to different in vitro assays: Trolox equivalent antioxidant activity, LDL oxidation and Fremy's salt assays to determine the total antioxidant activity (TAA). Assay results were compared, and the structure-antioxidant relationship was investigated. A decoupled LDL oxidation test was established with the objective of having an assay adapted more to an in vivo situation. The different in vitro methods were coupled offline to HPLC-DAD. Results from these coupled offline methods were compared to the TAA to assess the usefulness of the coupling setup. PMID:19156714

  4. Statistical Validation of Compound Structure-Selectivity Relationship Using NCI Cancer Database

    E-print Network

    Li, Jing

    1 Statistical Validation of Compound Structure-Selectivity Relationship Using NCI Cancer Database against specific cancers based on our statistical study is web-accessible. This method is superior, structure-activity relationship, compound fingerprint, growth inhibition, cancer cell line. Abstract

  5. Molecular Structures and Functional Relationships in Clostridial Neurotoxins

    SciTech Connect

    Swaminathan S.

    2011-12-01

    The seven serotypes of Clostridium botulinum neurotoxins (A-G) are the deadliest poison known to humans. They share significant sequence homology and hence possess similar structure-function relationships. Botulinum neurotoxins (BoNT) act via a four-step mechanism, viz., binding and internalization to neuronal cells, translocation of the catalytic domain into the cytosol and finally cleavage of one of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) causing blockage of neurotransmitter release leading to flaccid paralysis. Crystal structures of three holotoxins, BoNT/A, B and E, are available to date. Although the individual domains are remarkably similar, their domain organization is different. These structures have helped in correlating the structural and functional domains. This has led to the determination of structures of individual domains and combinations of them. Crystal structures of catalytic domains of all serotypes and several binding domains are now available. The catalytic domains are zinc endopeptidases and share significant sequence and structural homology. The active site architecture and the catalytic mechanism are similar although the binding mode of individual substrates may be different, dictating substrate specificity and peptide cleavage selectivity. Crystal structures of catalytic domains with substrate peptides provide clues to specificity and selectivity unique to BoNTs. Crystal structures of the receptor domain in complex with ganglioside or the protein receptor have provided information about the binding of botulinum neurotoxin to the neuronal cell. An overview of the structure-function relationship correlating the 3D structures with biochemical and biophysical data and how they can be used for structure-based drug discovery is presented here.