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Sample records for structure-activity relationship information

  1. Structure-activity relationships of bumetanide derivatives

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

    2015-01-01

    of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. EXPERIMENTAL APPROACH: In this study......, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its...... of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics....

  2. Quantitative Structure-Activity Relationship Analysis of the ...

    Erah

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

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

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

  4. Structure-activity relationship studies of citalopram derivatives

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

    2016-01-01

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

  5. Structure activity relationships to assess new chemicals under TSCA

    Auletta, A.E. [Environmental Protection Agency, Washington, DC (United States)

    1990-12-31

    Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the US Environmental Protection Agency (EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judgement of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of addition review of further testing. It should not be viewed as a replacement for testing. 4 tabs.

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

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

  7. 3-alkyl fentanyl analogues: Structure-activity-relationship study

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

    2012-01-01

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

  8. Structure-activity relationship of crustacean peptide hormones.

    Katayama, Hidekazu

    2016-01-01

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

  9. Structure and Structure-activity Relationship of Functional Organic Molecules

    2011-01-01

    @@ Research theme The group is made up of junior scientists from the State Key Laboratory of Elemento-organic Chemistry, Nankai University.The scientists focus their studis on the structure and structure-activity relationship of functional organic molecules not only because it has been the basis of their research, but also because the functional study of organic compounds is now a major scientific issue for organic chemists around the world.

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

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

    2009-01-01

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

  11. Chemistry and Structure-Activity Relationships of Psychedelics.

    Nichols, David E

    2018-01-01

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

  12. Structure-activity relationship of CART peptide fragments

    Maletínská, Lenka; Maixnerová, Jana; Hlaváček, Jan; Blokešová, Darja; Elbert, Tomáš; Šanda, Miloslav; Slaninová, Jiřina; Železná, Blanka

    2007-01-01

    Roč. 88, č. 4 (2007), s. 565 ISSN 0006-3525. [American Peptide Society Symposium /20./. 26.06.2007-30.06.2007, Montreal] Institutional research plan: CEZ:AV0Z40550506 Keywords : cocaine and amphetamine regulated transcript peptide * structure * activity Subject RIV: CE - Biochemistry

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

    Lorentz JÄNTSCHI

    2007-12-01

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

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

    Lorentz JÄNTSCHI

    2005-01-01

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

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

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

    2017-01-01

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

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

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

    2018-08-30

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

  17. Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

    Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

    2012-01-01

    Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range...... of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

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

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

    2013-01-01

    , and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i......) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr(5) was only 13-fold less...

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

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

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

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

    Schaefers, Christoph; Sanderson, Hans; Boshof, Udo

    2009-01-01

    Daphnia magna reproduction tests were performed with C10, C12, C14 and C15 alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test...

  1. 3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

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

    2003-10-20

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

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

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

    2009-10-01

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

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

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

    2008-01-01

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

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

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

    2009-07-01

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

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

    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.

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

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

    2017-07-01

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

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

    Bhore, N. A.

    1989-05-01

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

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

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

    2016-01-01

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

  9. Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

    Jambalsuren Bayarmaa

    2008-06-01

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

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

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

    2016-09-15

    target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action. Copyright © 2016 Murgatroyd et al.

  11. Structure-activity relationship of surfactant for preparing DMFC anodic catalyst

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

    2006-01-01

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

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

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

    2014-12-15

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

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

    Fernandes, Joao Paulo dos Santos; Savino, Giovanna; Amarante, Andre Cortinas Goncalves, E-mail: joao.fernandes@mackenzie.br [Centro de Ciencias Biologicas e da Saude, Universidade Presbiteriana Mackenzie, Sao Paulo, SP (Brazil); Sousa, Milena Rodrigues de; Silva, Geane Ramos da [Universidade Camilo Castelo Branco, Sao Paulo, SP (Brazil); Cianciulli, Maria Eliza [Universidade do Grande ABC, Santo Andre, SP (Brazil); Correa, Michelle Fidelis; Ferrarini, Marcio [Centro Universitario Sao Camilo, Sao Paulo, SP (Brazil)

    2013-09-01

    Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

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

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

    2012-01-01

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

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

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

    2013-01-01

    Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

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

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

    2017-12-01

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

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

    Emmy Tuenter

    2017-02-01

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

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

    Xiao, Xirui; Sankaranarayanan, Karthik; Khosla, Chaitan

    2017-10-01

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

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

    Bolboacă, Sorana D; Jäntschi, Lorentz

    2013-05-01

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

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

    Podunavac-Kuzmanović Sanja O.

    2007-01-01

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

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

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

    2007-01-01

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

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

    Dongmei Yang

    2016-11-01

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

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

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

    2003-01-01

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

  4. Benzazepines: Structure-activity relationships between D1 receptor blockade and selected pharmacological effects

    Iorio, L.C.; Billiard, W.; Gold, E.H.

    1986-01-01

    This chapter describes the displacement of 3 H-23390 and 3 H-spiperone binding by dopamine agonists and antagonists. The authors undertook an evaluation of the ability of selected analogs of SCH 23390 to displace 3 H-SCH 23390 and 3 H-spiperone. Structure-activity relationships of SCH 23390 analogs: 7-position substituents, is shown. It is shown that, in general, benzazepines with a variety of substituents in the 7-position retain their selectivity for D 1 sites. Substituents at the 8-position and at the N-position are also discussed. The authors determine a correlation between displacement of 3 H-SCH 23390 and blockade of dopamine-sensitive adenylate cyclase (DSAC). These effects and inhibition of conditioned avoidance responsing (CAS) in rats was also studied. A detailed evaluation is presented of the effects of SCH 23390 and haloperidol in the Inclined Screen and CAR tests

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

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

    2017-02-01

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

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

    Shanty, Angamaly Antony; Mohanan, Puzhavoorparambil Velayudhan

    2018-03-01

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

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

    Nakai, S; Li-Chan, E

    1985-10-01

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

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

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

    2006-11-01

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

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

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

    2006-01-01

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

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

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

    2017-06-15

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

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

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

    2015-09-01

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

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

    Paul Robert Martin Werfette

    2010-06-01

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

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

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

    1999-01-01

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

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

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

    2009-10-15

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

  15. Scalable total synthesis and comprehensive structure-activity relationship studies of the phytotoxin coronatine.

    Littleson, Mairi M; Baker, Christopher M; Dalençon, Anne J; Frye, Elizabeth C; Jamieson, Craig; Kennedy, Alan R; Ling, Kenneth B; McLachlan, Matthew M; Montgomery, Mark G; Russell, Claire J; Watson, Allan J B

    2018-03-16

    Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

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

    Sorana BOLBOACĂ

    2005-06-01

    Full Text Available The antituberculotic activity of some polyhydroxyxanthones was estimated using the Molecular Descriptors Family on Structure Activity Relationships methodology. From a total number of 298110 real and distinct calculated descriptors, 94843 were significantly different and entered into multiple linear regression analysis. The best performing bi-varied model was obtained by use of all polyhydroxyxanthones. The MDF SAR model was validated splitting the molecules into training and test sets. A correlated correlations analysis was applied in other to compare the MDF SAR models with the previous SAR model. The prediction ability of antituberculotic activity of polyhydroxyxanthones with MDF SAR methodology is sustained by three arguments: leave-one-out procedure, training vs. test procedure, and the correlated correlations analysis. Looking at the bi-varied MDF SAR model, we can conclude that the antituberculotic activity of polyhydroxyxanthones is almost of geometrical nature (99% and is strongly dependent on partial atomic charge and group electronegativity.

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

    Gabriel F. dos Santos

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

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

    Edilson Beserra Alencar Filho

    2017-04-01

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

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

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

    2013-07-08

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

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

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

    2017-06-07

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

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

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

    2017-09-20

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

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

    Yongzhou Hu

    2011-09-01

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

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

    Hui Zhang

    Full Text Available The structure-activity relationship of a U-type antimicrobial microemulsion system containing glycerol monolaurate and ethanol at a 1∶1 mass ratio as oil phase and Tween 20 as surfactant were investigated along a water dilution line at a ratio of 80∶20 mass% surfactant/oil phase, based on a pseudo-ternary phase diagram. The differential scanning calorimetry results showed that in the region of up to 33% water, all water molecules are confined to the hydrophilic core of the reverse micelles, leading to the formation of w/o microemulsion. As the water content increases, the water gains mobility, and transforms into bicontinuous in the region of 33-39% water, and finally the microemulsion become o/w in the region of above 39% water. The microstructure characterization was confirmed by the dynamic light scattering measurements and freeze-fracture transmission electron microscope observation. The antimicrobial activity assay using kinetics of killing analysis demonstrated that the microemulsions in w/o regions exhibited relatively high antimicrobial activity against Escherichia coli and Staphylococcus aureus due to the antimicrobial oil phase as the continuous phase, while the antimicrobial activity started to decrease when the microemulsions entered the bicontinuous region, and decreased rapidly as the water content increased in the o/w region, as a result of the dilution of antimicrobial oil droplets in the aqueous continuous phase.

  4. The uridine diphosphate glucuronosyltransferases: quantitative structure-activity relationships for hydroxyl polychlorinated biphenyl substrates

    Wang, Degao [Dalian University of Technology, Department of Environmental Science and Technology, Dalian (China)

    2005-10-01

    Quantitative structure-activity relationships (QSARs), which relate the glucuronidation of hydroxyl polychlorinated biphenyls (OH-PCBs) - catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs) - to their physicochemical properties and molecular structural parameters, can be used to predict the rate constants and interpret the mechanism of glucuronidation. In this study, QSARs have been developed that use 23 semi-empirical calculated quantum chemical descriptors to predict the logarithms of the constants 1/K{sub m} and V{sub max}, related to enzyme kinetics. A partial least squares regression method was used to select the optimal set of descriptors to minimize the multicollinearity between the descriptors, as well as to maximize the cross-validated coefficient (Q{sup 2} {sub cum}) values. The key descriptors affecting log(1/K{sub m}) were E{sub lumo}- E{sub homo} (the energy gap between the lowest unoccupied molecular orbital and the highest occupied molecular orbital) and q{sub C}{sup -} (the largest negative net atomic charge on a carbon atom), while the key descriptors affecting log V{sub max} were the polarizability {alpha}, the Connolly solvent-excluded volume (CSEV), and logP (the logarithm of the partition coefficient for octanol/water). From the results obtained it can be concluded that hydrophobic and electronic aspects of OH-PCBs are important in the glucuronidation of OH-PCBs. (orig.)

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

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

    2015-11-17

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

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

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

    2018-01-01

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

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

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

    2017-10-01

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

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

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

    2012-10-01

    Full Text Available Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR models were used to predict the residues of unknown pesticides in the milk of cattle using their known physicochemical properties such as molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w as well as the milk characteristics such as pH, % fat, and specific gravity (SG in this species. The analysis revealed good correlation coefficients (R2 = 0.91 for cattle QSAR model. The coefficient for Ko/w for the studied pesticides was higher in cattle milk. Risk analysis was conducted based upon the determined pesticide residues and their provisional tolerable daily intakes. The daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study were 3, 11, 2.5 times higher, respectively in cattle milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

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

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

    2016-02-03

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

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

    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

  11. Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors

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

    2018-03-01

    Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson’s disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM - 1 µM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

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

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

    2016-11-01

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

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

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

    2018-04-01

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

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

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

    2006-02-08

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

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

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

    2017-04-13

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

  16. Compound toxicity screening and structure-activity relationship modeling in Escherichia coli.

    Planson, Anne-Gaëlle; Carbonell, Pablo; Paillard, Elodie; Pollet, Nicolas; Faulon, Jean-Loup

    2012-03-01

    Synthetic biology and metabolic engineering are used to develop new strategies for producing valuable compounds ranging from therapeutics to biofuels in engineered microorganisms. When developing methods for high-titer production cells, toxicity is an important element to consider. Indeed the production rate can be limited due to toxic intermediates or accumulation of byproducts of the heterologous biosynthetic pathway of interest. Conversely, highly toxic molecules are desired when designing antimicrobials. Compound toxicity in bacteria plays a major role in metabolic engineering as well as in the development of new antibacterial agents. Here, we screened a diversified chemical library of 166 compounds for toxicity in Escherichia coli. The dataset was built using a clustering algorithm maximizing the chemical diversity in the library. The resulting assay data was used to develop a toxicity predictor that we used to assess the toxicity of metabolites throughout the metabolome. This new tool for predicting toxicity can thus be used for fine-tuning heterologous expression and can be integrated in a computational-framework for metabolic pathway design. Many structure-activity relationship tools have been developed for toxicology studies in eukaryotes [Valerio (2009), Toxicol Appl Pharmacol, 241(3): 356-370], however, to the best of our knowledge we present here the first E. coli toxicity prediction web server based on QSAR models (EcoliTox server: http://www.issb.genopole.fr/∼faulon/EcoliTox.php). Copyright © 2011 Wiley Periodicals, Inc.

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

    Mendenhall, Jeffrey; Meiler, Jens

    2016-02-01

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

  18. 6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

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

    2012-02-15

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

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

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

    2009-12-01

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

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

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

    2008-05-15

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

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

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

    2014-04-22

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

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

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

    2016-05-17

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

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

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

    2016-01-01

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

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

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

    2009-01-01

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

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

    Cunningham AlbertR

    2009-11-01

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

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

    Albert R. Cunningham

    2009-01-01

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

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

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

    1998-01-15

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

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

    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.

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

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

    2017-12-07

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

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

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

    2006-01-01

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

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

    Kaiser, K L E

    2007-01-01

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

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

    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 lipofection increased linearly with LI (EGFP approximately 0 for LI 29, thus providing a predictive design rule based on Log P of the hydrophobic moiety of the cationic steroid lipid. Copyright (c) 2007 John Wiley & Sons, Ltd.

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

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

    2013-01-04

    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.

  14. Quantitative Structure Activity Relationship and Risk Analysis of Some Pesticides in the Goat milk

    Faqir Muhammad

    2013-01-01

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

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

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

    2013-01-01

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

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

    Punit P Seth

    2012-01-01

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

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

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

    1990-01-01

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

  18. QUANTITAVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR OF ANTIMALARIAL 1,10-PHENANTHROLINE DERIVATIVES COMPOUNDS

    Ruslin Hadanu

    2010-06-01

    Full Text Available Quantitative Electronic Structure-Activity Relationship (QSAR analysis of a series of 1,10-phenanthroline derivatives as antiplasmodial compounds have been conducted using atomic net charges (q, dipole moment (μ ELUMO, EHOMO, polarizability (α and log P as the descriptors. The descriptors were obtained from computational chemistry method using semi-empirical PM3. Antiplasmodial activities were taken as the activity of the drugs  against  chloroquine-resistant Plasmodium falciparum FCR3 strain and are presented as the value of ln (1/IC50 where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best model of QSAR model was determine by multiple linear regression method and giving equation of QSAR: ln 1/IC50  =  3.732 + (5.098 qC5 + (7.051 qC7 + (36.696 qC9 + (41.467 qC11 -(135.497 qC12 + (0.332 μ -                    (0.170 α + (0.757 log P. The equation was significant on the 95% level with statistical parameters: n=16; r=0.987; r2= 0.975; SE=0.317;  Fcalc/Ftable = 15.337 and gave the PRESS=0.707. Its means that there were only a relatively few deviations between the experimental and theoretical data of antimalarial activity.   Keywords: QSAR, antimalarial, semi-empirical method, 1,10-phenanthroline.

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

    Sharifuddin M. Zain

    2011-11-01

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

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

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

    2017-01-01

    that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery...

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

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

    2009-01-01

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

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

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

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

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

    2016-01-01

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

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

    Li-Wei Zou

    2017-06-01

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

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

    Gullbo Joachim

    2009-06-01

    ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. Conclusion According to this structure-activity relationship (SAR study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

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

    Lorentz JÄNTSCHI

    2006-01-01

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

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

    Guangchao Chen

    2017-08-01

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

  8. A Structure-Activity Relationship (SAR Study of Neolignan Compounds with Anti-schistosomiasis Activity

    Alves Claúdio N.

    2002-01-01

    Full Text Available A set of eighteen neolignan derivative compounds with anti-schistosomiasis activity was studied by using the quantum mechanical semi-empirical method PM3 and other theoretical methods in order to calculate selected molecular properties (variables or descriptors to be correlated to their biological activities. Exploratory data analysis (principal component analysis, PCA, and hierarchical cluster analysis, HCA, discriminant analysis (DA and the Kth nearest neighbor (KNN method were employed for obtaining possible relationships between the calculated descriptors and the biological activities studied and predicting the anti-schistosomiasis activity of new compounds from a test set. The molecular descriptors responsible for the separation between active and inactive compounds were: hydration energy (HE, molecular refractivity (MR and charge on the C19 carbon atom (Q19. These descriptors give information on the kind of interaction that can occur between the compounds and their respective biological receptor. The prediction study was done with a new set of ten derivative compounds by using the PCA, HCA, DA and KNN methods and only five of them were predicted as active against schistosomiasis.

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

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

    2010-01-20

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

  10. Obscure phenomena in statistical analysis of quantitative structure-activity relationships. Part 1: Multicollinearity of physicochemical descriptors.

    Mager, P P; Rothe, H

    1990-10-01

    Multicollinearity of physicochemical descriptors leads to serious consequences in quantitative structure-activity relationship (QSAR) analysis, such as incorrect estimators and test statistics of regression coefficients of the ordinary least-squares (OLS) model applied usually to QSARs. Beside the diagnosis of the known simple collinearity, principal component regression analysis (PCRA) also allows the diagnosis of various types of multicollinearity. Only if the absolute values of PCRA estimators are order statistics that decrease monotonically, the effects of multicollinearity can be circumvented. Otherwise, obscure phenomena may be observed, such as good data recognition but low predictive model power of a QSAR model.

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

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

    2017-08-01

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

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

    Li, Minyong; Xia, Lin

    2007-11-01

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

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

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

    2009-01-30

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

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

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

    2017-10-01

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

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

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

    2010-01-01

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

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

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

    2010-08-15

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

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

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

    2017-12-04

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

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

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

    2018-05-24

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

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

    Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2013-11-01

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

  20. Information Systems Outsourcing Relationship Model

    Richard Flemming

    2007-09-01

    Full Text Available Increasing attention is being paid to what determines the success of an information systems outsourcing arrangement. The current research aims to provide an improved understanding of the factors influencing the outcome of an information systems outsourcing relationship and to provide a preliminary validation of an extended outsourcing relationship model by interviews with information systems outsourcing professionals in both the client and vendor of a major Australian outsourcing relationship. It also investigates whether the client and the vendor perceive the relationship differently and if so, how they perceive it differently and whether the two perspectives are interrelated.

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

    Barratt, Martin D

    2004-11-01

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

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

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

    2017-04-01

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

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

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

    2017-12-01

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

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

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

    2003-08-01

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

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

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

    2012-01-01

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

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

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

    2005-01-01

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

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

    Sıdır, Yadigar Gülseven; Sıdır, İsa

    2013-08-01

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

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

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

    2017-01-05

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

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

    Ysabel Santos

    2013-01-01

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

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

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

    2012-06-01

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

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

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

    2008-10-01

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

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

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

    2016-04-01

    α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1' and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50=1.32±0.26μM, 1.88±0.35μM and 1.52±0.31μM, respectively) and favorable CC50 values (CC50>100μM). α-Keto amide may represent a good choice as a warhead for EV71 3C(pro) inhibitor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Structure-Activity Relationship of α Mating Pheromone from the Fungal Pathogen Fusarium oxysporum.

    Vitale, Stefania; Partida-Hanon, Angélica; Serrano, Soraya; Martínez-Del-Pozo, Álvaro; Di Pietro, Antonio; Turrà, David; Bruix, Marta

    2017-03-03

    During sexual development ascomycete fungi produce two types of peptide pheromones termed a and α. The α pheromone from the budding yeast Saccharomyces cerevisiae , a 13-residue peptide that elicits cell cycle arrest and chemotropic growth, has served as paradigm for the interaction of small peptides with their cognate G protein-coupled receptors. However, no structural information is currently available for α pheromones from filamentous ascomycetes, which are significantly shorter and share almost no sequence similarity with the S. cerevisiae homolog. High resolution structure of synthetic α-pheromone from the plant pathogenic ascomycete Fusarium oxysporum revealed the presence of a central β-turn resembling that of its yeast counterpart. Disruption of the-fold by d-alanine substitution of the conserved central Gly 6 -Gln 7 residues or by random sequence scrambling demonstrated a crucial role for this structural determinant in chemoattractant activity. Unexpectedly, the growth inhibitory effect of F. oxysporum α-pheromone was independent of the cognate G protein-coupled receptors Ste2 and of the central β-turn but instead required two conserved Trp 1 -Cys 2 residues at the N terminus. These results indicate that, despite their reduced size, fungal α-pheromones contain discrete functional regions with a defined secondary structure that regulate diverse biological processes such as polarity reorientation and cell division. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

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

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

    2013-10-30

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

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

    Eliška Potůčková

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

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

    Hui Wang

    2016-11-01

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

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

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

    2017-01-15

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

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

    Yilmaz, Hayriye; Rasulev, Bakhtiyor; Leszczynski, Jerzy

    2015-01-01

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

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

    Hayriye Yilmaz

    2015-05-01

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

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

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

    2015-08-01

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

  1. Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

    Soliman, Wael; Wang, Liru; Bhattacharjee, Subir; Kaur, Kamaljit

    2011-04-14

    Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (Pls), against four pathogenic gram-positive bacteria, including Listeria monocytogenes. The structure-activity relationships for Pls were studied using activity assays, circular dichroism (CD), and molecular dynamics (MD) simulations. The two Pls peptides and five Pls derived fragments were synthesized. The CD spectra of the Pls and selected fragments revealed helical conformations in aqueous 2,2,2-trifluoroethanol. The MD simulations showed that when the two Pls peptides are in antiparallel orientation, the helical regions interact and align, mediated by strong attraction between conserved GxxxG/AxxxA motifs. The results strongly correlate with the antimicrobial activity suggesting that helix-helix alignment of the two Pls peptides and interaction between the conserved motifs are crucial for interaction with the target cell membrane.

  2. Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities.

    Bahl, Deepa; Athar, Fareeda; Soares, Milena Botelho Pereira; de Sá, Matheus Santos; Moreira, Diogo Rodrigo Magalhães; Srivastava, Rajendra Mohan; Leite, Ana Cristina Lima; Azam, Amir

    2010-09-15

    A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells. Copyright (c) 2010. Published by Elsevier Ltd.

  3. Determination of boiling point of petrochemicals by gas chromatography-mass spectrometry and multivariate regression analysis of structural activity relationship.

    Fakayode, Sayo O; Mitchell, Breanna S; Pollard, David A

    2014-08-01

    Accurate understanding of analyte boiling points (BP) is of critical importance in gas chromatographic (GC) separation and crude oil refinery operation in petrochemical industries. This study reported the first combined use of GC separation and partial-least-square (PLS1) multivariate regression analysis of petrochemical structural activity relationship (SAR) for accurate BP determination of two commercially available (D3710 and MA VHP) calibration gas mix samples. The results of the BP determination using PLS1 multivariate regression were further compared with the results of traditional simulated distillation method of BP determination. The developed PLS1 regression was able to correctly predict analytes BP in D3710 and MA VHP calibration gas mix samples, with a root-mean-square-%-relative-error (RMS%RE) of 6.4%, and 10.8% respectively. In contrast, the overall RMS%RE of 32.9% and 40.4%, respectively obtained for BP determination in D3710 and MA VHP using a traditional simulated distillation method were approximately four times larger than the corresponding RMS%RE of BP prediction using MRA, demonstrating the better predictive ability of MRA. The reported method is rapid, robust, and promising, and can be potentially used routinely for fast analysis, pattern recognition, and analyte BP determination in petrochemical industries. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Discovery and structure-activity relationships study of thieno[2,3-b]pyridine analogues as hepatic gluconeogenesis inhibitors.

    Ma, Fei; Liu, Jian; Zhou, Tingting; Lei, Min; Chen, Jing; Wang, Xiachang; Zhang, Yinan; Shen, Xu; Hu, Lihong

    2018-05-25

    Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC 50  = 33.8 μM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF 3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC 50  = 16.8 μM) and 9d (IC 50  = 12.3 μM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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

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

    2017-06-07

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

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

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

    2011-01-15

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

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

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

    2016-08-01

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

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

    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.

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

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

    2014-05-05

    Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees.

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

    Thiago R. Morais

    2014-05-01

    Full Text Available Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae, and nine semi-synthetic derivatives were investigated against Leishmania (L. infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR data as well as electrospray ionization mass spectrometry (ESI-MS. Additionally, structure-activity relationships were performed using Decision Trees.

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

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

    2015-11-15

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

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

    Iqmal Tahir

    2010-06-01

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

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

    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.

  14. Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

    Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

    2013-09-01

    Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone.

  15. Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.

    Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V; Tekwani, Babu L; Madgula, Vamsi; Khan, Shabana I; Wang, Bin; Mayer, Alejandro M S; Jacob, Melissa R; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T

    2010-01-14

    Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

  16. Dihydro-β-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

    Núñez, Marvin J; Jiménez, Ignacio A; Mendoza, Cristina R; Chavez-Sifontes, Marvin; Martinez, Morena L; Ichiishi, Eiichiro; Tokuda, Ryo; Tokuda, Harukuni; Bazzocchi, Isabel L

    2016-03-23

    Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-β-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of β-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

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

    1994-10-14

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

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

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

    2014-02-01

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

  19. Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

    Dostanić, J., E-mail: jasmina@nanosys.ihtm.bg.ac.rs [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Lončarević, D. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Zlatar, M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade (Serbia); Vlahović, F. [University of Belgrade, Innovation center of the Faculty of Chemistry, 11000 Belgrade (Serbia); Jovanović, D.M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia)

    2016-10-05

    Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ{sub p} constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ{sub p} constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO{sub 2} photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

  20. Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

    Dostanić, J.; Lončarević, D.; Zlatar, M.; Vlahović, F.; Jovanović, D.M.

    2016-01-01

    Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ_p constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ_p constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO_2 photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

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

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

    2009-01-15

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

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

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

    2015-01-28

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

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

    Samir Chtita

    2016-01-01

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

  4. Stereodivergent Synthesis of 1,3-Syn-Polyol Natural Product for Stereochemical-Based Structure Activity Relationship Studies

    Zheng, Jiamin

    The 1,3-syn-diol functionality is very common in many natural products. An important class containing this moiety are the 1,3-syn-polyol/pyranone natural products, which have been isolated from a variety of plant sources, and possess biological activities like plant growth inhibition as well as antifeedant, antifungal, antibacterial, and antitumor properties. The feature of this class is a 6-membered lactone where the lactoe oxygen is part of a 1,3-syn-diol motif. To pursue the 1,3-syn-polyol/pyranone natural products, an iterative hydration of polyene strategy was utilized to provide the 1,3- syn-diol functionality, and asymmetric synthetic strategies were explored to form the requisite stereochemistry. The versatility of the asymmetric approach was demonstrated in the synthesis of eupatorium pyranone and also in an ongoing project aimed at the synthesis of SIA7248. As an outgrowth of our work on the total syntheses of 1,3-syn -polyol natural products inspired a stereo-divergent synthesis of 1,3-syn-polyol natural products and their analogs for stereochemical-based structure-activity relationship (SSAR) studies. To identify the key structural factors important for the anticancer activity of the 1,3-syn-polyol/pyranones, a stereo-divergent 16-member library of pyranone/polyol congeners was designed, synthesized and tested with variations in both stereochemistry and numbers of polyol repeat units. Having access to stereochemical isomers of the biologically active natural products allowed us to design experiments that help illustrate their mechanisms of action.

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

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

    2015-04-15

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

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

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

    1991-01-01

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

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

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

    2008-05-01

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

  8. Quantitative structure-activity relationship study of antioxidative peptide by using different sets of amino acids descriptors

    Li, Yao-Wang; Li, Bo; He, Jiguo; Qian, Ping

    2011-07-01

    A database consisting of 214 tripeptides which contain either His or Tyr residue was applied to study quantitative structure-activity relationships (QSAR) of antioxidative tripeptides. Partial Least-Squares Regression analysis (PLSR) was conducted using parameters individually of each amino acid descriptor, including Divided Physico-chemical Property Scores (DPPS), Hydrophobic, Electronic, Steric, and Hydrogen (HESH), Vectors of Hydrophobic, Steric, and Electronic properties (VHSE), Molecular Surface-Weighted Holistic Invariant Molecular (MS-WHIM), isotropic surface area-electronic charge index (ISA-ECI) and Z-scale, to describe antioxidative tripeptides as X-variables and antioxidant activities measured with ferric thiocyanate methods were as Y-variable. After elimination of outliers by Hotelling's T 2 method and residual analysis, six significant models were obtained describing the entire data set. According to cumulative squared multiple correlation coefficients ( R2), cumulative cross-validation coefficients ( Q2) and relative standard deviation for calibration set (RSD c), the qualities of models using DPPS, HESH, ISA-ECI, and VHSE descriptors are better ( R2 > 0.6, Q2 > 0.5, RSD c 0.44). Furthermore, the predictive ability of models using DPPS descriptor is best among the six descriptors systems (cumulative multiple correlation coefficient for predict set ( Rext2) > 0.7). It was concluded that the DPPS is better to describe the amino acid of antioxidative tripeptides. The results of DPPS descriptor reveal that the importance of the center amino acid and the N-terminal amino acid are far more than the importance of the C-terminal amino acid for antioxidative tripeptides. The hydrophobic (positively to activity) and electronic (negatively to activity) properties of the N-terminal amino acid are suggested to play the most important significance to activity, followed by the hydrogen bond (positively to activity) of the center amino acid. The N-terminal amino acid

  9. The influence of R and S configurations of a series of amphetamine derivatives on quantitative structure-activity relationship models

    Fresqui, Maira A.C., E-mail: maira@iqsc.usp.br [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil); Ferreira, Marcia M.C., E-mail: marcia@iqm.unicamp.br [Institute of Chemistry, University of Campinas - UNICAMP, POB 6154, 13083-970 Campinas, SP (Brazil); Trsic, Milan, E-mail: cra612@gmail.com [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil)

    2013-01-08

    Highlights: Black-Right-Pointing-Pointer The QSAR model is not dependent of ligand conformation. Black-Right-Pointing-Pointer Amphetamines were analyzed by quantum chemical, steric and hydrophobic descriptors. Black-Right-Pointing-Pointer CHELPG atomic charges on the benzene ring are one of the most important descriptors. Black-Right-Pointing-Pointer The PLS models built were extensively validated. Black-Right-Pointing-Pointer Manual docking supports the QSAR results by pi-pi stacking interactions. - Abstract: Chiral molecules need special attention in drug design. In this sense, the R and S configurations of a series of thirty-four amphetamines were evaluated by quantitative structure-activity relationship (QSAR). This class of compounds has antidepressant, anti-Parkinson and anti-Alzheimer effects against the enzyme monoamine oxidase A (MAO A). A set of thirty-eight descriptors, including electronic, steric and hydrophobic ones, were calculated. Variable selection was performed through the correlation coefficients followed by the ordered predictor selection (OPS) algorithm. Six descriptors (CHELPG atomic charges C3, C4 and C5, electrophilicity, molecular surface area and log P) were selected for both configurations and a satisfactory model was obtained by PLS regression with three latent variables with R{sup 2} = 0.73 and Q{sup 2} = 0.60, with external predictability Q{sup 2} = 0.68, and R{sup 2} = 0.76 and Q{sup 2} = 0.67 with external predictability Q{sup 2} = 0.50, for R and S configurations, respectively. To confirm the robustness of each model, leave-N-out cross validation (LNO) was carried out and the y-randomization test was used to check if these models present chance correlation. Moreover, both automated or a manual molecular docking indicate that the reaction of ligands with the enzyme occurs via pi-pi stacking interaction with Tyr407, inclined face-to-face interaction with Tyr444, while aromatic hydrogen-hydrogen interactions with Tyr197 are preferable

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

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

    2017-01-01

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

  11. Polybrominated diphenyl ether (PBDE) effects in rat neuronal cultures: 14C-PBDE accumulation, biological effect, and structure-activity relationships

    Kodavanti, P.R.; Ward, T. [Neurotoxicology Div., NHEERL/ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Burka, T. [National Insts. of Environmental Health Sciences, Research Triangle Park, NC (United States); Ludewig, G.; Robertson, L. [The Univ. of Iowa Coll. of Public Health, Iowa City, IA (United States); Birnbaum, L. [Experimental Toxicology Div., NHEERL/ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States)

    2004-09-15

    Polybrominated diphenyl ethers (PBDEs) are used as flame-retardants in many types of consumer products such as electrical equipment, plastics, and building materials. PBDEs are structurally similar to dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs). PBDEs are now ubiquitous; they can be found in air, water, fish, birds, marine mammals, and humans, and in many cases, they are increasing over time. In spite of their widespread occurrence in the environment, only limited information is available on the toxicology of PBDEs. Recent studies showed that PBDE exposure caused aberrations in spontaneous behavior and reduced learning and memory in mice these effects are similar to those seen after exposure to DDT or PCBs. However, the mode of action for this group of chemicals remains unclear. Previously, we demonstrated that PCBs, which are known to cause neurotoxic effects, affected intracellular signaling pathways including [{sup 3}H]arachidonic acid ([{sup 3}H]AA) release, calcium homeostasis, and translocation of protein kinase C (PKC). Regarding PBDEs, we have reported that PBDEs altered [{sup 3}H]AA release in neuronal cultures like PCBs. These signaling pathways have been associated with learning and memory, and the development of the nervous system. The objectives of the present study were to test: (a) whether biologically relevant PBDE congeners affected PKC translocation in neuronal cultures in a similar way to those of other organohalogens; (b) compare the potency and efficacy of PBDE congeners with their 14C-accumulation; and (c) understand the structure-activity relationships among PBDE congeners.

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

    Yongcheng Lin

    2011-10-01

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

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

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

    2017-03-01

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

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

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

    2005-10-01

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

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

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

    2002-01-07

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

  16. Interaction of cholesterol-conjugated ionizable amino lipids with biomembranes: lipid polymorphism, structure-activity relationship, and implications for siRNA delivery.

    Zhang, Jingtao; Fan, Haihong; Levorse, Dorothy A; Crocker, Louis S

    2011-08-02

    Delivery of siRNA is a major obstacle to the advancement of RNAi as a novel therapeutic modality. Lipid nanoparticles (LNP) consisting of ionizable amino lipids are being developed as an important delivery platform for siRNAs, and significant efforts are being made to understand the structure-activity relationship (SAR) of the lipids. This article uses a combination of small-angle X-ray scattering (SAXS) and differential scanning calorimetry (DSC) to evaluate the interaction between cholesterol-conjugated ionizable amino lipids and biomembranes, focusing on an important area of lipid SAR--the ability of lipids to destabilize membrane bilayer structures and facilitate endosomal escape. In this study, cholesterol-conjugated amino lipids were found to be effective in increasing the order of biomembranes and also highly effective in inducing phase changes in biological membranes in vitro (i.e., the lamellar to inverted hexagonal phase transition). The phase transition temperatures, determined using SAXS and DSC, serve as an indicator for ranking the potency of lipids to destabilize endosomal membranes. It was found that the bilayer disruption ability of amino lipids depends strongly on the amino lipid concentration in membranes. Amino lipids with systematic variations in headgroups, the extent of ionization, tail length, the degree of unsaturation, and tail asymmetry were evaluated for their bilayer disruption ability to establish SAR. Overall, it was found that the impact of these lipid structure changes on their bilayer disruption ability agrees well with the results from a conceptual molecular "shape" analysis. Implications of the findings from this study for siRNA delivery are discussed. The methods reported here can be used to support the SAR screening of cationic lipids for siRNA delivery, and the information revealed through the study of the interaction between cationic lipids and biomembranes will contribute significantly to the design of more efficient si

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

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

    2016-07-25

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

  18. Identification of residues important for the activity of aldehyde-deformylating oxygenase through investigation into the structure-activity relationship.

    Wang, Qing; Bao, Luyao; Jia, Chenjun; Li, Mei; Li, Jian-Jun; Lu, Xuefeng

    2017-03-16

    Aldehyde-deformylating oxygenase (ADO) is a key enzyme involved in the biosynthetic pathway of fatty alk(a/e)nes in cyanobacteria. However, cADO (cyanobacterial ADO) showed extreme low activity with the k cat value below 1 min -1 , which would limit its application in biofuel production. To identify the activity related key residues of cADO is urgently required. The amino acid residues which might affect cADO activity were identified based on the crystal structures and sequence alignment of cADOs, including the residues close to the di-iron center (Tyr39, Arg62, Gln110, Tyr122, Asp143 of cADO-1593), the protein surface (Trp 178 of cADO-1593), and those involved in two important hydrogen bonds (Gln49, Asn123 of cADO-1593, and Asp49, Asn123 of cADO-sll0208) and in the oligopeptide whose conformation changed in the absence of the di-iron center (Leu146, Asn149, Phe150 of cADO-1593, and Thr146, Leu148, Tyr150 of cADO-sll0208). The variants of cADO-1593 from Synechococcus elongatus PCC7942 and cADO-sll0208 from Synechocystis sp. PCC6803 were constructed, overexpressed, purified and kinetically characterized. The k cat values of L146T, Q49H/N123H/F150Y and W178R of cADO-1593 and L148R of cADO-sll0208 were increased by more than two-fold, whereas that of R62A dropped by 91.1%. N123H, Y39F and D143A of cADO-1593, and Y150F of cADO-sll0208 reduced activities by ≤ 20%. Some important amino acids, which exerted some effects on cADO activity, were identified. Several enzyme variants exhibited greatly reduced activity, while the k cat values of several mutants are more than two-fold higher than the wild type. This study presents the report on the relationship between amino acid residues and enzyme activity of cADOs, and the information will provide a guide for enhancement of cADO activity through protein engineering.

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

    Sangeetha, M.; Mathammal, R.

    2018-02-01

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

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

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

    2015-07-15

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

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

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

    2007-09-01

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

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

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

    2015-01-01

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

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

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

    2018-05-25

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

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

    Norinder, U; Högberg, T

    1992-04-01

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

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

    Gimenéz-Arnau, Elena; Andersen, K E; Bruze, M

    2000-01-01

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

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

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

    2016-10-01

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

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

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

    2012-01-01

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

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

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

    2000-12-01

    Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

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

    Salahinejad, M.; Mirshojaei, S.F.

    2016-01-01

    This study aims to establish molecular modeling methods for predicting the liver and kidney uptakes of Tc-99m labeled quinolone antibiotics. Some three-dimensional quantitative-activity relationships (3D-QSAR) models were developed using comparative molecular field analysis and grid-independent descriptors procedures. As a first report on 3D-QSAR modeling, the predicted liver and kidney uptakes for quinolone antibiotics were in good agreement with the experimental values. The obtained results confirm the importance of hydrophobic interactions, size and steric hindrance of antibiotic molecules in their liver uptakes, while the electrostatic interactions and hydrogen bonding ability have impressive effects on their kidney uptakes. (author)

  10. Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.

    Perucca, Paola; Savio, Monica; Cazzalini, Ornella; Mocchi, Roberto; Maccario, Cristina; Sommatis, Sabrina; Ferraro, Daniela; Pizzala, Roberto; Pretali, Luca; Fasani, Elisa; Albini, Angelo; Stivala, Lucia Anna

    2014-11-01

    The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

    Stefanie Zimmermann

    2014-03-01

    Full Text Available Sesquiterpene lactones (STLs are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness and mammalian cancer cells (rat bone myoblast L6 cells. It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethylacrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

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

    Tian, Dayong; Lin, Zhifen; Yin, Daqiang

    2013-01-01

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

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

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

    2015-12-15

    Quantitative structure–activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application.

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

    Chen, Baiyang; Zhang, Tian; Bond, Tom; Gan, Yiqun

    2015-01-01

    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.

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

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

    2017-12-01

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

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

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

    2014-02-15

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

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

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

    2007-01-01

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

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

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

    2014-02-03

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

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

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

    2016-01-01

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

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

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

    2013-07-01

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

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

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

    2001-03-01

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

  2. Inhibition of 125I-labeled ristocetin binding to Micrococcus luteus cells by the peptides related to bacterial cell wall mucopeptide precursors: quantitative structure-activity relationships

    Kim, K.H.; Martin, Y.; Otis, E.; Mao, J.

    1989-01-01

    Quantitative structure-activity relationships (QSAR) of N-Ac amino acids, N-Ac dipeptides, and N-Ac tripeptides in inhibition of 125 I-labeled ristocetin binding to Micrococcus luteus cell wall have been developed to probe the details of the binding between ristocetin and N-acetylated peptides. The correlation equations indicate that (1) the binding is stronger for peptides in which the side chain of the C-terminal amino acid has a large molar refractivity (MR) value, (2) the binding is weaker for peptides with polar than for those with nonpolar C-terminal side chains, (3) the N-terminal amino acid in N-Ac dipeptides contributes 12 times that of the C-terminal amino acid to binding affinity, and (4) the interactions between ristocetin and the N-terminal amino acid of N-acetyl tripeptides appear to be much weaker than those with the first two amino acids

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

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

    2000-01-01

    Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application......" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance...

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

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

    2015-05-08

    A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

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

    Shijie Du

    2015-05-01

    Full Text Available A series of novel 3-(difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-ylphenyl-3-(difluoro-methyl-1-methyl-1H-pyrazole-4-carboxamide (9m exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

  6. Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist.

    Dolciami, Daniela; Gargaro, Marco; Cerra, Bruno; Scalisi, Giulia; Bagnoli, Luana; Servillo, Giuseppe; Fazia, Maria Agnese Della; Puccetti, Paolo; Quintana, Francisco J; Fallarino, Francesca; Macchiarulo, Antonio

    2018-02-06

    Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    APURBA K. BHATTACHARJEE

    2005-03-01

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

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

    Chiara Cheng Lim

    2009-03-01

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

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

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

    2014-05-22

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

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

    Utpal Chandra De

    2015-01-01

    Full Text Available Aldose reductase (AR plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC 50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux. A model with partial least squares factor 5, standard deviation 0.2482, R 2 = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

  11. Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery.

    Wada, Shun-Ichi; Takesada, Anna; Nagamura, Yurie; Sogabe, Eri; Ohki, Rieko; Hayashi, Junsuke; Urata, Hidehito

    2017-12-15

    The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Linear and non-linear quantitative structure-activity relationship models on indole substitution patterns as inhibitors of HIV-1 attachment.

    Nirouei, Mahyar; Ghasemi, Ghasem; Abdolmaleki, Parviz; Tavakoli, Abdolreza; Shariati, Shahab

    2012-06-01

    The antiviral drugs that inhibit human immunodeficiency virus (HIV) entry to the target cells are already in different phases of clinical trials. They prevent viral entry and have a highly specific mechanism of action with a low toxicity profile. Few QSAR studies have been performed on this group of inhibitors. This study was performed to develop a quantitative structure-activity relationship (QSAR) model of the biological activity of indole glyoxamide derivatives as inhibitors of the interaction between HIV glycoprotein gp120 and host cell CD4 receptors. Forty different indole glyoxamide derivatives were selected as a sample set and geometrically optimized using Gaussian 98W. Different combinations of multiple linear regression (MLR), genetic algorithms (GA) and artificial neural networks (ANN) were then utilized to construct the QSAR models. These models were also utilized to select the most efficient subsets of descriptors in a cross-validation procedure for non-linear log (1/EC50) prediction. The results that were obtained using GA-ANN were compared with MLR-MLR and MLR-ANN models. A high predictive ability was observed for the MLR, MLR-ANN and GA-ANN models, with root mean sum square errors (RMSE) of 0.99, 0.91 and 0.67, respectively (N = 40). In summary, machine learning methods were highly effective in designing QSAR models when compared to statistical method.

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

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

    2007-03-08

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

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

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

    1989-01-01

    A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na + , K + -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na + , K + -ATPase from dog kidney cortex when present at concentrations from 40-1000 μM. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC 50 at 257-320 μM. Structure-activity relationships were observed among the following mono-substituted flavones as: (i) 2-cyclohexyl-benzopyran-4-one much-gt 2-phenyl-benzopyran-4-one; (ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one > 2-cyclohexyl-6-hydroxy-benzopyran-4-one > 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly and of the flavonoids were able to block [ 3 H] ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na + , K + -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme

  15. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

    Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte

    2015-01-01

    Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD...... and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

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

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

    2005-10-06

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

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

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

    2017-06-16

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

  18. In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii

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

    2011-01-01

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

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

    Katalin Prokai-Tatrai

    2013-01-01

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

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

    Chen-Peng Chen

    2018-04-01

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

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

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

    2006-08-01

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

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

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

    2017-03-01

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

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

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

    2007-02-15

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

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

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

    2016-01-01

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

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

    Fabiola Pizzo

    2016-11-01

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

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

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

    2016-07-28

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

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

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

    2017-08-15

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

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

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

    2017-11-01

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

  9. Effects of heterocyclic-based head group modifications on the structure-activity relationship of tocopherol-based lipids for non-viral gene delivery.

    Gosangi, Mallikarjun; Mujahid, Thasneem Yoosuf; Gopal, Vijaya; Patri, Srilakshmi V

    2016-07-12

    Gene therapy, a promising strategy for the delivery of therapeutic nucleic acids, is greatly dependent on the development of efficient vectors. In this study, we designed and synthesized several tocopherol-based lipids varying in the head group region. Here, we present the structure-activity relationship of stable aqueous suspensions of lipids that were synthetically prepared and formulated with 1,2-dioleoyl phosphatidyl ethanolamine (DOPE) as the co-lipid. The physicochemical properties such as the hydrodynamic size, zeta potential, stability and morphology of these formulations were investigated. Interaction with plasmid DNA was clearly demonstrated through gel binding and EtBr displacement assays. Further, the transfection potential was examined in mouse neuroblastoma Neuro-2a, hepatocarcinoma HepG2, human embryonic kidney and Chinese hamster ovarian cell lines, all of different origins. Cell-uptake assays with N-methylpiperidinium, N-methylmorpholinium, N-methylimidazolium and N,N-dimethylaminopyridinium head group containing formulations evidently depicted efficient cell uptake as observed by particulate cytoplasmic fluorescence. Trafficking of lipoplexes using an endocytic marker and rhodamine-labeled phospholipid DHPE indicated that the lipoplexes were not sequestered in the lysosomes. Importantly, lipoplexes were non-toxic and mediated good transfection efficiency as analyzed by β-Gal and GFP reporter gene expression assays which established the superior activity of lipids whose structures correlate strongly with the transfection efficiency.

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

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

    1989-01-01

    A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na{sup +}, K{sup +} -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na{sup +}, K{sup +} -ATPase from dog kidney cortex when present at concentrations from 40-1000 {mu}M. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC{sub 50} at 257-320 {mu}M. Structure-activity relationships were observed among the following mono-substituted flavones as: (i) 2-cyclohexyl-benzopyran-4-one {much gt} 2-phenyl-benzopyran-4-one; (ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one {gt} 2-cyclohexyl-6-hydroxy-benzopyran-4-one {gt} 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly and of the flavonoids were able to block ({sup 3}H) ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na{sup +}, K{sup +} -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme.

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

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

    2015-11-01

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

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

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

    2017-02-22

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

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

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

    2017-11-22

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

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

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

    2018-04-15

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

  15. Information from Relationship Lending : Evidence from China

    Chang, C.; Liao, G.; Yu, X.; Ni, Z.

    2009-01-01

    We study the economic role of banks’ soft information, which evolved from repeated lending relationships, in the context of loan default. Using a proprietary database from one of the largest state-owned commercial banks in China, we find that the bank’s internal credit rating scores play a

  16. INFORMATION ASSURANCE - INTELLIGENCE - INFORMATION SUPERIORITY RELATIONSHIP WITHIN NATO OPERATIONS

    Gheorghe BOARU, Ioan-Mihai ILIEŞ

    2011-01-01

    Full Text Available There is a tight relationship between information assurance, the intelligence cycle and information superiority within NATO operations. The intelligence cycle has a discrete architecture and provides on-time and relevant intelligence products to the joint force commanders and to other authorized users in a specifi c joint area of operations. The intelligence cycle must follow the evolution of the operation. A permanent intelligence estimate will be performed during the military decision making process and operations execution. Information superiority is one of the most powerful intelligence cycle achievements. and decisively infuences the success of NATO joint operations. Information superiority must be preserved and enhanced through information assurance. Information assurance is an information operation that must be planned by the military in charge of operation security or by non-military experts, executed by all personnel during the entire intelligence cycle life time and employed during the planning and execution of NATO joint operations.

  17. Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

    Kharkar, Prashant S.; Reith, Maarten E. A.; Dutta, Aloke K.

    2008-01-01

    Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of -OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.

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

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

    2012-04-24

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

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

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

    2017-08-01

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

  20. Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

    Haadsma-Svensson, S R; Cleek, K A; Dinh, D M; Duncan, J N; Haber, C L; Huff, R M; Lajiness, M E; Nichols, N F; Smith, M W; Svensson, K A; Zaya, M J; Carlsson, A; Lin, C H

    2001-12-20

    5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

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

    Jerzy Leszczynski

    2000-10-01

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

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

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

    2017-07-15

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

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

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

    2015-02-01

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

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

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

    2017-01-27

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

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

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

    2017-06-21

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

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

    Huang, Mengmeng; Wei, Yan; Wang, Jun; Zhang, Yu

    2016-09-01

    We used the support vector regression (SVR) approach to predict and unravel reduction/promotion effect of characteristic flavonoids on the acrylamide formation under a low-moisture Maillard reaction system. Results demonstrated the reduction/promotion effects by flavonoids at addition levels of 1-10000 μmol/L. The maximal inhibition rates (51.7%, 68.8% and 26.1%) and promote rates (57.7%, 178.8% and 27.5%) caused by flavones, flavonols and isoflavones were observed at addition levels of 100 μmol/L and 10000 μmol/L, respectively. The reduction/promotion effects were closely related to the change of trolox equivalent antioxidant capacity (ΔTEAC) and well predicted by triple ΔTEAC measurements via SVR models (R: 0.633-0.900). Flavonols exhibit stronger effects on the acrylamide formation than flavones and isoflavones as well as their O-glycosides derivatives, which may be attributed to the number and position of phenolic and 3-enolic hydroxyls. The reduction/promotion effects were well predicted by using optimized quantitative structure-activity relationship (QSAR) descriptors and SVR models (R: 0.926-0.994). Compared to artificial neural network and multi-linear regression models, SVR models exhibited better fitting performance for both TEAC-dependent and QSAR descriptor-dependent predicting work. These observations demonstrated that the SVR models are competent for predicting our understanding on the future use of natural antioxidants for decreasing the acrylamide formation.

  7. Quantitative Structure-Activity Relationship Modeling Coupled with Molecular Docking Analysis in Screening of Angiotensin I-Converting Enzyme Inhibitory Peptides from Qula Casein Hydrolysates Obtained by Two-Enzyme Combination Hydrolysis.

    Lin, Kai; Zhang, Lanwei; Han, Xue; Meng, Zhaoxu; Zhang, Jianming; Wu, Yifan; Cheng, Dayou

    2018-03-28

    In this study, Qula casein derived from yak milk casein was hydrolyzed using a two-enzyme combination approach, and high angiotensin I-converting enzyme (ACE) inhibitory activity peptides were screened by quantitative structure-activity relationship (QSAR) modeling integrated with molecular docking analysis. Hydrolysates (casein presents an excellent source to produce ACE inhibitory peptides.

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

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

    2017-09-10

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

  9. Relationship between stakeholders' information value perception and information security behaviour

    Tajuddin, Sharul; Olphert, Wendy; Doherty, Neil

    2015-02-01

    The study, reported in this paper, aims to explore the relationship between the stakeholders' perceptions about the value of information and their resultant information security behaviours. Moreover, this study seeks to explore the role of national and organisational culture in facilitating information value assignment. Information Security is a concept that formed from the recognition that information is valuable and that there is a need to protect it. The ISO 27002 defines information as an asset, which, like other important business assets, is essential to an organisation's business and consequently needs to be appropriately protected. By definition, an asset has a value to the organisation hence it requires protection. Information protection is typically accomplished through the implementation of countermeasures against the threats and vulnerabilities of information security, for example, implementation of technological processes and mechanisms such as firewall and authorization and authentication systems, set-up of deterrence procedures such as password control and enforcement of organisational policy on information handling procedures. However, evidence routinely shows that despite such measures, information security breaches and incidents are on the rise. These breaches lead to loss of information, personal records, or other data, with consequent implications for the value of the information asset. A number of studies have suggested that such problems are not related primarily to technology problems or procedural deficiencies, but rather to stakeholders' poor compliance with the security measures that are in place. Research indicates that compliance behaviour is affected by many variables including perceived costs and benefits, national and organisational culture and norms. However, there has been little research to understand the concept of information value from the perspective of those who interact with the data, and the consequences for information

  10. Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

    Megan Leander

    Full Text Available 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 (RhpMS-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

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

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

    2010-04-19

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

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

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

    2013-06-01

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

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

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

    2017-09-29

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

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

    Richard D. Beger

    2012-03-01

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

  15. Structure-activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter.

    Lykke, Kasper; Töllner, Kathrin; Römermann, Kerstin; Feit, Peter W; Erker, Thomas; MacAulay, Nanna; Löscher, Wolfgang

    2015-06-23

    The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na + , K + and Cl - ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. Bumetanide blocked hNKCC2A transport with an IC 50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r 2 = 0.817; P human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. © 2015 The British Pharmacological Society.

  16. Hydrogen Production by Ethanol Steam Reforming (ESR over CeO2 Supported Transition Metal (Fe, Co, Ni, Cu Catalysts: Insight into the Structure-Activity Relationship

    Michalis Konsolakis

    2016-03-01

    Full Text Available The aim of the present work was to investigate steam reforming of ethanol with regard to H2 production over transition metal catalysts supported on CeO2. Various parameters concerning the effect of temperature (400–800 °C, steam-to-carbon (S/C feed ratio (0.5, 1.5, 3, 6, metal entity (Fe, Co, Ni, Cu and metal loading (15–30 wt.% on the catalytic performance, were thoroughly studied. The optimal performance was obtained for the 20 wt.% Co/CeO2 catalyst, achieving a H2 yield of up to 66% at 400 °C. In addition, the Co/CeO2 catalyst demonstrated excellent stability performance in the whole examined temperature range of 400–800 °C. In contrast, a notable stability degradation, especially at low temperatures, was observed for Ni-, Cu-, and Fe-based catalysts, ascribed mainly to carbon deposition. An extensive characterization study, involving N2 adsorption-desorption (BET, X-ray diffraction (XRD, Scanning Electron Microscopy (SEM/EDS, X-ray Photoelectron Spectroscopy (XPS, and Temperature Programmed Reduction (H2-TPR was undertaken to gain insight into the structure-activity correlation. The excellent reforming performance of Co/CeO2 catalysts could be attributed to their intrinsic reactivity towards ethanol reforming in combination to their high surface oxygen concentration, which hinders the deposition of carbonaceous species.

  17. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Victoria S Paulsen

    Full Text Available Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2 terminus of the peptide and the fragment arasin 1(1-23 was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23 were shown to be non-toxic to human red blood cells and arasin 1(1-23 was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23 was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC, arasin 1(1-23 was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23 has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23 involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  18. Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives

    Asunción Burguete

    2008-12-01

    Full Text Available A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E-3-(3,4,5-trimethoxy-phenyl-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

  19. Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work.

    Pang, Siu-Kwong

    2017-03-30

    Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. The Evolution Process on Information Technology Outsourcing Relationship

    Duan Weihua

    2017-01-01

    Full Text Available Information technology outsourcing relationship is one of the key issues to IT outsourcing success. To explore how to manage and promote IT outsourcing relationship, it is necessary to understand its evolution process. Firstly, the types of IT outsourcing based on relationship quality and IT outsourcing project level will be analyzed; Secondly, two evolution process models of IT outsourcing relationship are proposed based on relationship quality and IT outsourcing project level, and the IT outsourcing relationship evolution process is indicated; Finally, an IT outsourcing relationship evolution process model is developed, and the development process of IT outsourcing relationship from low to high under the internal and external power is explained.

  1. Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

    Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

    2018-03-01

    We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

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

    Marcos Lorca

    2018-05-01

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

  3. The Evolution Process on Information Technology Outsourcing Relationship

    Duan Weihua

    2017-01-01

    Information technology outsourcing relationship is one of the key issues to IT outsourcing success. To explore how to manage and promote IT outsourcing relationship, it is necessary to understand its evolution process. Firstly, the types of IT outsourcing based on relationship quality and IT outsourcing project level will be analyzed; Secondly, two evolution process models of IT outsourcing relationship are proposed based on relationship quality and IT outsourcing project level, and the IT ou...

  4. Relationship between information asymmetry and cost of capital

    Fateme Rahmani

    2013-01-01

    Full Text Available Shareholders expected return is normally impacted by informational risk and informational asymmetry, on the other hand, creates informational risk. Thus, investors demand greater risk premium in the case of informational asymmetry and in turn corporate expenditures increase. In this study, we determine the relationship between informational asymmetry and capital cost. The study uses information of 109 companies listed in Tehran Securities Exchange over the period of 2005-2010 and the results suggest a positive and significant relationship between informational asymmetry and capital cost. In addition, the results from present research indicate that when capital markets are competitive, there is not a significant relationship between informational asymmetry and capital cost. But when markets are partially competitive there is a significant relationship between informational asymmetry and capital cost.

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

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

    1992-02-01

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

  6. 2-(Substituted phenyl-3,4-dihydroisoquinolin-2-iums as Novel Antifungal Lead Compounds: Biological Evaluation and Structure-Activity Relationships

    Xin-Juan Yang

    2013-08-01

    Full Text Available The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs. In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2–12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88–19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

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

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

    2011-04-21

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

  8. Designing Data Visualizations Representing Informational Relationships

    Steele, Julie

    2011-01-01

    Data visualization is an efficient and effective medium for communicating large amounts of information, but the design process can often seem like an unexplainable creative endeavor. This concise book aims to demystify the design process by showing you how to use a linear decision-making process to encode your information visually. Delve into different kinds of visualization, including infographics and visual art, and explore the influences at work in each one. Then learn how to apply these concepts to your design process. Learn data visualization classifications, including explanatory, expl

  9. Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

    Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele

    2017-03-09

    Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

  10. 1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

    La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

    2008-07-10

    New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC

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

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

    1998-03-01

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

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

    Qian, Shan; Shah, Aashay K; Head, Sarah A; Liu, Jun O; Jin, Zhendong

    2016-08-01

    Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, two new analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated trienyl lactone moiety of the molecule by replacing the C2-C3 double bond in ZJ-101 with a single bond and switching the geometry of the C4-C5 double bond in ZJ-101 from Z to E, respectively. Biological evaluation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of the molecule is critical for its anticancer activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Mapping chemical structure-activity information of HAART-drug cocktails over complex networks of AIDS epidemiology and socioeconomic data of U.S. counties.

    Herrera-Ibatá, Diana María; Pazos, Alejandro; Orbegozo-Medina, Ricardo Alfredo; Romero-Durán, Francisco Javier; González-Díaz, Humberto

    2015-06-01

    Using computational algorithms to design tailored drug cocktails for highly active antiretroviral therapy (HAART) on specific populations is a goal of major importance for both pharmaceutical industry and public health policy institutions. New combinations of compounds need to be predicted in order to design HAART cocktails. On the one hand, there are the biomolecular factors related to the drugs in the cocktail (experimental measure, chemical structure, drug target, assay organisms, etc.); on the other hand, there are the socioeconomic factors of the specific population (income inequalities, employment levels, fiscal pressure, education, migration, population structure, etc.) to study the relationship between the socioeconomic status and the disease. In this context, machine learning algorithms, able to seek models for problems with multi-source data, have to be used. In this work, the first artificial neural network (ANN) model is proposed for the prediction of HAART cocktails, to halt AIDS on epidemic networks of U.S. counties using information indices that codify both biomolecular and several socioeconomic factors. The data was obtained from at least three major sources. The first dataset included assays of anti-HIV chemical compounds released to ChEMBL. The second dataset is the AIDSVu database of Emory University. AIDSVu compiled AIDS prevalence for >2300 U.S. counties. The third data set included socioeconomic data from the U.S. Census Bureau. Three scales or levels were employed to group the counties according to the location or population structure codes: state, rural urban continuum code (RUCC) and urban influence code (UIC). An analysis of >130,000 pairs (network links) was performed, corresponding to AIDS prevalence in 2310 counties in U.S. vs. drug cocktails made up of combinations of ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4856 protocols, and 10 possible experimental measures. The best model found with the original

  14. Information retrieval models foundations and relationships

    Roelleke, Thomas

    2013-01-01

    Information Retrieval (IR) models are a core component of IR research and IR systems. The past decade brought a consolidation of the family of IR models, which by 2000 consisted of relatively isolated views on TF-IDF (Term-Frequency times Inverse-Document-Frequency) as the weighting scheme in the vector-space model (VSM), the probabilistic relevance framework (PRF), the binary independence retrieval (BIR) model, BM25 (Best-Match Version 25, the main instantiation of the PRF/BIR), and language modelling (LM). Also, the early 2000s saw the arrival of divergence from randomness (DFR).Regarding in

  15. Examining the Relationship between Organization Systems and Information Security Awareness

    Tintamusik, Yanarong

    2010-01-01

    The focus of this dissertation was to examine the crucial relationship between organization systems within the framework of the organizational behavior theory and information security awareness (ISA) of users within the framework of the information security theory. Despite advanced security technologies designed to protect information assets,…

  16. Effect of Information Asymmetry and Relationship Lending on ...

    Effect of Information Asymmetry and Relationship Lending on Financial ... from small- business- friendly financial institutions, hypotheses postulated by the ... a model of transaction costs of financial contracting that put into consideration the ...

  17. Structure Activity Relationship of Brevenal Hydrazide Derivatives

    Allan Goodman

    2014-03-01

    Full Text Available Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.

  18. The mutualistic relationship between information systems and the humanities

    Kroeze, Jan H

    2010-01-01

    The paper explores the nature of the relationship between the study fields of Information Systems and the humanities. Although literature on Humanities Computing states in principle that there is a bidirectional, beneficial symbiotic relationship, most studies and reflections investigate only the application of information technology in the humanities. This implies that the relation is commensalistic rather that multualistic. However, studies do exist that implement theoretical constructs bor...

  19. Information Systems and the Humanities: A Symbiotic Relationship?

    Kroeze, JH

    2009-01-01

    The lecture explores the nature of the relationship between the study fields of Information Systems and the humanities. Although literature on Humanities Computing states in principle that there is a bi-directional, beneficial symbiotic relationship, most studies and reflections investigate only the application of information technology in the humanities. This suggests that the relation is commensalistic rather that mutualistic. However, studies do exist that implement theor...

  20. Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

    Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

    2016-08-01

    The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect. © 2016 Institute of Food Technologists®

  1. Information sharing and relationships on social networking sites.

    Steijn, Wouter M P; Schouten, Alexander P

    2013-08-01

    This article investigates the relationship between sharing personal information and relationship development in the context of social networking sites (SNSs). Information disclosed on these sites could affect relationships in a different manner compared to more traditional interactions, such as instant messaging or face-to-face interaction. Respondents in the age range of 12 to 83 were surveyed about experiences of relationship development as a consequence of contact through Facebook or Hyves-the most popular Dutch SNSs. Results showed a primarily positive effect of information sharing on SNSs on our relationships. Furthermore, relationship development mainly occurs among acquaintances and friends, and public posts are most strongly related to relationship development. These findings suggest that SNSs might affect relationships in a distinct fashion as acquaintances and friends gain access to public self-disclosures that might normally only be reserved for close friends and family. Overall, this study provides an insight into some of the positive aspects of the public nature of SNSs in contrast with the general negative associations.

  2. An assessment of the relationship between indigenous information ...

    The study investigated the relationship between indigenous information channels and rural communication development in Okuku community in Nigeria. It sought to find out the extent to which indigenous information channels correlate to rural community development. The research design is a correlation survey. A total of ...

  3. Understanding of the structure activity relationship of PtPd bimetallic catalysts prepared by surface organometallic chemistry and ion exchange during the reaction of iso-butane with hydrogen

    Al-Shareef, Reem A.; Harb, Moussab; Saih, Youssef; Ould-Chikh, Samy; Roldan, Manuel A.; Anjum, Dalaver H.; Guyonnet, Elodie Bile; Candy, Jean-Pierre; Jan, Deng-Yang; Abdo, Suheil F.; Aguilar-Tapia, Antonio; Proux, Olivier; Hazemann, Jean-Louis; Basset, Jean-Marie

    2018-01-01

    Well-defined silica supported bimetallic catalysts Pt100-x Pdx were prepared by Surface Organometallic Chemistry (SOMC) and Ionic-Exchange (IE) methods. For all investigated catalysts, iso-butane reaction with hydrogen under differential conditions led to the formation of methane and propane, n-butane, and traces of iso-butylene. The total reaction rate decreased with increasing the Pd loading for both catalysts series as a result of decreasing turnover rate of both isomerization and hydrogenolysis. In the case of Pt100-x Pdx(SOMC) catalysts, the experimental results in combination with DFT calculations suggested a selective coverage of Pt (1 0 0) surface by agglomerated Pd atoms like “islands”, assuming that each metal roughly keeps its intrinsic catalytic properties with relatively small electron transfer from Pt to Pd in the case of Pt-rich sample and from Pd to Pt in the case of Pd-rich sample. For the PtPd catalysts prepared by IE, the catalytic behavior could be explained by the formation of a surface alloy between Pt and Pd in the case of Pd-rich sample and by the segregation of a small amount of Pd on the surface in the case of Pt-rich sample, as demonstrated by TEM, EXAFS and DFT. The catalytic results were explained by a structure activity relationship based on the proposed mechanism of CH bond and CC bond activation and cleavage for iso-butane hydrogenolysis, isomerization, cracking and dehydrogenation.

  4. Understanding of the structure activity relationship of PtPd bimetallic catalysts prepared by surface organometallic chemistry and ion exchange during the reaction of iso-butane with hydrogen

    Alshareef, Reem Abdul aziz Hamed

    2018-04-25

    Well-defined silica supported bimetallic catalysts Pt100-x Pdx were prepared by Surface Organometallic Chemistry (SOMC) and Ionic-Exchange (IE) methods. For all investigated catalysts, iso-butane reaction with hydrogen under differential conditions led to the formation of methane and propane, n-butane, and traces of iso-butylene. The total reaction rate decreased with increasing the Pd loading for both catalysts series as a result of decreasing turnover rate of both isomerization and hydrogenolysis. In the case of Pt100-x Pdx(SOMC) catalysts, the experimental results in combination with DFT calculations suggested a selective coverage of Pt (1 0 0) surface by agglomerated Pd atoms like “islands”, assuming that each metal roughly keeps its intrinsic catalytic properties with relatively small electron transfer from Pt to Pd in the case of Pt-rich sample and from Pd to Pt in the case of Pd-rich sample. For the PtPd catalysts prepared by IE, the catalytic behavior could be explained by the formation of a surface alloy between Pt and Pd in the case of Pd-rich sample and by the segregation of a small amount of Pd on the surface in the case of Pt-rich sample, as demonstrated by TEM, EXAFS and DFT. The catalytic results were explained by a structure activity relationship based on the proposed mechanism of CH bond and CC bond activation and cleavage for iso-butane hydrogenolysis, isomerization, cracking and dehydrogenation.

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

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

    2017-06-16

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

  6. Kinetic Study of the Aroxyl-Radical-Scavenging Activity of Five Fatty Acid Esters and Six Carotenoids in Toluene Solution: Structure-Activity Relationship for the Hydrogen Abstraction Reaction.

    Mukai, Kazuo; Yoshimoto, Maya; Ishikura, Masaharu; Nagaoka, Shin-Ichi

    2017-08-17

    A kinetic study of the reaction between an aroxyl radical (ArO • ) and fatty acid esters (LHs 1-5, ethyl stearate 1, ethyl oleate 2, ethyl linoleate 3, ethyl linolenate 4, and ethyl arachidonate 5) has been undertaken. The second-order rate constants (k s ) for the reaction of ArO • with LHs 1-5 in toluene at 25.0 °C have been determined spectrophotometrically. The k s values obtained increased in the order of LH 1 LHs 1-5. The k s value for LH 5 was 2.93 × 10 -3 M -1 s -1 . From the result, it has been clarified that the reaction of ArO • with LHs 1-5 was explained by an allylic hydrogen abstraction reaction. A similar kinetic study was performed for the reaction of ArO • with six carotenoids (Car-Hs 1-6, astaxanthin 1, β-carotene 2, lycopene 3, capsanthin 4, zeaxanthin 5, and lutein 6). The k s values obtained increased in the order of Car-H 1 LHs 1-5. The results of detailed analyses of the k s values for the above reaction indicated that the reaction was also explained by an allylic hydrogen abstraction reaction. Furthermore, the structure-activity relationship for the reaction was discussed by taking the result of density functional theory calculation reported by Martinez and Barbosa into account.

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

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

    2018-03-01

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

  8. Information Society and Knowledge Economy - Essence and Key Relationships

    Rafał Żelazny

    2015-04-01

    Full Text Available This paper focuses on essence and relationships between information society (IS and knowledge economy (KE concepts. The aim of this article is twofold. The first objective is to denominate the conceptual framework and relationships between IS and KE conceptions. The second is to present dependencies between the indexes of IS and KE development level in selected countries. Firstly, based on the notional relations between information and knowledge, there are characterized the relationships between concepts of information society, knowledge economy and knowledge society (KS. Secondly, using popular composite indexes evaluating the degree of IS and KE development i.e. Networked Readiness Index (NRI, ICT Development Index (IDI, Knowledge Economy Index (KEI and Summary Innovation Index (SII, there were studied corelations between information society and knowledge economy in 34 selected countries in 2012. The paper concludes by stating limits and implications for further research. This work contributes to systematization and integration of knowledge about the mutually permeable conceptions of information society and knowledge economy

  9. Reactions of OH radicals with 2-methyl-1-butyl, neopentyl and 1-hexyl nitrates. Structure-activity relationship for gas-phase reactions of OH with alkyl nitrates: An update

    Bedjanian, Yuri; Morin, Julien; Romanias, Manolis N.

    2018-05-01

    The kinetics of the reactions 2-methyl-1-butyl (2M1BNT), neopentyl (NPTNT) and 1-hexyl nitrates (1HXNT) with OH radicals has been studied using a low pressure flow tube reactor combined with a quadrupole mass spectrometer. The rate constants of the title reactions were determined under pseudo-first order conditions from kinetics of OH consumption in excess of nitrates. The overall rate coefficients, k2M1BNT = 1.54 × 10-14 (T/298)4.85 exp (1463/T) (T = 278-538 K), kNPTNT = 1.39 × 10-14 (T/298)4.89 exp (1189/T) (T = 278-500 K) and k1HXNT = 2.23 × 10-13 (T/298)2.83 exp (853/T) cm3molecule-1s-1 (T = 306-538 K) (with conservative 15% uncertainty), were determined at a total pressure of 1 Torr of helium. The yield of trimethylacetaldehyde ((CH3)3CCHO), resulting from the abstraction by OH of an α-hydrogen atom in neopentyl nitrate, followed by α-substituted alkyl radical decomposition, was determined as 0.31 ± 0.06 at T = 298 K. The calculated tropospheric lifetimes of 2M1BNT, NPTNT and 1HXNT indicate that reaction of these nitrates with OH represents an important sink of these compounds in the atmosphere. Based on the available kinetic data, we have updated the structure-activity relationship (SAR) for reactions of alkyl nitrates with OH at T = 298 K. Good agreement (within 20%) is obtained between experimentally measured rate constants (total and that for H-atom abstraction from α carbon) and those calculated from SAR using new substituents factors for almost all the experimental data available.

  10. Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

    Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie

    2005-04-21

    The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.

  11. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

    Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-07-20

    The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

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

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

    2017-06-01

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

  13. Discovery, characterization and structure-activity relationships of an inhibitor of inward rectifier potassium (Kir channels with preference for Kir2.3, Kir3.X and Kir7.1

    Jerod S Denton

    2011-11-01

    Full Text Available The inward rectifier family of potassium (Kir channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that GIRK (G protein-regulated inward rectifier K channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+ flux-based high-throughput screen (HTS of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 M and 19 M, respectively and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK and Kir3.1/3.4 (cardiac GIRK channels with equal potency and preferentially inhibited GIRK, Kir2.3 and Kir7.1 over Kir1.1 and Kir2.1. Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure-activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure-function relationships of these Kir channels.

  14. A framework for understanding culture and its relationship to information behaviour: Taiwanese aborigines' information behaviour

    Nei-Ching Yeh

    2007-01-01

    Full Text Available Introduction. This article proposes a model of culture and its relationship to information behaviour based on two empirical studies of Taiwanese aborigines' information behaviour. Method. The research approach is ethnographic and the material was collected through observations, conversations, questionnaires, interviews and relevant documents. In 2003-2004, the author lived with two Taiwan aboriginal tribes, the Yami tribe and the Tsau tribe and conducted forty-two theme-based interviews. Analysis. Data were analysed with the help of software for qualitative analysis (NVivo, where all sentences from both interviews and field notes were coded. The conceptual framework used is the sociology of knowledge. Results. The model of culture and its relationship to information behaviour can show us how to think about the relationship between culture and human information behaviour. This model also identifies elements of the model, which are habitus, tradition and prejudice and suggests how we can apply the concepts of information fullness and emptiness to view the relationship between culture and human information behaviour. Conclusion. . Theoretically, this research puts forward a new model of information behaviour and focuses on the role and the importance of culture when thinking about and studying human information behaviour. Methodologically, this study demonstrates how an ethnographic research method can contribute to exploring the influence that culture has on human life and the details of the human life world and information behaviour.

  15. Relationship between Teacher Candidates’ Literacy of Science and Information Technology

    Orhan Karamustafaoğlu; Recep Çakır; Mert Kaya

    2013-01-01

    This study aims to determine the science teacher candidates’ literacy levels of science and information technology and intends to find out the relationship between them. In the study, correlational research methodology was used in the scope of correlational screening model. Research sample consists of totally 264 teacher candidates who are in their 3rd and 4th years and studying at the Department of Science and Technology Education in Amasya University. As the data collection instruments, the...

  16. Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.

    Lin, C H; Haadsma-Svensson, S R; Lahti, R A; McCall, R B; Piercey, M F; Schreur, P J; Von Voigtlander, P F; Smith, M W; Chidester, C G

    1993-04-16

    The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

  17. Toward the prediction of class I and II mouse major histocompatibility complex-peptide-binding affinity: in silico bioinformatic step-by-step guide using quantitative structure-activity relationships.

    Hattotuwagama, Channa K; Doytchinova, Irini A; Flower, Darren R

    2007-01-01

    Quantitative structure-activity relationship (QSAR) analysis is a cornerstone of modern informatics. Predictive computational models of peptide-major histocompatibility complex (MHC)-binding affinity based on QSAR technology have now become important components of modern computational immunovaccinology. Historically, such approaches have been built around semiqualitative, classification methods, but these are now giving way to quantitative regression methods. We review three methods--a 2D-QSAR additive-partial least squares (PLS) and a 3D-QSAR comparative molecular similarity index analysis (CoMSIA) method--which can identify the sequence dependence of peptide-binding specificity for various class I MHC alleles from the reported binding affinities (IC50) of peptide sets. The third method is an iterative self-consistent (ISC) PLS-based additive method, which is a recently developed extension to the additive method for the affinity prediction of class II peptides. The QSAR methods presented here have established themselves as immunoinformatic techniques complementary to existing methodology, useful in the quantitative prediction of binding affinity: current methods for the in silico identification of T-cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate computational prediction of peptide-MHC affinity. We have reviewed various human and mouse class I and class II allele models. Studied alleles comprise HLA-A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3101, HLA-A*6801, HLA-A*6802, HLA-B*3501, H2-K(k), H2-K(b), H2-D(b) HLA-DRB1*0101, HLA-DRB1*0401, HLA-DRB1*0701, I-A(b), I-A(d), I-A(k), I-A(S), I-E(d), and I-E(k). In this chapter we show a step-by-step guide into predicting the reliability and the resulting models to represent an advance on existing methods. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method

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

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

    2017-04-24

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

  19. A framework for understanding culture and its relationship to information behaviour: Taiwanese aborigines' information behaviour

    Nei-Ching Yeh

    2007-01-01

    Introduction. This article proposes a model of culture and its relationship to information behaviour based on two empirical studies of Taiwanese aborigines' information behaviour. Method. The research approach is ethnographic and the material was collected through observations, conversations, questionnaires, interviews and relevant documents. In 2003-2004, the author lived with two Taiwan aboriginal tribes, the Yami tribe and the Tsau tribe and conducted forty-two theme-based interviews. An...

  20. Focusing on relationships, not information, respects autonomy during antenatal consultations.

    Gaucher, Nathalie; Payot, Antoine

    2017-01-01

    Policy statements regarding antenatal consultations for preterm labour are guided by physicians' concerns for upholding the legal doctrine of informed consent, through the provision of standardised homogeneous medical information. This approach, led by classical in-control conceptions of patient autonomy, conceives moral agents as rational, independent, self-sufficient decision-makers. Recent studies on these antenatal consultations have explored patients' perspectives, and these differ from guidelines' suggestions. Relational autonomy - which understands moral agents as rational, emotional, creative and interdependent - resonates impressively with these new data. A model for antenatal consultations is proposed. This approach encourages clinicians to explore individual patients' lived experiences and engage in trusting empowering relationships. Moreover, it calls on physicians to enhance patients' relational autonomy by becoming advocates for their patients within healthcare institutions and professional organisations, while calling for broadscale policy changes to encourage further funding and support in investigations of the patient's voice. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  1. Customer relationship management: Modern aspects of information technology application

    Soldić-Aleksić Jasna

    2008-01-01

    Full Text Available The concept of Customer Relationship Management has emerged around the maxim on the essential importance of the customers for business success of the company. The vital role in the concept development is assigned to an employment of the various information communication technologies: in the scope of operational CRM that is the application of Internet technologies, web browsers, e-mails, POS terminals, call centers; on the other side, analytical CRM involves activities such as data mining, web mining, click stream analysis etc. Modern tendencies in the development of information-communication technologies have generated new communication models between company and its customers, therefore companies are not only focused on the products and services, but also on the communication channels and techniques with customers. On that ground many companies are accepting and using new tools belonging to the web 2.0 technologies which have produced the new CRM model - CRM 2.0.

  2. Phylogenetically informed logic relationships improve detection of biological network organization

    2011-01-01

    Background A "phylogenetic profile" refers to the presence or absence of a gene across a set of organisms, and it has been proven valuable for understanding gene functional relationships and network organization. Despite this success, few studies have attempted to search beyond just pairwise relationships among genes. Here we search for logic relationships involving three genes, and explore its potential application in gene network analyses. Results Taking advantage of a phylogenetic matrix constructed from the large orthologs database Roundup, we invented a method to create balanced profiles for individual triplets of genes that guarantee equal weight on the different phylogenetic scenarios of coevolution between genes. When we applied this idea to LAPP, the method to search for logic triplets of genes, the balanced profiles resulted in significant performance improvement and the discovery of hundreds of thousands more putative triplets than unadjusted profiles. We found that logic triplets detected biological network organization and identified key proteins and their functions, ranging from neighbouring proteins in local pathways, to well separated proteins in the whole pathway, and to the interactions among different pathways at the system level. Finally, our case study suggested that the directionality in a logic relationship and the profile of a triplet could disclose the connectivity between the triplet and surrounding networks. Conclusion Balanced profiles are superior to the raw profiles employed by traditional methods of phylogenetic profiling in searching for high order gene sets. Gene triplets can provide valuable information in detection of biological network organization and identification of key genes at different levels of cellular interaction. PMID:22172058

  3. [Linking: relationships between health professionals in the informal health networks].

    Sarradon-Eck, A; Vega, A; Faure, M; Humbert-Gaudart, A; Lustman, M

    2008-07-01

    During the last years, the french health system has been developing formal health networks. So, it was necessary to study informal health networks as networks. More precisely, we studied the nature of relationships between various stakeholders around general practionners wich are commonly considering as the stakeholder of the health system private sector. Fieldwork (ethnography based on direct observations and interviews) was conducted between October 2002 and april 2004, in the South-East of France. Ten monographs of general practioner's offices were achieved in a rural area; then, we achieved fieldwork of the informal health networks identified. There is a cultural frame wich is common to all private professionals. This frame includes a triple ideal (teamwork built up the hospital model, independance, and an relational approach with patients). This frame does not square with the real practices. In fact, regulation mechanisms preserve the balance of relashionships between professionnal groups, by restricting/promoting exchanges and complex alliance strategies. These mecanisms include: (1) a few professionnal's rule as disponibility (to the patients and to the professionnals), as communication about patient, as patient's reference, as obligation to communicate between professionals; (2) some constraints such as territory superposition and competition with other professional groups; (3) some needs for: rileiving (of emotions and worries connected to work), sharing (decisions, responsabilities), of delegation (medical treatment, practices), protection against social and legal risk through the creation of trust relationships. These trust relationships are based on several logics (affinity, solidarity, similarity). The study shows the major place of the patient who is often the main organizer of his network, and even though he makes an important structuring work between medical staff, and an information transfer (on his diagnosis, on his treatment, and professionals

  4. Revealing Relationships among Relevant Climate Variables with Information Theory

    Knuth, Kevin H.; Golera, Anthony; Curry, Charles T.; Huyser, Karen A.; Kevin R. Wheeler; Rossow, William B.

    2005-01-01

    The primary objective of the NASA Earth-Sun Exploration Technology Office is to understand the observed Earth climate variability, thus enabling the determination and prediction of the climate's response to both natural and human-induced forcing. We are currently developing a suite of computational tools that will allow researchers to calculate, from data, a variety of information-theoretic quantities such as mutual information, which can be used to identify relationships among climate variables, and transfer entropy, which indicates the possibility of causal interactions. Our tools estimate these quantities along with their associated error bars, the latter of which is critical for describing the degree of uncertainty in the estimates. This work is based upon optimal binning techniques that we have developed for piecewise-constant, histogram-style models of the underlying density functions. Two useful side benefits have already been discovered. The first allows a researcher to determine whether there exist sufficient data to estimate the underlying probability density. The second permits one to determine an acceptable degree of round-off when compressing data for efficient transfer and storage. We also demonstrate how mutual information and transfer entropy can be applied so as to allow researchers not only to identify relations among climate variables, but also to characterize and quantify their possible causal interactions.

  5. A Study of the Relationship between Information Technology and Changes in Culture and Social Relationships

    Hosein Ebrahimabadi

    2014-03-01

    Full Text Available Information technology and its consequent virtual space are opening up a new sphere in psychological, sociological and cultural studies associated with the mutual effect of technology, culture and human beings in general, and the interaction of cyberspace and culture, identity and human relationships. Recent studies in this field should be examined at least to realize whether the psychological and social outcomes and the pathology of virtual spaces are the result of the overflow of problems and issues of society and the real space into virtual space, and to decide if the challenges and the social problems in question are due to the development and growth of electronic media and virtual space? While describing and explaining  the effect of culture, society and their consequent traditions on virtual spaces, relationships and their content, and examining the effect of virtual space on culture, social actions, identity, attitudes and individual and collective behavior, the present article stresses that considering the short history and the little experience of the interaction between human and information technology and virtual space, it seems too soon to speak decisively about the outcomes of information technology and virtual spaces. Therefore, two principles are suggested to be established in cultural and social research on cyberspace. First, in the study of virtual space, priorities should be identified correctly and one should not merely focus on the problems resulting from information and communication technology instead of dealing with fundamental issues. Second, both in the theoretical and the methodological aspects of studies on virtual space, in different social and cultural spheres, one cannot rely merely on traditional theories and method, and new methods, in terms of theory, methodology and tools, should be applied.

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

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

    2012-05-15

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

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

    Ghasemi, Jahan B.; Zolfonoun, Ehsan

    2012-01-01

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

  8. Relationship between the international marketing research and the international marketing information system

    Grubor Aleksandar

    2004-01-01

    Real and complete understanding relationship between the international marketing research and the international marketing information system requires recognizing essentials of the both concept. The international marketing research constitutes a process with coherent phases, whereas the international marketing information system is a part of integrated company's information system. Approach to learning relationship between the international marketing research and the international marketing in...

  9. The influence of customer relationship management information on customer loyalty

    Ignatovič, Eva

    2009-01-01

    The purpose of this master thesis is to approve that customer relationship management (CRM) has influenced on customer loyalty. In order to achieve this purpose the work was divided into four main tasks: review of the relevant literature; analyze the influence of customer relationship management on customer loyalty and approve its importance for companies, research of the concrete business-to-business (B2B) Company CRM process and its customer loyalty, and the development of the customer rela...

  10. Data Discretization for Novel Relationship Discovery in Information Retrieval.

    Benoit, G.

    2002-01-01

    Describes an information retrieval, visualization, and manipulation model which offers the user multiple ways to exploit the retrieval set, based on weighted query terms, via an interactive interface. Outlines the mathematical model and describes an information retrieval application built on the model to search structured and full-text files.…

  11. Consonance in Information System Projects: A Relationship Marketing Perspective

    Lin, Pei-Ying

    2010-01-01

    Different stakeholders in the information system project usually have different perceptions and expectations of the projects. There is seldom consistency in the stakeholders' evaluations of the project outcome. Thus the outcomes of information system projects are usually disappointing to one or more stakeholders. Consonance is a process that can…

  12. Relationship between the international marketing research and the international marketing information system

    Grubor Aleksandar

    2004-01-01

    Full Text Available Real and complete understanding relationship between the international marketing research and the international marketing information system requires recognizing essentials of the both concept. The international marketing research constitutes a process with coherent phases, whereas the international marketing information system is a part of integrated company's information system. Approach to learning relationship between the international marketing research and the international marketing information system is distinguish in domestic than in the foreign expert literature.

  13. A Systematic Review of Informal Relationships among Parents of Individuals with Intellectual Disability or Autism

    Boehm, Thomas L.; Carter, Erik W.

    2016-01-01

    Social relationships can shape the well-being of parents of children with intellectual and developmental disabilities (IDDs). Although much attention has focused on relationships with other family members or professionals, less is known about the place and contributions of informal relationships (i.e., non-family, unpaid others) in the lives of…

  14. 12 CFR 407.7 - Relationship to Freedom of Information Act.

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Relationship to Freedom of Information Act. 407.7 Section 407.7 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED STATES REGULATIONS GOVERNING PUBLIC OBSERVATION OF EX-IM BANK MEETINGS § 407.7 Relationship to Freedom of Information Act. Nothing in...

  15. Knowledge sharing and innovation in relationships interorganizational type of information technology outsourcing

    Roberta Rodrigues Faoro; Mírian Oliveira; Marcelo Faoro de Abreu

    2017-01-01

    Introduction: this paper presents an analysis of the sharing of knowledge and innovation in the inter-relationships of the type outsourcing of Information Technology. Objective: analyze the existence of relationship between knowledge sharing and innovation in the inter-relationships of the type of outsourcing information technology (IT). Methodology: research is exploratory, qualitative and using as a strategy the multiple case study, which analyzed 12 companies in IT outsourci...

  16. Evaluation and structure-activity relationship analysis of a new series of 4-imino-5H-pyrazolo[3,4-d]pyrimidin-5-amines as potential antibacterial agents

    Beyzaei, Hamid; Aryan, Reza; Moghaddam-Manesh, Mohammadreza; Ghasemi, Behzad; Karimi, Pouya; Samareh Delarami, Hojat; Sanchooli, Mahmood

    2017-09-01

    The synthesis of pyrazolo[3,4-d]pyrimidine derivatives is important due to their presence in various biologically active compounds such as anticancer, antimicrobial, antiparasitic, anti-inflammatory and antidiabetic agents. In this project, a new and efficient approach for the synthesis of some novel 4-imino-5H-pyrazolo[3,4-d]pyrimidin-5-amines from reaction of 5-amino-pyrazole-4-carbonitrile with various hydrazides in ethanolic sodium ethoxide medium was reported. Antimicrobial activities of all synthesized derivatives were evaluated against eight Gram-positive and five Gram-negative pathogenic bacteria. The moderate to good inhibitory effects were observed based on inhibition zone diameter (IZD), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. In order to determine the reasonable relationship between antibacterial activities and physiochemical properties of the derivatives, computational studies were carried out in terms of geometry optimization, short-range van der Waals forces, dipole moments, atomic charges and frontier orbital energies. It was found that both short-range forces and covalent bonds are important in the observed inhibitory effects of the molecules. The results suggested that pyrazolo[3,4-d]pyrimidine derivatives prefer a soft nucleophilic attack on bio-macromolecular targets. Furthermore, our models proposed that the antibacterial activities of these derivatives can be improved by substituting large electron donating groups on the 6-phenyl rings.

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

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

    2016-04-22

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

  18. Internet Health Information Seeking and the Patient-Physician Relationship: A Systematic Review

    2017-01-01

    Background With online health information becoming increasingly popular among patients, concerns have been raised about the impact of patients’ Internet health information-seeking behavior on their relationship with physicians. Therefore, it is pertinent to understand the influence of online health information on the patient-physician relationship. Objective Our objective was to systematically review existing research on patients’ Internet health information seeking and its influence on the patient-physician relationship. Methods We systematically searched PubMed and key medical informatics, information systems, and communication science journals covering the period of 2000 to 2015. Empirical articles that were in English were included. We analyzed the content covering themes in 2 broad categories: factors affecting patients’ discussion of online findings during consultations and implications for the patient-physician relationship. Results We identified 18 articles that met the inclusion criteria and the quality requirement for the review. The articles revealed barriers, facilitators, and demographic factors that influence patients’ disclosure of online health information during consultations and the different mechanisms patients use to reveal these findings. Our review also showed the mechanisms in which online information could influence patients’ relationship with their physicians. Conclusions Results of this review contribute to the understanding of the patient-physician relationship of Internet-informed patients. Our main findings show that Internet health information seeking can improve the patient-physician relationship depending on whether the patient discusses the information with the physician and on their prior relationship. As patients have better access to health information through the Internet and expect to be more engaged in health decision making, traditional models of the patient-provider relationship and communication strategies must be

  19. Leader-Member Exchange Relationships in Health Information Management

    Hunt, T.J.

    2014-01-01

    This article seeks to raise awareness of the leader-member exchange (LMX) theory of leadership and its potential benefit to the health information management (HIM) profession. A literature review that was conducted identified a leadership challenge for HIM practitioners. The review also provides examples of leadership definitions, and potential benefits of LMX to HIM professionals in leading people and influencing leaders in their organizations. The LMX concept may be an avenue to investigate...

  20. Customer Relationship Management in Higher Education: Using Information Systems to Improve the Student-School Relationship

    Seeman, Elaine D.; O'Hara, Margaret

    2006-01-01

    Purpose: The purpose of this paper is to explore customer relationship management (CRM) in a higher education setting. Design/methodology/approach: The development and implementation of a CRM project in a state community college was examined as were the benefits realized by implementing CRM. As colleges increasingly embrace distance learning and…

  1. Relationship between information-seeking behavior and innovative behavior in Chinese nursing students.

    Zhong, Zhuqing; Hu, Dehua; Zheng, Feng; Ding, Siqing; Luo, Aijing

    2018-04-01

    In the information-based economy, information literacy has become the foundation of scientific literacy, and provides the basis for innovative growth. Exploring the relationship between information-seeking behaviors and innovative behaviors of nursing students could help guide the development of information literacy education and training for nursing students. The relationship between information-seeking behavior and innovative behavior in nursing students has received little attention, however. This study aims to explore the relationship between information-seeking behavior and innovative behavior of nursing students. Nursing students in Xiangya Medical School, Central South University and Medical School of Hunan Normal University in the Chinese Province of Hunan were surveyed with an information-seeking behavior scale and an innovative behavior scale. A total of 1247 nursing students were included in the final analysis. The results showed that both information-seeking behavior and innovative behavior were significantly better in undergraduates than in junior college nursing students (P information-seeking behavior was positively related to innovative behavior (r = 0.63, P information-seeking behavior were also correlated with innovative behavior in varying degrees. Furthermore, information utilization was proved to be the strongest predictor of innovative behavior. Information-seeking behavior is positively associated with innovative behavior among nursing students. There is a need to integrate information literacy education with information retrieval courses, especially in the aspects of information utilization, retrieval, and assessment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. The Link Between Communication and Information Technology / non-Information Technology Relationship

    Gilicka, Adrianna

    2015-01-01

    There is a considerable interest in the role of organizational interpersonal relationships regarding communication, in supporting management. The problem stated in our thesis discloses, that one of the hidden reasons for not satisfied IT / non-IT Relationship are difficulties in communication. The cause of these difficulties are: (1) inadequate communication between different organizational units by imposing a variety of purposes and perception of the world from different perspectives. Opport...

  3. Formal and Informal Work Group Relationships With Performance: A Moderation Model Using Social

    Knost, Benjamin R

    2006-01-01

    .... This field study, conducted at a military training course, attempted to further refine this social network-performance relationship by modeling characteristics of both the formal and informal work...

  4. 77 FR 20010 - Proposed Information Collection; Comment Request; Online Customer Relationship Management (CRM...

    2012-04-03

    ... DEPARTMENT OF COMMERCE Minority Business Development Agency Proposed Information Collection; Comment Request; Online Customer Relationship Management (CRM)/Performance Databases, the Online Phoenix... of program goals via the Online CRM/Performance Databases. The data collected through the Online CRM...

  5. From purists to players? How service industry professionals develop social skills for informal client relationships.

    Taminiau, Y.T.A.; Ferguson, J.E.

    2015-01-01

    Developing informal client relationships is an essential social skill for service industry professionals, such as accountants. This skill can be considered a form of 'social knowledge', a key enabler in facilitating communications, and helping professionals distinguish themselves from competitors.

  6. Dynamic modelling of inter-organisational information management systems and relationships in food chains

    Storer, C.E.; Soutar, G.N.; Trienekens, J.H.; Beulens, A.J.M.; Quaddus, M.A.

    2004-01-01

    It is agreed that good communication systems between organisations increase customer satisfaction and relationship behaviour. However, less is known about the details of how information is used to manage relationships. Theories that have been found have either been tested on non-perishable goods or

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

    Doan, Thi Quynh Nhu; Christensen, Søren Brøgger

    2015-01-01

    Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. The biological activity was related to the subnanomolar affinity for the sarco-endoplasmic reticulum calcium ATPase. Prolonged......) targeted against prostate cancer. Conjugation to a peptide, which only is a substrate for prostate specific membrane antigen enabled development of a prodrug (G202), which is targeted towards a number of cancer diseases including hepatocellular carcinoma. G202 has under the name of mipsagargin in clinical...

  8. Quantitative structure-activity relationships of salicylamide neuroleptic agents.

    Gupta, S P; Saha, R N; Singh, P

    1990-05-01

    The in vitro antidopamine activity of substituted N-[(1-alkyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides was found to be well correlated with the hydrophobic and electronic nature of substituents at the 3-position, and with the steric nature of groups replacing the hydrogen atom of the salicyl hydroxy group. In contrast, only the hydrophobic and steric characteristics were found to be important in the in vivo activity of these neuroleptics. This difference suggests that different mechanisms are probably involved in their in vitro and in vivo actions, and that the relevant receptors are slightly different in structure. The in vitro results suggest that electron donation by the 3-substituent strengthens the formation of a hydrogen bond between the carbonyl group of the amide moiety and a hydrogen of the receptor.

  9. Structure-activity relationships of strychnine analogues at glycine receptors

    Mohsen, A.M.Y.; Heller, Eberhard; Holzgrabe, Ulrike

    2014-01-01

    Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best...... pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)[DOUBLE BOND]C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine...

  10. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    Rajagopal, Appavu; Deepa, Mohan; Govindaraju, Munisamy

    2016-01-01

    While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”

  11. Preliminary structure-activity relationship studies on some novel s ...

    yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated ... inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. ... sulfonyl chloride (30 mmol) in 30 mL distilled.

  12. Structure-activity relationship of immunostimulatory effects of phthalates

    Nielsen Gunnar D

    2008-10-01

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

  13. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    Rajagopal, Appavu; Deepa, Mohan [Molecular Biophysics Unit, Indian Institute of Sciences-Bangalore, Karnataka (India); Govindaraju, Munisamy [Bio-Spatial Technology Research Unit, Department of Environmental Biotechnology, School of Environmental Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu (India)

    2016-02-26

    While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”.

  14. Distributing Correlation Coefficients of Linear Structure-Activity/Property Models

    Sorana D. BOLBOACA

    2011-12-01

    Full Text Available Quantitative structure-activity/property relationships are mathematical relationships linking chemical structure and activity/property in a quantitative manner. These in silico approaches are frequently used to reduce animal testing and risk-assessment, as well as to increase time- and cost-effectiveness in characterization and identification of active compounds. The aim of our study was to investigate the pattern of correlation coefficients distribution associated to simple linear relationships linking the compounds structure with their activities. A set of the most common ordnance compounds found at naval facilities with a limited data set with a range of toxicities on aquatic ecosystem and a set of seven properties was studied. Statistically significant models were selected and investigated. The probability density function of the correlation coefficients was investigated using a series of possible continuous distribution laws. Almost 48% of the correlation coefficients proved fit Beta distribution, 40% fit Generalized Pareto distribution, and 12% fit Pert distribution.

  15. How Supervisor Relationships and Protection Rules Affect Employees' Attempts to Manage Health Information at Work.

    Westerman, Catherine Y K; Currie-Mueller, Jenna L; Motto, Justin S; Curti, Logan C

    2017-12-01

    This article explores the issue of health information sharing at work through the lens of Communication Privacy Management theory. As employees must often share some health information at work for various reasons (e.g., to obtain sick leave or accommodations), determining how much to share and how to manage health information is important. The leader-member exchange relationship, stigma, risk perceptions, and the degree of privacy of each individual's health information were investigated. The results show that leader-member exchange, stigma, and privacy contribute to an individual's willingness to disclose health information at work and that leader-member exchange impacts perceptions of risk associated with sharing health information.

  16. Relationship between availability of contraceptive products and pharmacists as information sources.

    Cook, Elizabeth A; Farris, Karen B; Chrischilles, Elizabeth; Aquilino, Mary

    2012-01-01

    To describe the relationship between the availability and accessibility of contraceptives in Iowa pharmacies and the extent to which pharmacists act as an information source regarding contraceptives. Descriptive, exploratory, nonexperimental study. Iowa in fall 2008. 282 pharmacists at Iowa community pharmacies. Cross-sectional survey. Contraceptive availability score, contraceptive accessibility score, and total access score. Regression analyses tested the relationships between the pharmacist information source score and the contraceptive availability, accessibility, and total access scores, controlling for geography, ownership, staff size, and average number of prescriptions per day. Significant positive relationships between the pharmacist information source score and product accessibility, product availability, and total access were observed. The relationship appeared to be driven primarily by product availability, and all were significantly influenced by pharmacy type. Significant negative relationships were found between product accessibility and independent/small chain pharmacies and mass merchandiser/grocery store pharmacies relative to large chain pharmacies. A significant negative relationship was found between independent/small chain pharmacies and the product availability score. Significant relationships were found between pharmacists' ability to act as sources of information for contraceptive products and the availability, accessibility, and overall access to contraceptives in the pharmacy.

  17. Conceptualizing Context and Its Relationship to the Information Behavior in Disseertation Research Process

    Shan-Ju L.Chang、Yu-Ya Lee

    2000-10-01

    Full Text Available

    頁次:4-18

    Context has been addressed as an influential factor of human information behavior. However, there is no consensus on what constitutes a context, or what the relationship between context and information behavior is. In this paper we explore the notions of context and describe the relationship between context and information behavior based on empirical findings, and reviews of current· literature. Our finding suggests that context is stratified and dynamic.

    A context is consisted of several situations, and each situation is defined by a set of related contextual factors. In this way, we propose a new approach to represent the context and situation. At different levels of context, multiple relationships between context and information behavior are identified, including the association relationship, the interaction relationship, and the one-directional relationship. These findings substantiate the concept of situation in Dervin's Sense-making approach, the concept of information horizon proposed by Sonnenwald, and Ingwersen's cognitive model of IR interaction. The multiple relationships between context and information behavior imply that information behavior is related to, but not equal to the process of problem solving. In contrast, information behavior can be viewed as a response of certain situation in the context.

  18. Examining the Relationship between Faculty-Librarian Collaboration and First-Year Students' Information Literacy Abilities

    Douglas, Veronica Arellano; Rabinowitz, Celia E.

    2016-01-01

    Using surveys, interviews, and a rubric-based assessment of student research essays, the St. Mary's College of Maryland Assessment in Action team investigated the relationship between faculty-librarian collaboration in a First Year Seminar (FYS) course and students' demonstrated information literacy (IL) abilities. In gathering information on the…

  19. The Relationship between Return on Profitability and Costs of Outsourcing Information Technology Technical Support

    Odion, Segun

    2011-01-01

    The purpose of this quantitative correlational research study was to examine the relationship between costs of operation and total return on profitability of outsourcing information technology technical support in a two-year period of outsourcing operations. United States of America list of Fortune 1000 companies' chief information officers…

  20. Relationship between Lifelong Learning Levels and Information Literacy Skills in Teacher Candidates

    Solmaz, Dilek Yaliz

    2017-01-01

    This study aims to examine the relationship between lifelong learning levels and information literacy skills in teacher candidates. The research group consists of 127 physical education and sports teacher candidates. Data were collected by means of "Lifelong Learning Scale (LLL)" and "Information Literacy Scale". In the data…

  1. Breach of belongingness: Newcomer relationship conflict, information, and task-related outcomes during organizational socialization.

    Nifadkar, Sushil S; Bauer, Talya N

    2016-01-01

    Previous studies of newcomer socialization have underlined the importance of newcomers' information seeking for their adjustment to the organization, and the conflict literature has consistently reported negative effects of relationship conflict with coworkers. However, to date, no study has examined the consequences of relationship conflict on newcomers' information seeking. In this study, we examined newcomers' reactions when they have relationship conflict with their coworkers, and hence cannot obtain necessary information from them. Drawing upon belongingness theory, we propose a model that moves from breach of belongingness to its proximal and distal consequences, to newcomer information seeking, and then to task-related outcomes. In particular, we propose that second paths exist-first coworker-centric and the other supervisor-centric-that may have simultaneous yet contrasting influence on newcomer adjustment. To test our model, we employ a 3-wave data collection research design with egocentric and Likert-type multisource surveys among a sample of new software engineers and their supervisors working in India. This study contributes to the field by linking the literatures on relationship conflict and newcomer information seeking and suggesting that despite conflict with coworkers, newcomers may succeed in organizations by building relationships with and obtaining information from supervisors. (c) 2016 APA, all rights reserved).

  2. Investigating the relationship between information literacy and academic performance among students.

    Soleymani, Mohammad Reza

    2014-01-01

    Nowadays, no student can ever pursue the ends of his studies unless he makes use of his information literacy skills. To become lifelong learners, they do need these skills. Information literacy is a set of information needed for searching, retrieval, evaluating, and making best use of information. This study uncovers the relationship between information literacy and academic performance among students at Isfahan University of Medical Sciences. This is a practical study using a survey method. All MA students in Isfahan University of Medical Sciences make the statistical population for this study, according to the sample size determined by using Cochran formula 265 samples that were selected by stratified random sampling. Data collection was through information literacy questionnaires designed by Davarpanah and Siamak, verified by Library and Information Sciences experts; and finally, gave a Cronbach's alpha of 0.83. To determine academic performance, the average scores of the students in previous semesters were considered. The information literacy of all other students was significantly higher than medium except for students at Nursing and Nutrition faculties. The students of Management and Information Sciences faculty had the highest level of information literacy and students of nutrition faculty were attributed with the least level. There was no significant difference between male and female students' information literacy. We also found out that there was a significant positive relationship between information literacy and students' academic performance in Isfahan University of Medical Sciences. Information literacy is one of the most important factors that leads to educational success. As there is a significant positive relationship between information literacy and students' academic performance, we should necessarily provide them with relative skills dealing with information literacy to improve their academic performance.

  3. Analysis of the Relationship between Hamming Distance and the Electromagnetic Information Leakage

    Sun Haimeng; Liu Jinming; Zhang Jiemin; Mao Jian

    2013-01-01

    Electromagnetic information leak as a potential data security risk is more and more serious. Discussing the relationship between compromising emanations and Hamming distance is directed to preventing or reducing the electromagnetic information leakage. The paper presents the model of electromagnetic information leak, then the hierarchical protection strategy based on the model is proposed, that is anti-radiation, anti-intercept and anti-reconstruction. Analyzing the causes of electromagnetic ...

  4. 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure-activity relationship profile.

    Nawrozkij, Maxim B; Rotili, Dante; Tarantino, Domenico; Botta, Giorgia; Eremiychuk, Alexandre S; Musmuca, Ira; Ragno, Rino; Samuele, Alberta; Zanoli, Samantha; Armand-Ugón, Mercedes; Clotet-Codina, Imma; Novakov, Ivan A; Orlinson, Boris S; Maga, Giovanni; Esté, José A; Artico, Marino; Mai, Antonello

    2008-08-14

    A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl- S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L100I mutated RTs) assays, compounds carrying an ethyl/ iso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.

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

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

    2018-04-25

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

  6. A Qualitative Study into Dependent Relationships and Voluntary Informed Consent for Research in Pediatric Oncology.

    Dekking, Sara A S; van der Graaf, Rieke; Schouten-van Meeteren, Antoinette Y N; Kars, Marijke C; van Delden, Johannes J M

    2016-04-01

    In pediatric oncology, many oncologists invite their own patients to participate in research. Inclusion within a dependent relationship is considered to potentially compromise voluntariness of consent. Currently, it is unknown to what extent those involved in pediatric oncology experience the dependent relationship as a threat to voluntary informed consent, and what they see as safeguards to protect voluntary informed consent within a dependent relationship. We performed a qualitative study among key actors in pediatric oncology to explore their experiences with the dependent relationship and voluntary informed consent. We conducted three focus groups and 25 semi-structured, in-depth interviews with pediatric oncologists, research coordinators, Research Ethics Committee members, parents of children with cancer, and adolescents with cancer. Professionals regarded the dependent relationship both as a potential threat to and as a positive influence on voluntary decision making. Parents and adolescents did not feel as though dependency upon the oncologist influenced their decisions. They valued the involvement of their own physician in the informed consent process. The professionals suggested three strategies to protect voluntariness: emphasizing voluntariness; empowering families; involvement of an independent person. Although the dependent relationship between pediatric oncologists, patients and parents may be problematic for voluntary informed consent, this is not necessarily the case. Moreover, the involvement of treating physicians may even have a positive impact on the informed consent process. Although we studied pediatric oncology, our results may also apply to many other fields of pediatric medicine where research and care are combined, for example, pediatric rheumatology, neurology and nephrology. Clinical trials in these fields are inevitably often designed, initiated and conducted by medical specialists closely involved in patient care.

  7. Information technology innovation - a genuine driver of improving customer relationship management in romanian companies

    Ph.D.Associate Professor Camelia Cojocaru

    2012-05-01

    Full Text Available Consolidating the IT field of the company represents a target for most IT responsible, nowadays. At the same time, organizations expect their IT expenditure to increase in the next decade. This paper aims to underline the new generation of information technology and how to use them to make better business decisions in managing enterprise resources and improve customer relationships. The alternative goal is to place the focus not only on developing new software but also on achieving business results, placing particular emphasis on customer relationship management. The purpose of technology is to solve practical business problems, and one of them is the necessity to understand and maintain relationships with the customers. The paper will reveal the companies’ responses to the latest dramatic changes in the informational technologies, in order to cope with the persistence of the global economic crisis and to assure increase of organizational efficiency and profit.

  8. INFORMAL INTERPERSONAL VERBAL COMMUNICATION CONCEPTUALIZATION AND ITS RELATIONSHIP WITH CUSTOMER SATISFACTION

    Isac Florin Lucian

    2012-12-01

    Full Text Available The literature reviewing of Word-of-Mouth Communication shows a few deficiencies in conceptualization of this informal communication form. The paper synthesizes some of the views that authors identified in the literature and explores the relationship between customer satisfaction and this particular form of communicative behavior.

  9. Children's Representations of Family Relationships, Peer Information Processing, and School Adjustment

    Bascoe, Sonnette M.; Davies, Patrick T.; Sturge-Apple, Melissa L.; Cummings, E. Mark

    2009-01-01

    This study examined children's peer information processing as an explanatory mechanism underlying the association between their insecure representations of interparental and parent-child relationships and school adjustment in a sample of 210 first graders. Consistent with emotional security theory (P. T. Davies & E. M. Cummings, 1994), results…

  10. Informality, Power and Relationships in Postgraduate Supervision: Supervising PhD Candidates over Coffee

    Hemer, Susan R.

    2012-01-01

    A great deal of literature in recent years has focused on the supervisory relationship, yet very little has been written about the nature or content of supervisory meetings, beyond commenting on the frequency and length of meetings. Through semi-structured interviews, informal discussions with colleagues and students, a critical review of…

  11. The Relationship between Teacher Attitudes toward the Common Core State Standards and Informational Text

    Estruch, Marcie Jane

    2018-01-01

    This study sought to determine the relationship between teachers' attitudes toward the Common Core State Standards and three predetermined factors. These factors were (1) teachers' attitudes toward the practicality of pedagogical shift three, balancing informational and literary texts, (2) teachers' attitudes toward school support with the…

  12. Students' Attitudes towards Information Technology and the Relationship with Their Academic Achievement

    Abdullah, Zhwan Dalshad; Bit Abu Ziden, Azidah; Binti Chi Aman, Rahimi; Mustafa, Khalid Ismail

    2015-01-01

    The present quantitative study aims to find out the underlying factors of attitudes towards information technology and the relationship with academic achievement among students, through a self-developed questionnaire. The attitudes of the respondents were assessed in terms of three dimensions; namely affection, behavior, and belief. The results…

  13. The relationship between telehealth and information technology ranges from that of uneasy bedfellows to creative partnerships.

    Wade, Victoria A; Hamlyn, Jeremy S

    2013-10-01

    The relationship between the clinical and technical aspects of a telehealth operation is frequently problematic, and technically-driven projects often fail to achieve sustainability. Qualitative data from a study of 37 Australian telehealth services were analysed to understand how the relationship between telehealth providers and information technology (IT) departments helps or hinders the development of telehealth. The most frequent difficulties reported were between telehealth services and the internal IT departments of health services, rather than with external vendors. The difficulties included barriers to installing telehealth over IT networks, a lack of priority given to telehealth services, and IT departments insisting on standardised approach. Alternatively, when IT staff were assigned to supporting clinical staff and had a close working relationship with them, they were major enablers of telehealth services. Authorising dedicated IT support and encouraging joint problem solving should provide a strong foundation for a healthy relationship which contributes to the growth and sustainability of telehealth.

  14. Processing information about support exchanges in close relationships: The role of a knowledge structure

    Bulent eTuran

    2016-02-01

    Full Text Available People develop knowledge of interpersonal interaction patterns (e.g., prototypes and schemas, which shape how they process incoming information. One such knowledge structure based on attachment theory was examined: the secure base script (the prototypic sequence of events when an attachment figure comforts a close relationship partner in distress. In two studies (N = 53 and N = 119, participants were shown animated film clips in which geometric figures depicted the secure base script and asked to describe the animations. Both studies found that many people readily recognize the secure-base script from these minimal cues quite well, suggesting that this script is not only available in the context of specific relationships (i.e., a relationship-specific knowledge: The generalized (abstract structure of the script is also readily accessible, which would make it possible to apply it to any relationship (including new relationships. Regression analyses suggested that participants who recognized the script were more likely to (a include more animation elements when describing the animations, (b see a common theme in different animations, (c create better organized stories, and (d later recall more details of the animations. These findings suggest that access to this knowledge structure helps a person organize and remember relevant incoming information. Furthermore, in both Study 1 and Study 2, individual differences in the ready recognition of the script were associated with individual differences in having access to another related knowledge: indicators suggesting that a potential relationship partner can be trusted to be supportive and responsive at times of stress. Results of Study 2 also suggest that recognizing the script is associated with those items of an attachment measure that concern giving and receiving support. Thus, these knowledge structures may shape how people process support-relevant information in their everyday lives, potentially

  15. Exploring interdisciplinary relationships between linguistics and information retrieval from the 1960s to today

    Engerer, Volkmar Paul

    2017-01-01

    This article explores how linguistics has influenced information retrieval (IR) and attempts to explain the impact of linguistics through an analysis of internal developments in information science generally, and IR in particular. It notes that information science/IR has been evolving from a case...... science into a fully fledged, “disciplined”/disciplinary science. The article establishes correspondences between linguistics and information science/IR using the three established IR paradigms—physical, cognitive, and computational—as a frame of reference. The current relationship between information...... science/IR and linguistics is elucidated through discussion of some recent information science publications dealing with linguistic topics and a novel technique, “keyword collocation analysis,” is introduced. Insights from interdisciplinarity research and case theory are also discussed. It is demonstrated...

  16. Relationship Between Parental and Adolescent eHealth Literacy and Online Health Information Seeking in Taiwan.

    Chang, Fong-Ching; Chiu, Chiung-Hui; Chen, Ping-Hung; Miao, Nae-Fang; Lee, Ching-Mei; Chiang, Jeng-Tung; Pan, Ying-Chun

    2015-10-01

    This study examined the relationship between parental and adolescent eHealth literacy and its impact on online health information seeking. Data were obtained from 1,869 junior high school students and 1,365 parents in Taiwan in 2013. Multivariate analysis results showed that higher levels of parental Internet skill and eHealth literacy were associated with an increase in parental online health information seeking. Parental eHealth literacy, parental active use Internet mediation, adolescent Internet literacy, and health information literacy were all related to adolescent eHealth literacy. Similarly, adolescent Internet/health information literacy, eHealth literacy, and parental active use Internet mediation, and parental online health information seeking were associated with an increase in adolescent online health information seeking. The incorporation of eHealth literacy courses into parenting programs and school education curricula is crucial to promote the eHealth literacy of parents and adolescents.

  17. Exploring moderating effects of proactivity on the relationship between market information and innovation performance

    Branka Ahlin

    2012-04-01

    Full Text Available Despite its importance, the relationship between market information and innovation performance has seldom been investigated in SMEs, much less in multiple-country settings. Given the limited body of knowledge on this important topic, the question of why some entrepreneurs use market information better than others for the purpose of innovation has yet to be addressed. In this study we propose that entrepreneur’s proactivity influences the effectiveness of market information in the innovation process. We propose a conceptual model and test it on SMEs from the United States and Slovenia. The paper concludes by discussing the implications of these results for entrepreneurship theory and practice.

  18. The relationship between information, organizational culture and decision making in an organization

    Paulo Danelon Lopes

    2015-09-01

    Full Text Available Introduction: Includes a documentary research on the relationship between information, organizational culture and decision making in an organization. Objective: The goal is to check the influence of information, considering the organizational culture, decision making in an organization. Methodology: The literature review include authors specialized in the areas of information (Belkin; Borko; Capurro; Choo; Tarapanoff; among others; culture (Fleury et al.; Moraes and Fadel; Nassar and Schein, decision making (Angeloni; Hoppen; Leitão and Nassif; Lousada and Valentim and Oliveira and organization (Bernardes and Marcondes and Maximiano. Results: That there may be a strong interdependency between information, culture and decision making in an organization. Conclusions: The information can facilitate understanding of the culture of an organization, how the processes of change occur and what alternatives can be raised so that she can achieve success in their decision-making process in order to ensure its perpetuation over time.

  19. Has the American Public's Interest in Information Related to Relationships Beyond "The Couple" Increased Over Time?

    Moors, Amy C

    2017-01-01

    Finding romance, love, and sexual intimacy is a central part of our life experience. Although people engage in romance in a variety of ways, alternatives to "the couple" are largely overlooked in relationship research. Scholars and the media have recently argued that the rules of romance are changing, suggesting that interest in consensual departures from monogamy may become popular as people navigate their long-term coupling. This study utilizes Google Trends to assess Americans' interest in seeking out information related to consensual nonmonogamous relationships across a 10-year period (2006-2015). Using anonymous Web queries from hundreds of thousands of Google search engine users, results show that searches for words related to polyamory and open relationships (but not swinging) have significantly increased over time. Moreover, the magnitude of the correlation between consensual nonmonogamy Web queries and time was significantly higher than popular Web queries over the same time period, indicating this pattern of increased interest in polyamory and open relationships is unique. Future research avenues for incorporating consensual nonmonogamous relationships into relationship science are discussed.

  20. Information System Success Model for Customer Relationship Management System in Health Promotion Centers

    Choi, Wona; Rho, Mi Jung; Park, Jiyun; Kim, Kwang-Jum; Kwon, Young Dae

    2013-01-01

    Objectives Intensified competitiveness in the healthcare industry has increased the number of healthcare centers and propelled the introduction of customer relationship management (CRM) systems to meet diverse customer demands. This study aimed to develop the information system success model of the CRM system by investigating previously proposed indicators within the model. Methods The evaluation areas of the CRM system includes three areas: the system characteristics area (system quality, information quality, and service quality), the user area (perceived usefulness and user satisfaction), and the performance area (personal performance and organizational performance). Detailed evaluation criteria of the three areas were developed, and its validity was verified by a survey administered to CRM system users in 13 nationwide health promotion centers. The survey data were analyzed by the structural equation modeling method, and the results confirmed that the model is feasible. Results Information quality and service quality showed a statistically significant relationship with perceived usefulness and user satisfaction. Consequently, the perceived usefulness and user satisfaction had significant influence on individual performance as well as an indirect influence on organizational performance. Conclusions This study extends the research area on information success from general information systems to CRM systems in health promotion centers applying a previous information success model. This lays a foundation for evaluating health promotion center systems and provides a useful guide for successful implementation of hospital CRM systems. PMID:23882416

  1. The Concept of the Relationship between Information System Maturity and Industry Performance in Indonesia

    Palilingan, V. R.; Mario, T. P.

    2018-01-01

    Industry in Indonesia continues to grow from year to year. Along with these developments, the use of information technology, which is the basis of information systems, should be considered as a handy tool to survive in the competition in the industry. Various previous studies have discussed much the use of information systems and their role at the strategic level. But more in-depth research is still needed to find out the extent to which the maturity of the use of information systems through its elements can affect the performance of companies in various sectors industries in Indonesia. It is hoped that this concept can be used as a subsequent research by distributing questionnaires based on the method of statements that have been defined by researchers. With this concepts, the next development will continue to measure the relationship information systems maturity in general with the organizations performance. The result of the concept proposed by the researcher is expected to be able to measure the maturity relationship of an information system with the connection with the consumer, demand/supply planning element, innovation, performance measurement, IT impact management and also internal process.

  2. Information system success model for customer relationship management system in health promotion centers.

    Choi, Wona; Rho, Mi Jung; Park, Jiyun; Kim, Kwang-Jum; Kwon, Young Dae; Choi, In Young

    2013-06-01

    Intensified competitiveness in the healthcare industry has increased the number of healthcare centers and propelled the introduction of customer relationship management (CRM) systems to meet diverse customer demands. This study aimed to develop the information system success model of the CRM system by investigating previously proposed indicators within the model. THE EVALUATION AREAS OF THE CRM SYSTEM INCLUDES THREE AREAS: the system characteristics area (system quality, information quality, and service quality), the user area (perceived usefulness and user satisfaction), and the performance area (personal performance and organizational performance). Detailed evaluation criteria of the three areas were developed, and its validity was verified by a survey administered to CRM system users in 13 nationwide health promotion centers. The survey data were analyzed by the structural equation modeling method, and the results confirmed that the model is feasible. Information quality and service quality showed a statistically significant relationship with perceived usefulness and user satisfaction. Consequently, the perceived usefulness and user satisfaction had significant influence on individual performance as well as an indirect influence on organizational performance. This study extends the research area on information success from general information systems to CRM systems in health promotion centers applying a previous information success model. This lays a foundation for evaluating health promotion center systems and provides a useful guide for successful implementation of hospital CRM systems.

  3. Detection of relationships among multi-modal brain imaging meta-features via information flow.

    Miller, Robyn L; Vergara, Victor M; Calhoun, Vince D

    2018-01-15

    Neuroscientists and clinical researchers are awash in data from an ever-growing number of imaging and other bio-behavioral modalities. This flow of brain imaging data, taken under resting and various task conditions, combines with available cognitive measures, behavioral information, genetic data plus other potentially salient biomedical and environmental information to create a rich but diffuse data landscape. The conditions being studied with brain imaging data are often extremely complex and it is common for researchers to employ more than one imaging, behavioral or biological data modality (e.g., genetics) in their investigations. While the field has advanced significantly in its approach to multimodal data, the vast majority of studies still ignore joint information among two or more features or modalities. We propose an intuitive framework based on conditional probabilities for understanding information exchange between features in what we are calling a feature meta-space; that is, a space consisting of many individual featurae spaces. Features can have any dimension and can be drawn from any data source or modality. No a priori assumptions are made about the functional form (e.g., linear, polynomial, exponential) of captured inter-feature relationships. We demonstrate the framework's ability to identify relationships between disparate features of varying dimensionality by applying it to a large multi-site, multi-modal clinical dataset, balance between schizophrenia patients and controls. In our application it exposes both expected (previously observed) relationships, and novel relationships rarely considered investigated by clinical researchers. To the best of our knowledge there is not presently a comparably efficient way to capture relationships of indeterminate functional form between features of arbitrary dimension and type. We are introducing this method as an initial foray into a space that remains relatively underpopulated. The framework we propose is

  4. Relationship between determinant factors of disclosure of information on environmental impacts of Brazilian companies

    Mara Vogt

    2017-01-01

    Full Text Available This study aims at analyzing the relationship between determinant factors of disclosure of information on environmental impacts of Brazilian companies. A descriptive, documental and quantitative research was conducted through a sample of 97 Brazilian companies. In the Sustainability Reports and in the Annual Reports information, five environmental aspects were collected: emissions, effluents, wastes, products and services; and transport, which were used to measure the degree of environmental disclosure. This concludes that there is a relationship between the variables investigated in all analyzed years. The size, audit and Global Reporting Initiative (GRI are associated with disclosure and the Corporate Sustainability Index (CSI, Pollution Potential (POTEN, governance, stocks, Return on Assets (ROA and Return on Equity (ROE are not.

  5. A genetically informative developmental study of the relationship between conduct disorder and peer deviance in males

    Kendler, K. S.; Jacobson, K.; Myers, J. M.; Eaves, L. J.

    2014-01-01

    Background Conduct disorder (CD) and peer deviance (PD) both powerfully predict future externalizing behaviors. Although levels of CD and PD are strongly correlated, the causal relationship between them has remained controversial and has not been examined by a genetically informative study. Method Levels of CD and PD were assessed in 746 adult male–male twin pairs at personal interview for ages 8–11, 12–14 and 15–17 years using a life history calendar. Model fitting was performed using the Mx program. Results The best-fit model indicated an active developmental relationship between CD and PD including forward transmission of both traits over time and strong causal relationships between CD and PD within time periods. The best-fit model indicated that the causal relationship for genetic risk factors was from CD to PD and was constant over time. For common environmental factors, the causal pathways ran from PD to CD and were stronger in earlier than later age periods. Conclusions A genetically informative model revealed causal pathways difficult to elucidate by other methods. Genes influence risk for CD, which, through social selection, impacts on the deviance of peers. Shared environment, through family and community processes, encourages or discourages adolescent deviant behavior, which, via social influence, alters risk for CD. Social influence is more important than social selection in childhood, but by late adolescence social selection becomes predominant. These findings have implications for prevention efforts for CD and associated externalizing disorders. PMID:17935643

  6. Shared Management Information in Buyer/Supplier Relationships: Its Usefulness and its Influence on Continuity Expectations

    Juan Manuel Ramón Jerónimo

    2007-12-01

    Full Text Available This paper is focused on the effect that the exchange of management information has on client and/or supplier relationships. Moreover, this study extends the concept of the usefulness of management control information to inter-organizational relationships, analysing how the scope of such information affects continuity expectations, and how these in turn influence opportunistic behaviour and the mutual adaptation of production systems. The data was gathered from 104 purchasing and 90 sales managers of equipment manufacturers on the nature of their respective relationships with their suppliers/ clients. The results confirm that the use of broad-scope management control information sharing in buyer-supplier relationships increases continuity expectations and reduces opportunistic behaviour.El objetivo de este trabajo es analizar el efecto que ejerce el intercambio de información de gestión sobre las relaciones con clientes y/o proveedores. Para ello, se extiende el concepto de la utilidad de información de control de gestión a las relaciones ínter-organizativas, analizando cómo su contenido afecta a las expectativas de continuidad y éstas a su vez influyen en el comportamiento oportunista y en la adaptación mutua de sistemas de producción. Los datos analizados se han obtenido de las relaciones entre 104 directores de compras y 90 directores de ventas de empresas industriales con sus proveedores y clientes. Los resultados confirman que utilizar información compartida de control de gestión con un contenido más amplio en las relaciones compredor/proveedor favorece la creación de expectativas de continuidad y reduce comportamientos oportunistas.

  7. Informal caregiving and intimate relationships: the experiences of spouses of UK military personnel

    Thandi, Gursimran; Oram, S.; Verey, A.; Greenberg, N.; Fear, N. T.

    2017-01-01

    Aim Currently, there is no research available on the experiences of spouses providing informal care to wounded, injured or sick (WIS) UK military personnel. The aim of this study was to fill this gap by investigating the relationship experiences of non-military partners caring for WIS UK military personnel.Methods Spouses of WIS military personnel (n=25) completed telephone interviews with the research team. The data were transcribed and analysed using thematic analysis. The transcripts were ...

  8. Knowledge sharing and innovation in relationships interorganizational type of information technology outsourcing

    Roberta Rodrigues Faoro

    2017-04-01

    Full Text Available Introduction: this paper presents an analysis of the sharing of knowledge and innovation in the inter-relationships of the type outsourcing of Information Technology. Objective: analyze the existence of relationship between knowledge sharing and innovation in the inter-relationships of the type of outsourcing information technology (IT. Methodology: research is exploratory, qualitative and using as a strategy the multiple case study, which analyzed 12 companies in IT outsourcing environments, 4 suppliers of IT and IT 8 client companies. Data were collected through semi structured interviews, documentary and direct observation. Results: it can be noted that the sharing of knowledge showed contribute to the existence of innovation in IT outsourcing environment. The suppliers prioritize the codification of shared knowledge, while customers prefer the sharing of knowledge through informal conversations. It was identified that the motives for outsourcing IT may be related to the sharing of knowledge and innovation. Conclusions: this research contributes to the advancement of knowledge about the knowledge and innovation sharing phenomena in outsourcing of IT environments.

  9. Perception and Assessment of Verbal and Written Information on Sex and Relationships after Hematopoietic Stem Cell Transplantation.

    Wendt, Christel

    2017-12-01

    This study aimed to investigate experiences of verbal and written information about sex and relationships among men and women treated with hematopoietic stem cell transplantation. The study also aimed to investigate the demand for information and assessment of the quality of written patient information material entitled "Sex and relationships in the treatment of blood diseases." Few studies exist that shed any light on the demand for information about sex and relationships on the part of patients with hematological diseases before, during, and after their treatment. A total of 216 patients undergoing treatment for malignant blood diseases between 2000 and 2010 participated in this study. Patients' experiences of information about sex and relationships, and their opinions about the written patient information, were assessed using a questionnaire created specifically for this study. Most patients (81 %) had not received information about sex and relationships from a healthcare professional. Almost 90 % of men felt that verbal information was important, compared with 82 % of women. The majority also held that written information was important. These results indicate that patients, regardless of gender, age, and treatment, consider oral and written information about sex and relationships to be important and that the healthcare system should provide the information. The written patient information was considered to play an important role in creating an opening for a conversation about a sensitive topic such as sexuality, and also as a source of reference and support for the patient and his/her partner.

  10. The relationship between students’ use of ICT for social communication and their computer and information literacy

    Meral Alkan

    2016-09-01

    Full Text Available Abstract This study investigates the relationship between students’ use of information and communication technology (ICT for social communication and their computer and information literacy (CIL scores. It also examines whether gender and socioeconomic background moderates this relationship. We utilized student data from IEA’s International Computer and Information Study (ICILS to build multivariate regression models for answering the research questions, and accounted for the complex sample structure of the data by using weights for all statistical analyses, employing jackknife repeated replication for variance estimation. Students who frequently use the internet for messaging and participation in social networks (i.e., at least once a week scored on average 44 points higher than those who use ICT for the same purpose only less than once a week or never. The direction of this effect was the same in all 21 participating educational systems, the difference ranging from 19 to 75 points (always statistically significant. We continued the analysis by testing whether the relationship is moderated by gender; as girls use more often ICT for social communication and have higher CIL scores on average. After controlling for the gender effect the CIL scores between the two examined groups decreased only by 2 points on average. Even after including students’ socio-economic background into the model, the difference in CIL between the two groups of interest declined only little—to 32 points on average across all countries. The difference remained to be statistically significant in all countries but one. The results suggest a strong relationship between students’ CIL proficiency level and the frequency of their use of electronic devices for social communication; hence, respective skills needed at schools and later on at the workplace are reflected in their use outside of school and for socializing.

  11. Doing the Organizational Tango: Symbiotic Relationship between Formal and Informal Organizational Structures for an Agile Organization

    Irena Malgorzata Ali

    2016-04-01

    Full Text Available This paper reports on research with a broad objective to examine the relationship between two organizational entities, the formally structured organization and informal organizational structures, in a changing operational environment, more specifically during military deployments. The paper draws on organizational and complexity paradigms; based on empirical evidence obtained through qualitative techniques, it describes mechanisms that enable a symbiotic relationship between these two organizational structures in a complex operational landscape. Substantive findings provide insights into the dynamics of the interactions between these structures and illuminate the relationship between three enabling factors – accountability, responsible autonomy, and command and control arrangements – that need to be considered to fully exploit the strengths inherent in both formal and informal structures. Based on these findings, a model for enhancement of organizational agility in response to changes in a complex operational environment is described. The model is predicated on feedback and mutual adjustment of the organization, institution and individual through sensemaking; it illustrates the dynamic nature of interactions that are required for such a response.

  12. Nurses' Perceptions of Their Relationships with Informal Carers in Institutional Respite Care for Older People

    Sirpa Salin

    2013-01-01

    Full Text Available The purpose of this study was to describe nurses' experiences of their collaboration and relationships with family members in institutional respite care for the elderly. The family has a particularly important role in respite care, which is an extension of care provided at home. However no published studies were found on this subject. The data were collected through qualitative interviews (N=22. Content analysis of the nurses’ descriptions of their collaboration with family members yielded four main categories as follows: (1 conscious ignoring, (2 attempting to understand the family’s situation, (3 hinting at private family matters, and (4 being a friend. The results lend support to earlier findings which emphasize the complexity of relationships between nurses and family carers. A novel finding here is that these relationships may also develop into friendships. Greater emphasis must be placed on primary nursing so that the nurse and informal carer can build up a genuine relationship of trust. If periods of respite care are to help older people and their families to manage independently, it is imperative that nurses have the opportunity to visit their patients at home.

  13. RELATIONSHIP BETWEEN INWARD FOREIGN DIRECT INVESTMENT, DOMESTIC INVESTMENT, FORMAL AND INFORMAL INSTITUTIONS: EVIDENCE FROM CHINA

    Waqar Ameer

    2017-07-01

    Full Text Available This study examines relationship between Inward FDI and domestic investment in China, using co-integration and Granger causality analysis (Including bivariate and multivariate Granger causality models. We have used auto-regressive distributed lags(ARDL econometric methodology technique to define relationship between inward FDI and domestic investment using time series data for China. Our study examines long run effects of FDI inflows on domestic investment over time span 1990-2014 for China using informal, formal institutions and key macroeconomic variables as control variables in the model. The results suggest that conclusions drawn from bivariate model may not be valid because of omission of important control variables. Our results of multivariate model show that there is positive unidirectional causality running from IFDI to DI in the long run. In the short run, both inward FDI and domestic investment do not allow Granger causality.

  14. IMPACT OF INFORMATION TECHNOLOGY (IT TOOLS, PARTNER RELATIONSHIP AND SUPPLY CHAIN PERFORMANCE

    Ramayah T.

    2008-01-01

    Full Text Available This paper proposes a model that assesses the usage of information technology (IT tools, commitment of partner relationships, and supply chain performance in the Malaysian manufacturing industry. A total of 250 questionnaires were distributed to manufacturingcompanies located in Penang, which is in the northern region of Malaysia. Applying multiple regression analysis, the study indicated that a higher level of supply chain partner commitment leads to a higher level of supply chain reliability and flexibility. Trust among supply chain partners also contributes to improving supply chain flexibility. The study focused only on inter-organisational relationships. Future research should examine how both inter- and intra-organisational collaboration impact supply chain performance. Although researchers have recognised that IT is an enabler of supply chain management (SCM activities, there has been limited research that has directly associated the usage of IT and partner relationships to supply chain performance. This research is essential in order to ascertain the impact of IT usage and partnerrelationships on improving supply chain performance, particularly in the Malaysian manufacturing environment.

  15. A study on relationship between information technology facilities and performance of banking industry

    M. Khodaei Valahzaghard

    2013-03-01

    Full Text Available The recent advances on information technology have made tremendous change on traditional banking. These days, people do not carry cash and prefer to use electronic devices such as point of sale system (POS or PIN entry devices (PinPad to do desirable transactions. These technologies could facilitate e-business and increase profitability in various industries including banking sector. The purpose of this paper is to investigate the effect of five new products namely ATM, POS Machines, PinPad machines, online and swift branches on banking performance indicators including return on assets (ROA, return on equities (ROE and operating investment return (OIR. We use the information of 19 private and governmental banks, which were active in Iran over the period of 2005-2010. The study uses linear regression analysis as well as VAR technique to study the effects of the independent variables on bank performance indicators. The results indicate that while there are some weak and positive relationships between three technology indicators including POS, PinPad and online businesses and ROA as well as ROE, there is relatively strong and positive relationship between these three independent variables and OIR. In addition, while the results of VAR analysis have shown that any reduction on PinPad will reduce OIR but this reduction will disappear after approximately four periods.

  16. Investigation of relationship between mental workload and information flow rate of accident diagnosis tasks in NPPs

    Ha, Chang Hoon

    2005-02-01

    The objective of this study is to investigate experimentally the relationship between an operator's mental workload and the information flow rate of accident diagnosis tasks and further to propose the information flow rate as an analytic method for measuring the mental workload. There are two types of mental workload in the advanced MCR of NPPs: the information processing workload, which is the processing that the human operator must actually perform in order to complete the diagnosis task, and emotional stress workload experienced by the operator. In this study, the focus is on the former. Three kinds of methods are used to measure the operator's workload: information flow rate, subjective methods, and physiological measures. Information flows for eight accident diagnosis tasks are modeled qualitatively using a stage model and are quantified using Conant's model. The eight accident cases are considered here are: Loss Of Coolant Accident (LOCA), Steam Generator Tube Rupture (SGTR), Steam Line Break (SLB), Feedwater Line Break (FLB), Pressurizer (PZR) spray and heater failure, Reactor Coolant Pump (RCP) trip, Main Steam Isolation Valve (MSIV) failure, and PZR spray failure. The information flow rate is obtained for each diagnosis task by imposing time limit restrictions for the tasks. Subjective methods require the operators to respond to questionnaires to rate their level of mental effort. NASA-TLX and MCH scale are selected as subjective methods. NASA-TLX is a subjective method used in the various fields including the aviation, automobile, and nuclear industries. It has a multi-dimensional rating technique and provides an overall workload score based on a weighted average on six subscales using pair-wise comparison tests. MCH, on the other hand, is one-dimensional and uses a 10- point rating technique. As with NASA-TLX, the higher the score is, the higher the subjective workload is. For the physiological measurements, an eye tracking system analyzes eye movements

  17. Investigation of relationship between mental workload and information flow rate of accident diagnosis tasks in NPPs

    Ha, Chang Hoon

    2005-02-15

    The objective of this study is to investigate experimentally the relationship between an operator's mental workload and the information flow rate of accident diagnosis tasks and further to propose the information flow rate as an analytic method for measuring the mental workload. There are two types of mental workload in the advanced MCR of NPPs: the information processing workload, which is the processing that the human operator must actually perform in order to complete the diagnosis task, and emotional stress workload experienced by the operator. In this study, the focus is on the former. Three kinds of methods are used to measure the operator's workload: information flow rate, subjective methods, and physiological measures. Information flows for eight accident diagnosis tasks are modeled qualitatively using a stage model and are quantified using Conant's model. The eight accident cases are considered here are: Loss Of Coolant Accident (LOCA), Steam Generator Tube Rupture (SGTR), Steam Line Break (SLB), Feedwater Line Break (FLB), Pressurizer (PZR) spray and heater failure, Reactor Coolant Pump (RCP) trip, Main Steam Isolation Valve (MSIV) failure, and PZR spray failure. The information flow rate is obtained for each diagnosis task by imposing time limit restrictions for the tasks. Subjective methods require the operators to respond to questionnaires to rate their level of mental effort. NASA-TLX and MCH scale are selected as subjective methods. NASA-TLX is a subjective method used in the various fields including the aviation, automobile, and nuclear industries. It has a multi-dimensional rating technique and provides an overall workload score based on a weighted average on six subscales using pair-wise comparison tests. MCH, on the other hand, is one-dimensional and uses a 10- point rating technique. As with NASA-TLX, the higher the score is, the higher the subjective workload is. For the physiological measurements, an eye tracking system analyzes

  18. The Relationship between Environmental Turbulence, Management Support, Organizational Collaboration, Information Technology Solution Realization, and Process Performance, in Healthcare Provider Organizations

    Muglia, Victor O.

    2010-01-01

    The Problem: The purpose of this study was to investigate relationships between environmental turbulence, management support, organizational collaboration, information technology solution realization, and process performance in healthcare provider organizations. Method: A descriptive/correlational study of Hospital medical services process…

  19. The Relationship between Job Satisfaction and Intent to Turnover among Software Engineers in the Information Technology Industry

    Agada, Chuks N.

    2013-01-01

    The focus of this study was to examine the relationship between job satisfaction and intent to turnover among software engineers in the information technology (IT) industry. The population that was analyzed in this study was software engineers in the IT industry to determine whether there is a relationship between job satisfaction and intent to…

  20. The Relationship between Information Exchange Benefits and Performance: the Mediating Effect of Supply Chain Compliance in the Chinese Poultry Chain

    Peng, G.; Trienekens, J.H.; Omta, S.W.F.; Wang, W.

    2012-01-01

    This paper aims to examine the relationships between information exchange benefits and company performance, and the mediating effect of supply chain compliance on this relationship. A sample of 165 buying companies and of 96 suppliers were analyzed by partial least square (PLS) path modeling. Five

  1. Reconnect on Facebook: The Role of Information Seeking Behavior and Individual- and Relationship-Level Factors.

    Ramirez, Artemio; Sumner, Erin M; Hayes, Jameson

    2016-08-01

    Social network sites (SNSs) such as Facebook function as both venues for reconnecting with associates from a user's past and sources of social information about them. Yet, little is known about what factors influence the initial decision to reconnect with a past associate. This oversight is significant given that SNSs and other platforms provide an abundance of social information that may be utilized for reaching such decisions. The present study investigated the links among relational reconnection, information seeking (IS) behavior, and individual- and relationship-level factors in user decisions to reconnect on Facebook. A national survey of 244 Facebook users reported on their most recent experience of receiving a friend request from someone with whom they had been out of contact for an extended period. Results indicated that uncertainty about the potential reconnection partner and forecast about the reconnection's potential reward level significantly predicted IS behavior (passive on both target and mutual friends' SNS pages as well as active). However, the emergence of their two-way interaction revealed that the forecasts moderated the IS-uncertainty link on three of the strategies (extractive, both passive approaches). Moreover, social anxiety, sociability, uncertainty about the partner, the forecast about the reconnection's reward level, and extractive and passive (target SNS pages) strategies significantly predicted user decisions to reconnect. Future directions for research on relational reconnection on SNSs are offered.

  2. A study on technology development strategy and collaborative relationships using patent information

    Nakaoka, Iori; Fujino, Hayato; Chen, Yunju; Park, Yousin; Matsuno, Seigo

    2017-10-01

    Japanese economy has fallen into a long downturn called "The Lost Two Decades" after the collapse of bubble economy in early 1990s. Many companies could not gain competitive advantages although they conducted various management reforms to restore their competitiveness. The companies that have played the main role of the Japanese economy growth until then have lost the sustained competitive advantage. Moreover, they have struggled in the global market even now. On the other hand, Japanese automobile companies have high competitiveness and market share due to their advanced technology development. It is considered that personnel groups engaged in research and development of their companies cannot turn into core rigidity and the structure also hinders new core capabilities. In addition, there is a hypothesis that the close relationships with many suppliers contribute to acquisition of competitive advantage. Therefore, this paper focuses on the collaboration relationships with suppliers and core rigidity of human resources related to research and development as the analysis factors. First, we analyze the composition and core rigidity degree of human resources involved in technology development by social network analysis using patent information, which represents the research and development capability. Second, we analyze the degree of collaboration among companies based on the hypothesis that advanced technology development can be executed by joint research and developments with many kinds of suppliers. As a result, features of close collaboration with suppliers and high core rigidity rate in the Japanese automobile industry are clarified.

  3. Informal caregiving and intimate relationships: the experiences of spouses of UK military personnel.

    Thandi, Gursimran; Oram, S; Verey, A; Greenberg, N; Fear, N T

    2017-08-01

    Currently, there is no research available on the experiences of spouses providing informal care to wounded, injured or sick (WIS) UK military personnel. The aim of this study was to fill this gap by investigating the relationship experiences of non-military partners caring for WIS UK military personnel. Spouses of WIS military personnel (n=25) completed telephone interviews with the research team. The data were transcribed and analysed using thematic analysis. The transcripts were cross-coded and checked for inter-rater reliability. Six major themes were identified: (1) communication between couples, (2) adverse family environment, (3) reintegration, (4) intimacy, (5) financial uncertainty and (6) transition from partner to caregiver. Partners caring for injured/ill military personnel appear to be at risk of experiencing personal distress caused by impaired relationship functioning, which may lead to diminished physical and mental well-being. Partners of WIS military personnel experience significant levels of distress and burden associated with caregiving in the form of arguments with the military partner, problems in reintegration and a lack of physical and emotional intimacy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. A Quantitative Study on the Relationship of Information Security Policy Awareness, Enforcement, and Maintenance to Information Security Program Effectiveness

    Francois, Michael T.

    2016-01-01

    Today's organizations rely heavily on information technology to conduct their daily activities. Therefore, their information security systems are an area of heightened security concern. As a result, organizations implement information security programs to address and mitigate that concern. However, even with the emphasis on information security,…

  5. Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

    Silva, Wender A.; Andrade, Carlos Kleber Z.; Napolitano, Hamilton B., E-mail: wender@unb.br, E-mail: ckleber@unb.br [Universidade de Brasilia (LaQMOS/UnB), DF (Brazil). Inst. de Quimica; Vencato, Ivo; Castro, Miriam R.C. de; Camargo, Ademir J. [Universidade Estadual de Goias (UEG), Anapolis, GO (Brazil). Ciencias Exatas e Tecnologicas; Lariucci, Carlito [Universidade Estadual de Goias (UEG), Goiania, GO (Brazil). Inst. de Fisica

    2013-01-15

    The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structure activity relationship. (author)

  6. A qualitative analysis of changes in relationship dynamics and roles between people with cancer and their primary informal carer.

    Ussher, Jane M; Tim Wong, W K; Perz, Janette

    2011-11-01

    It is widely accepted that cancer is an intersubjective experience that impacts upon the psychological well-being of people with cancer and informal carers, as well as on couple relationships. This qualitative study examined the nature and consequences of cancer on the relationship between informal carers and the person with cancer, from the perspective of Australian cancer carers. Sixty-two carers (42 women and 20 men), across a range of cancer types, stages and relationship dyads took part in semi-structured interviews. Participants reported that cancer had precipitated a change in roles and in the dynamics of the relationship, including having to take on quasi-medical tasks and decisions, neglecting self and other relationships, changes to the emotions or personality of the person with cancer, changed patterns of communication, and changes to sexuality and intimacy. The impact of the changed relationship included sadness, anger and frustration, as well as feelings of love and being closer together, resulting in relationship enhancement. Women were more likely to report changes in the person with cancer and to mourn the previous relationship, while more men reported relationship enhancement.

  7. [The relationship between self-esteem and self-disclosure of negative information].

    Katayama, M

    1996-12-01

    Although self-disclosure after a negative experience may be good for our adjustment, we also feel hesitant to do so. This study investigated the relationship between self-esteem and hesitancy to disclose negative information about one's self. One hundred and fifty-five undergraduates imagined self-disclosure to a friend of high or low intimacy. They then answered a questionnaire concerning hesitancy to self-disclose negative information to friends, as well as expected negative consequences of such self-disclosure. Main results were: (1) Low intimacy strongly affected the hesitancy. (2) Factor analysis of the negative consequences found three factors: interpersonal and intra-personal negative-effect, and no positive expectation. (3) Hesitancy of high self-esteem students was most affected by the interpersonal factor. Impression management may be the reason. (4) On the other hand, low students tended to feel hurt after negative self-disclosure. Theirs was affected by the intra-personal and no positive expectation factors. Defensiveness may be the reason. The results were discussed from the viewpoint of adjustment when people have had a negative experience.

  8. Information processing speed mediates the relationship between white matter and general intelligence in schizophrenia.

    Alloza, Clara; Cox, Simon R; Duff, Barbara; Semple, Scott I; Bastin, Mark E; Whalley, Heather C; Lawrie, Stephen M

    2016-08-30

    Several authors have proposed that schizophrenia is the result of impaired connectivity between specific brain regions rather than differences in local brain activity. White matter abnormalities have been suggested as the anatomical substrate for this dysconnectivity hypothesis. Information processing speed may act as a key cognitive resource facilitating higher order cognition by allowing multiple cognitive processes to be simultaneously available. However, there is a lack of established associations between these variables in schizophrenia. We hypothesised that the relationship between white matter and general intelligence would be mediated by processing speed. White matter water diffusion parameters were studied using Tract-based Spatial Statistics and computed within 46 regions-of-interest (ROI). Principal component analysis was conducted on these white matter ROI for fractional anisotropy (FA) and mean diffusivity, and on neurocognitive subtests to extract general factors of white mater structure (gFA, gMD), general intelligence (g) and processing speed (gspeed). There was a positive correlation between g and gFA (r= 0.67, p =0.001) that was partially and significantly mediated by gspeed (56.22% CI: 0.10-0.62). These findings suggest a plausible model of structure-function relations in schizophrenia, whereby white matter structure may provide a neuroanatomical substrate for general intelligence, which is partly supported by speed of information processing. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. The relationship between hospital and ehr vendor market dynamics on health information organization presence and participation.

    Lin, Sunny C; Adler-Milstein, Julia

    2018-05-08

    Health Information Organizations (HIOs) are third party organizations that facilitate electronic health information exchange (HIE) between providers in a geographic area. Despite benefits from HIE, HIOs have struggled to form and subsequently gain broad provider participation. We sought to assess whether market-level hospital and EHR vendor dynamics are associated with presence and level of hospital participation in HIOs. 2014 data on 4523 hospitals and their EHR vendors were aggregated to the market level. We used multivariate OLS regression to analyze the relationship between hospital and vendor dynamics and (1) probability of HIO presence and (2) percent of hospitals participating in an HIO. 298 of 469 markets (64%) had HIO presence, and in those markets, 47% of hospitals participated in an HIO on average. In multivariate analysis, four characteristics were associated with HIO presence. Markets with more hospitals, markets with more EHR vendors, and markets with an EHR vendor-led HIE approach were more likely to have an HIO. Compared to markets with low hospital competition, markets with high hospital competition had a 25 percentage point lower probability of HIO presence. Two characteristics were associated with level of hospital HIO participation. Markets with more hospitals as well as markets with high vendor competition (compared to low competition) had lower participation. Both hospital and EHR vendor dynamics are associated with whether a market has an HIO as well as the level of hospital participation in HIOs.

  10. [Sex differences in relationship between creativity and hemispheric information processing in global and local levels].

    Razumnikova, O M; Vol'f, N V

    2012-01-01

    Sex differences in creativity related global-local hemispheric selective processing were examined by hierarchical letter presenting in conditions of their perception and comparison. Fifty-six right-handed males and 68 females (aged 17-22 years) participated in the experiments. Originality-imagery was assessed by a computer-based Torrance 'Incomplete Figures' test software. Verbal creativity was valued by original sentence using of three nouns from remote semantic categories. The results show that irrespectively of the sex factor and the type of creative thinking, its originality is provided by high speed of right-hemispheric processes of information selection on the global level and delay in the interhemispheric communication. Relationships between originality of ideas and hemispheric attentional characteristics are presented mostly in men while verbal creative problem solving, and in women while figurative original thinking. Originality of verbal activity in men is more associated with success of selective processes in the left hemisphere, but in women--with selective functions of both hemispheres. Figurative thinking in men is less related to hemispheric characteristics of attention compared with women. Increase of figurative originality in women is accompanied acceleration of processes of selection of the information in the right hemisphere, and also higher efficiency of local attention as well as speeds ofglobal processing in the left hemisphere.

  11. Combining Empirical Relationships with Data Based Mechanistic Modeling to Inform Solute Tracer Investigations across Stream Orders

    Herrington, C.; Gonzalez-Pinzon, R.; Covino, T. P.; Mortensen, J.

    2015-12-01

    Solute transport studies in streams and rivers often begin with the introduction of conservative and reactive tracers into the water column. Information on the transport of these substances is then captured within tracer breakthrough curves (BTCs) and used to estimate, for instance, travel times and dissolved nutrient and carbon dynamics. Traditionally, these investigations have been limited to systems with small discharges (turbidity (e.g., nitrate signals with SUNA instruments or fluorescence measures) and/or high total dissolved solids (e.g., making prohibitively expensive the use of salt tracers such as NaCl) in larger systems. Additionally, a successful time-of-travel study is valuable for only a single discharge and river stage. We have developed a method to predict tracer BTCs to inform sampling frequencies at small and large stream orders using empirical relationships developed from multiple tracer injections spanning several orders of magnitude in discharge and reach length. This method was successfully tested in 1st to 8th order systems along the Middle Rio Grande River Basin in New Mexico, USA.

  12. Information technology as a facilitator of suppliers’ collaborative communication, network governance and relationship longevity in supply chains

    Richard Chinomona

    2013-08-01

    Full Text Available There is an increasing awareness about the paramount importance of information technology within business in the context of large businesses. However, research about the investigation of the role of information technology resources in fostering collaborative communication, network governance and relationship longevity in the small and medium enterprise sector has remained scant. The primary objective of this study was to investigate the influence of information technology on collaborative communication, network governance and relationship longevity in Zimbabwe’s SME sector. Five research hypotheses were posited and sample data from 162 small and medium enterprise suppliers were collected and used to empirically test the hypotheses. The results of this study showed that information technology resources positively influenced small and medium enterprise suppliers’ collaborative communication, network governance and consequential relationship longevity with their buyers in a significant way. Overall, the current study findings provided tentative support to the proposition that information technology resources, collaborative communication and network governance should be recognised as significant antecedents for improved relationship longevity between suppliers and their buyers in the SME setting. Therefore, managers in the small and medium enterprise sector and small and medium enterprise owners need to pay attention to both collaborative communication and network governance in order to optimise information technology resource impact on their relationship longevity with their business counterparts. Limitations and future research directions were also indicated.

  13. Sex, Body Image, and Relationships: A BRIGHTLIGHT Workshop on Information and Support Needs of Adolescents and Young Adults.

    Martins, Ana; Taylor, Rachel M; Lobel, Brian; McCann, Beth; Soanes, Louise; Whelan, Jeremy S; Fern, Lorna A

    2018-05-09

    Discovering sexuality and romantic relationships are important development milestones in adolescence and young adulthood. A cancer diagnosis imposes obstacles for young people such as changes in their sexual function due to the disease and/or side effects of treatment, body image concerns, and interpersonal relationship difficulties. This can cause psychological distress and can impact on quality of life. We aimed to explore sexual health information and support needs of adolescents and young adults with cancer. Five young people aged 16-24 years, with a previous cancer diagnosis when aged 13-22 years, attended an in-depth 4-hour workshop. The framework approach was used to analyze workshop transcripts. Three overarching themes emerged: (i) information sharing; (ii) contexts and relationships (influencing factors); and (iii) information sharing preferences. Information shared by healthcare professionals was focused on a medicalized view of sex with symptoms, infection control, and protected sex at its core. Young people had unanswered questions related to sexual function, the impact of cancer and how to manage it, and about pleasure, body image, and relationships. Parents' presence at clinical consultations inhibited discussions about sex. Young people wanted professionals who were comfortable to talk about sex with them. Young people exhibited significant unmet needs around information provision on sex, body image, and relationships. They wanted information to be given by professionals and access to online resources. Development of training for professionals and resources to support young people requires further work.

  14. Identification of hidden relationships from the coupling of hydrophobic cluster analysis and domain architecture information.

    Faure, Guilhem; Callebaut, Isabelle

    2013-07-15

    Describing domain architecture is a critical step in the functional characterization of proteins. However, some orphan domains do not match any profile stored in dedicated domain databases and are thereby difficult to analyze. We present here an original novel approach, called TREMOLO-HCA, for the analysis of orphan domain sequences and inspired from our experience in the use of Hydrophobic Cluster Analysis (HCA). Hidden relationships between protein sequences can be more easily identified from the PSI-BLAST results, using information on domain architecture, HCA plots and the conservation degree of amino acids that may participate in the protein core. This can lead to reveal remote relationships with known families of domains, as illustrated here with the identification of a hidden Tudor tandem in the human BAHCC1 protein and a hidden ET domain in the Saccharomyces cerevisiae Taf14p and human AF9 proteins. The results obtained in such a way are consistent with those provided by HHPRED, based on pairwise comparisons of HHMs. Our approach can, however, be applied even in absence of domain profiles or known 3D structures for the identification of novel families of domains. It can also be used in a reverse way for refining domain profiles, by starting from known protein domain families and identifying highly divergent members, hitherto considered as orphan. We provide a possible integration of this approach in an open TREMOLO-HCA package, which is fully implemented in python v2.7 and is available on request. Instructions are available at http://www.impmc.upmc.fr/∼callebau/tremolohca.html. isabelle.callebaut@impmc.upmc.fr Supplementary Data are available at Bioinformatics online.

  15. Dynamic relationships between microbial biomass, respiration, inorganic nutrients and enzyme activities: informing enzyme based decomposition models

    Daryl L Moorhead

    2013-08-01

    Full Text Available We re-examined data from a recent litter decay study to determine if additional insights could be gained to inform decomposition modeling. Rinkes et al. (2013 conducted 14-day laboratory incubations of sugar maple (Acer saccharum or white oak (Quercus alba leaves, mixed with sand (0.4% organic C content or loam (4.1% organic C. They measured microbial biomass C, carbon dioxide efflux, soil ammonium, nitrate, and phosphate concentrations, and β-glucosidase (BG, β-N-acetyl-glucosaminidase (NAG, and acid phosphatase (AP activities on days 1, 3, and 14. Analyses of relationships among variables yielded different insights than original analyses of individual variables. For example, although respiration rates per g soil were higher for loam than sand, rates per g soil C were actually higher for sand than loam, and rates per g microbial C showed little difference between treatments. Microbial biomass C peaked on day 3 when biomass-specific activities of enzymes were lowest, suggesting uptake of litter C without extracellular hydrolysis. This result refuted a common model assumption that all enzyme production is constitutive and thus proportional to biomass, and/or indicated that part of litter decay is independent of enzyme activity. The length and angle of vectors defined by ratios of enzyme activities (BG/NAG versus BG/AP represent relative microbial investments in C (length, and N and P (angle acquiring enzymes. Shorter lengths on day 3 suggested low C limitation, whereas greater lengths on day 14 suggested an increase in C limitation with decay. The soils and litter in this study generally had stronger P limitation (angles > 45˚. Reductions in vector angles to < 45˚ for sand by day 14 suggested a shift to N limitation. These relational variables inform enzyme-based models, and are usually much less ambiguous when obtained from a single study in which measurements were made on the same samples than when extrapolated from separate studies.

  16. Electronic Warfare (EW) Historical Perspectives and Its Relationship to Information Operations (IO) - Considerations for Turkey

    Kucukozyigit, Ali C

    2006-01-01

    ...) and Information Operations (IO) core, supporting and related competencies. Understanding the definitions of information and its value, information superiority, and the decision making cycle provides the foundation for the thesis...

  17. The Relationship between Application of Information, Communication Technology and Organizational Effectiveness in Physical Education Departments of Universities of Tehran

    Hamid Ghasemi; Abolfazl Farahani; Maryam Mashatan

    2012-01-01

    The purpose of this study was to determine the relationship between use of information communication technology (ITC) and organizational effectiveness in physical education departments of the University of Tehran carried out through the correlation method and the field research. All employees of Physical Education departments comprised our statistical population of whom 114 were randomly taken as the survey sample. We administered researcher-made information and communication technology (α=0....

  18. Parent's use of the Internet in the search for healthcare information and subsequent impact on the doctor-patient relationship.

    Harvey, S; Memon, A; Khan, R; Yasin, F

    2017-11-01

    The Internet is an unavoidable source of healthcare information. This information, both reliable and unreliable, has previously been shown to influence carer's decisions. Our aim was to evaluate this information seeking behavior among parents and its subsequent potential impact on the doctor-patient relationship. We undertook a cross-sectional questionnaire-based survey of paediatric outpatients. Enrollment took place over 4 weeks in March 2015. There were no inclusion or exclusion criteria and enrollment was voluntary. In total 100 questionnaires were completed. General Practitioners were the most common source of healthcare information. The Internet ranked third as a reliable source of healthcare information. The Internet was commonly used as an educational resource to learn about causes, treatment, and medications. A significant percentage of our population expressed concern regarding Internet information reliability. A small percentage of parents were concerned that disclosing Internet usage may worsen the relationship with their doctor. Parents showed a willingness to learn about diseases and treatments, and felt that the Internet was a good resource to do so. This study shows that open discussion about Internet usage between parents and doctors is not common and carers feel at risk of judgment should they admit to Internet usage. The Internet should be seen as a positive adjunct to patient education which can improve understanding, thus strengthening the doctor-patient relationship. The Internet will never replace the role of healthcare professionals but must be seen as an integral part of a multi-disciplinary approach.

  19. A Ligand Structure-Activity Study of DNA-Based Catalytic Asymmetric Hydration and Diels-Alder Reactions

    Rosati, F.; Roelfes, J.G.

    A structure-activity relationship study of the first generation ligands for the DNA-based asymmetric hydration of enones and Diels-Alder reaction in water is reported. The design of the ligand was optimized resulting in a maximum ee of 83% in the hydration reaction and 75% in the Diels-Alder

  20. A review of the federal guidelines that inform and influence relationships between physicians and industry.

    Birkhahn, Robert H; Jauch, Edward; Kramer, David A; Nowak, Richard M; Raja, Ali S; Summers, Richard L; Weber, Jim Edward; Diercks, Deborah B

    2009-08-01

    The effective delivery and continued advancement of health care is critically dependent on the relationship between physicians and industry. The private sector accounts for 60% of the funding for clinical research and more than 50% of the funding sources for physician education. The nature of the physician-industry relationship and the role of the physician as a gatekeeper for health care make this association vulnerable to abuse if certain safeguards are not observed. This article will review the current federal guidelines that affect the physician-industry relationship and highlight several illustrative cases to show how the potential for abuse can subvert this relationship. The recommendations and "safe harbors" that have been designed to guide business relationships in health care are discussed.

  1. The Effect Social Information Processing in Six-Year-Old Children Has on Their Social Competence and Peer Relationships

    Ogelman, Hulya Gulay; Seven, Serdal

    2012-01-01

    The purpose of this study was to investigate the effect social information processing levels has on the social competence (entering a peer group, response towards provocation, response to failure, response to success, social expectations, teacher expectations, reactive aggression, proactive aggression) and peer relationship (prosocial behaviour,…

  2. The Mediating Effect of Innovation on the Relationship between Information Technology Investments and Firm Performance: An Empirical Study

    Karanja, Erastus

    2011-01-01

    The last couple of decades has witnessed a plethora of research studies addressing the cause-and-effect relationship between Information Technology (IT) investments and performance at the firm level. These studies elicited mixed results between IT investments and performance which led to various points of view from IT Scholars and Practitioners.…

  3. Relationships among Career and Life Stress, Negative Career thoughts, and Career Decision State: A Cognitive Information Processing Perspective

    Bullock-Yowell, Emily; Peterson, Gary W.; Reardon, Robert C.; Leierer, Stephen J.; Reed, Corey A.

    2011-01-01

    According to cognitive information processing theory, career thoughts mediate the relationship between career and life stress and the ensuing career decision state. Using a sample of 232 college students and structural equation modeling, this study found that an increase in career and life stress was associated with an increase in negative career…

  4. Information from the Internet and the doctor-patient relationship: the patient perspective – a qualitative study

    Murray Elizabeth

    2007-08-01

    Full Text Available Abstract Background Both doctors and patients may perceive the Internet as a potential challenge to existing therapeutic relationships. Here we examine patients' views of the effect of the Internet on their relationship with doctors. Methods We ran 8 disease specific focus groups of between 2 and 8 respondents comprising adult patients with diabetes mellitus, ischaemic heart disease or hepatitis C. Results Data are presented on (i the perceived benefits and (ii limitations of the Internet in the context of the doctor-patient relationship, (iii views on sharing information with doctors, and (iv the potential of the Internet for the future. Information from the Internet was particularly valued in relation to experiential knowledge. Conclusion Despite evidence of increasing patient activism in seeking information and the potential to challenge the position of the doctor, the accounts here do not in any way suggest a desire to disrupt the existing balance of power, or roles, in the consultation. Patients appear to see the Internet as an additional resource to support existing and valued relationships with their doctors. Doctors therefore need not feel challenged or threatened when patients bring health information from the Internet to a consultation, rather they should see it as an attempt on the part of the patient to work with the doctor and respond positively.

  5. Has Web 2.0 Revitalized Informal Learning? The Relationship between Web 2.0 and Informal Learning

    Song, D.; Lee, J.

    2014-01-01

    Learning is becoming increasingly self-directed and often occurs away from schools and other formal educational settings. The development of a myriad of new technologies for learning has enabled people to learn anywhere and anytime. Web 2.0 technology allows researchers to shed a new light on the importance and prevalence of informal learning.…

  6. Informal in Formal: The Relationship of Informal and Formal Learning in Popular and Jazz Music Master Workshops in Conservatoires

    Virkkula, Esa

    2016-01-01

    The present article will examine informal learning in popular and jazz music education in Finland and evaluate it as a part of formal upper secondary vocational musicians' training, which is typically teacher directed. It is not necessarily the best model of working in popular and jazz music learning, which has traditionally benefitted from…

  7. Information Technology Governance Maturity: Examining the Moderating Effect on the Relationship between Strategic Alignment Maturity and Information Technology Effectiveness

    Kouakou, Claude N.

    2013-01-01

    The positive contribution of information technology (IT) in an organization is undeniable. Most organizations take advantage of that contributive benefit by aligning their business strategy with their IT strategy. This alignment is known as IT-business strategic alignment. Strategic alignment involves making the best possible use of corporate IT…

  8. Information Memory Processing and Retrieval: Relationships of Concrete Learning and Concrete and Abstract Cognitions.

    Dean, Bonnie L.

    Reported is a study related to the Project on an Information Memory Model and designed to encompass the claims of Piaget and Inhelder on differences of kinds of cognition and recall done on figural sorting task cognition at the Project on an Information Memory Model. The work of Piaget and Inhelder has defined learning information flow and related…

  9. Examining the Relationship of Business Operations and the Information Security Culture in the United States

    Wynn, Cynthia L.

    2017-01-01

    An increase in information technology has caused and increased in threats towards information security. Threats are malware, viruses, sabotage from employees, and hacking into computer systems. Organizations have to find new ways to combat vulnerabilities and threats of internal and external threats to protect their information security and…

  10. Exploring the Relationship between Authentic Leadership and Project Outcomes and Job Satisfaction with Information Technology Professionals

    Fischer, Mark A.

    2014-01-01

    One of the most important issues for organizations and information technology (IT) professionals is measuring the success or failure of information technology projects. How we understand the value and usefulness of IT projects is critical to how information technology executives evaluate and decide on technology investments. In a 2009 CHAOS…

  11. PBDE: Structure-Activity Studies for the Inhibition of Hepatitis C Virus NS3 Helicase

    Kazi Abdus Salam

    2014-04-01

    Full Text Available The helicase portion of the hepatitis C virus nonstructural protein 3 (NS3 is considered one of the most validated targets for developing direct acting antiviral agents. We isolated polybrominated diphenyl ether (PBDE 1 from a marine sponge as an NS3 helicase inhibitor. In this study, we evaluated the inhibitory effects of PBDE (1 on the essential activities of NS3 protein such as RNA helicase, ATPase, and RNA binding activities. The structure-activity relationship analysis of PBDE (1 against the HCV ATPase revealed that the biphenyl ring, bromine, and phenolic hydroxyl group on the benzene backbone might be a basic scaffold for the inhibitory potency.

  12. Listening to community health workers: how ethnographic research can inform positive relationships among community health workers, health institutions, and communities.

    Maes, Kenneth; Closser, Svea; Kalofonos, Ippolytos

    2014-05-01

    Many actors in global health are concerned with improving community health worker (CHW) policy and practice to achieve universal health care. Ethnographic research can play an important role in providing information critical to the formation of effective CHW programs, by elucidating the life histories that shape CHWs' desires for alleviation of their own and others' economic and health challenges, and by addressing the working relationships that exist among CHWs, intended beneficiaries, and health officials. We briefly discuss ethnographic research with 3 groups of CHWs: volunteers involved in HIV/AIDS care and treatment support in Ethiopia and Mozambique and Lady Health Workers in Pakistan. We call for a broader application of ethnographic research to inform working relationships among CHWs, communities, and health institutions.

  13. The value of private information in the physician-patient relationship: a gametheoretic account

    De Jaegher, K.J.M.

    2012-01-01

    This paper presents a game-theoretical model of the physician-patient relationship. There is a conflict of interest between physician and patient, in that the physician prefers the patient to always obtain a particular treatment, even if the patient would not consider this treatment in his interest.

  14. Information asymmetries as antecedents of opportunism in buyer-supplier relationships: testing principal-agent theory

    Steinle, Claus; Schiele, Holger; Ernst, Tanja

    2014-01-01

    Purpose: A severe problem in supplier selection refers to moral hazard: suppliers not behaving in the expected way once contracted. Principal-agent theory could provide insights on how to reduce this problem. Because buyer–supplier relationships can be interpreted as principal-agent situations, the

  15. An examination of the relationships among uncertainty, appraisal, and information-seeking behavior proposed in uncertainty management theory.

    Rains, Stephen A; Tukachinsky, Riva

    2015-01-01

    Uncertainty management theory (UMT; Brashers, 2001, 2007) is rooted in the assumption that, as opposed to being inherently negative, health-related uncertainty is appraised for its meaning. Appraisals influence subsequent behaviors intended to manage uncertainty, such as information seeking. This study explores the connections among uncertainty, appraisal, and information-seeking behavior proposed in UMT. A laboratory study was conducted in which participants (N = 157) were primed to feel and desire more or less uncertainty about skin cancer and were given the opportunity to search for skin cancer information using the World Wide Web. The results show that desired uncertainty level predicted appraisal intensity, and appraisal intensity predicted information-seeking depth-although the latter relationship was in the opposite direction of what was expected.

  16. The Relationship between Hospital Financial Performance and Information Technology Integration Strategy Selection

    Xie, Yue

    2012-01-01

    In light of the new healthcare regulations, hospitals are increasingly reevaluating their IT integration strategies to meet expanded healthcare information exchange requirements. Nevertheless, hospital executives do not have all the information they need to differentiate between the available strategies and recognize what may better fit their…

  17. The Relationship between Ethical Decision Making and Ethical Reasoning in Information Technology Students

    Woodward, Belle; Davis, Diane C.; Hodis, Flaviu A.

    2007-01-01

    This study examined undergraduate information technology (IT) students' (N = 122) level of ethical reasoning and decision making at a Midwestern university. The purpose was to determine whether IT students' level of ethical reasoning provided information about the degree of their ethical decision making. The Defining Issues Test-2 (DIT-2) was used…

  18. The Relationship of Financial Incentives and Consumers' Willingness to Disclose Information to eCommerce Marketers

    Pourhosseini, Parissa

    2009-01-01

    In this study the problem examined was a lack of research based information on the degree to which incentives can be used to encourage consumers to volunteer private information. The purpose of this study was to determine if monetary incentives would be a beneficial means to increase consumers' involvement in eCommerce and thereby boost the growth…

  19. Correlationally Assessing the Relationship of Information Technology Investments in Electronic Medical Records to Business Value

    Richardson, Daniel J.

    2009-01-01

    The lag in information exchange and assimilation adoption experienced by modern primary care physicians in the conduct of evidence based medicine may be affecting health care system productivity and patient quality of care. Further, interest in whether or not information technology (IT) investments show an increase in business value has increased…

  20. Relationship between Corporate Governance and Information Security Governance Effectiveness in United States Corporations

    Davis, Robert E.

    2017-01-01

    Cyber attackers targeting large corporations achieved a high perimeter penetration success rate during 2013, resulting in many corporations incurring financial losses. Corporate information technology leaders have a fiduciary responsibility to implement information security domain processes that effectually address the challenges for preventing…

  1. Electronic Warfare (EW) Historical Perspectives and Its Relationship to Information Operations (IO) - Considerations for Turkey

    2006-09-01

    Information Operations IW Information Warfare JDAM Joint Direct Attack Munition JRFL Joint Restricted Frequency List JSTARS Joint...through the preparation of the joint restricted frequency list (JRFL), which includes taboo, guarded and protected frequencies. The EC-130H Compass Call

  2. The Relationship between Informal Learning, Burn out, Mental Health and Job Satisfaction among Workers of Esfahan Steel Company

    mohammad ali nadi

    2014-01-01

    Full Text Available The purpose of this research is to investigate the relationship between informal learning, job satisfaction, burn out and mental health among workers of Esfahan Steel Company. The research approach is typically descriptive and causal - solidarity and for data analysis and syntheses, descriptive statistics solution have been used including mean value, standard deviation and frequency percentages and the inferential statistics solutions included multiple correlation coefficient , Pearson correlation , multivariate analysis of variance and path analysis . In this study, the correlation between informal learning and job satisfaction and the correlation between burn out and job satisfaction level have been found significant at P 0.01. The correlation coefficient between burn out and mental health as well as mental health and job satisfaction have not been found as significant . Findings imply that burnout and informal learning can predict job satisfaction . Norelation ship has been observed between informal learning and burn out and between informal learning and mental health, while the relationships between informal learning and job satisfaction and between burn out and job satisfaction have been confirmed. The conceptual model of research has been evaluated using path analysis and Confirmatory Factor Analysis . Findings denote the direct effect of informal learning on job satisfaction and indirect effect of burn out on job satisfaction . Referring to the Structural Equation Modeling, among three main paths, the effect of informal learning and burn out on job satisfaction has been observed and it has been found that mental health has no effect on job satisfaction. Major limitation of this research is related to generalization of findings to other steel manufacturing companies, industries and public organizations.

  3. Leadership models with an emphasis on relationships and the completion of the project in information science

    Damaskinou, Aikaterini I.; Drivas, Ioannis C.; Sakas, Damianos P.

    2015-02-01

    While attempting decision-making in leadership, one of the criteria that should be considered is the actual behavior of the leader towards the work group. The object of this study is the prevalence of two key leadership models, the Task Behavior and the Relationship Behavior. Firstly, the leader's behavior is focused on completing the project combined with a leadership style which is more interventionist and less conciliatory. The second leadership model focuses on working relationships, developed between leaders and employees. In this case, the character of the model is associated with a leadership behavior more supportive, motivating and participative. This article refers to the characteristics of the two models and the mechanisms and strategies that can be adopted in both leadership behaviors. Furthermore, through the research which took place, we have come to conclusions regarding the public's views about the different leadership behaviors and, also, the possibility of combining the two styles of leadership.

  4. Investigation on the Relationship between Information Communication Technology and Reading Literacy for Northeast Asian Students

    Lai Yi-Horng

    2016-01-01

    Full Text Available The purpose of this study was to investigate the relationship of internet communication technologies (ICT usage and reading literacy of Northeast Asian Students in PISA 2009. ICT was crucial for all governments in the world towards promoting equity. ICT had been considered a low cost opportunity towards equalizing educational systems. A multilevel modelling (MLM was applied to identify at which school-level the largest variations in the three indicators exist in this study. With MLM, it could be examine simultaneously the effects of different hierarchical school-level variables; to take account of possible correlations of students’ reading literacy in this study within higher levels (Urbanization, Total number of students Computers for education which may otherwise lead to incorrect standard errors and inefficient estimates; to treat higher levels as related; and to examine inter-area variations at each level. The empirical results include the different between group components was significant. Self-confidence in ICT high level tasks was positive with students’ reading literacy, and self-confidence in ICT high level tasks was negative with students’ reading literacy. The urbanization of schools’ area and total number of students of schools were positive with students’ reading literacy. The urbanization of schools’ area was negative with the relationship of ICT for school related tasks and students’ reading literacy. Total number of students was negative with the relationship of ICT for school related tasks and students’ reading literacy, and ICT availability in school and students’ reading literacy.

  5. Examining the Relationship Between Nursing Informatics Competency and the Quality of Information Processing.

    Al-Hawamdih, Sajidah; Ahmad, Muayyad M

    2018-03-01

    The purpose of this study was to examine nursing informatics competency and the quality of information processing among nurses in Jordan. The study was conducted in a large hospital with 380 registered nurses. The hospital introduced the electronic health record in 2010. The measures used in this study were personal and job characteristics, self-efficacy, Self-Assessment Nursing Informatics Competencies, and Health Information System Monitoring Questionnaire. The convenience sample consisted of 99 nurses who used the electronic health record for at least 3 months. The analysis showed that nine predictors explained 22% of the variance in the quality of information processing, whereas the statistically significant predictors were nursing informatics competency, clinical specialty, and years of nursing experience. There is a need for policies that advocate for every nurse to be educated in nursing informatics and the quality of information processing.

  6. Exploring the Relationship Between Public Service Motivation and Formal and Informal Volunteering

    Richard M. Clerkin

    2017-03-01

    Full Text Available In this paper, we apply public service motivation to the ongoing discussion of formal and informal volunteering and whether these are two distinct constructs or variations on the same theme. This exploratory research uses survey data of undergraduate students reporting their participation in both types of volunteering activities. Using structural equation modeling, these formal and informal volunteering activities show different influences on three dimensions of PSM. In addition to PSM, high school volunteering and religiosity have direct effects on rates of formal volunteering, which in turn positively influence the PSM dimensions of civic duty and self-sacrifice. Being an Evangelical Christian is associated with increased informal volunteering, which is positively related to the PSM compassion dimension. These results indicate that the different dimensions of PSM, and how formal and informal volunteering influences them, should be useful tools for scholars and practitioners seeking to understand these distinct types of pro-social behaviors.

  7. SocialCloudShare: a Facebook Application for a Relationship-based Information Sharing in the Cloud

    Davide Albertini

    2014-10-01

    Full Text Available In last few years, Online Social Networks (OSNs have become one of the most used platforms for sharing data (e.g., pictures, short texts on the Internet. Nowadays Facebook and Twitter are the most popular OSN providers, though they implement different social models. However, independently from the social model they implement, OSN platforms have become a widespread repository of personal information. All these data (e.g., profile information, shared elements, users’ likes are stored in a centralized repository that can be exploited for data mining and marketing analysis. With this data collection process, lots of sensitive information are gathered by OSN providers that, in time, have become more and more targeted by malicious attackers. To overcome this problem, in this paper we present an architectural framework that, by means of a Social Application registered in Facebook, allows users to move their data (e.g., relationships, resources outside the OSN realm and to store them in the public Cloud. Given that the public Cloud is not a secure and private environment, our proposal provides users security and privacy guarantees over their data by encrypting the resources and by anonymizing their social graphs. The presented framework enforces Relationship-Based Access Control (ReBAC rules over the anonymized social graph, providing OSN users the possibility to selectively share information and resources as they are used to do in Facebook.

  8. The relationship between need for closure and memory for schema-related information among younger and older adults.

    Kossowska, Małgorzata; Jaśko, Katarzyna; Bar-Tal, Yoram; Szastok, Marta

    2012-01-01

    Two studies were conducted to examine the relationships among need for closure (NFC) and schematic information processing in younger and older adults. The results show increased NFC to be associated with less schematic processing (i.e., less memory for schema-consistent items, and more memory for schema-irrelevant items, out of all items memorized correctly), among older than younger adults. The findings of the studies are interpreted as demonstrating the age-associated deficit in information processing consistent with the level of NFC. Moreover, the results indicate that positive mood may play a role in facilitating information processing consistent with the level of NFC among older and younger adults. Finally, we present a framework for predicting when older adults will and will not effectively use schematic processing, considered a compensatory strategy for decline in cognitive abilities.

  9. A study on relationship between asymmetric information on dividend polices of companies listed in Tehran Stock Exchange

    Adineh Hayatbakhsh

    2013-07-01

    Full Text Available Explaining and the determinants of dividend policy is one of the biggest challenges that have long been the center of attention of accounting and financial researcher and theoreticians. There are many evidences that confirm the effects of dividend and there are a lot of other potential factors whose effects on the dividend policy have not been studied yet. In this study, the effects of four variables including asymmetric information, growth opportunities, cash holding and firm size in payout dividend policy are investigated, simultaneously. The study uses the information of 140 companies listed on Tehran Stock Exchange over the period 2005-2010. In this study, 4 hypotheses are proposed and investigated. There are positive and significant relationships between asymmetric information, growth opportunities, cash holding and company size on one side and payout dividend policy on the other side.

  10. Relationship between patient dependence and direct medical-, social-, indirect-, and informal-care costs in Spain

    Darbà J

    2015-07-01

    Full Text Available Josep Darbà,1 Lisette Kaskens2 1Department of Economics, University of Barcelona, 2BCN Health Economics and Outcomes Research SL, Barcelona, Spain Objective: The objectives of this analysis were to examine how patients' dependence on others relates to costs of care and explore the incremental effects of patient dependence measured by the Dependence Scale on costs for patients with Alzheimer's disease (AD in Spain. Methods: The Co-Dependence in Alzheimer's Disease study is an 18 multicenter, cross-sectional, observational study among patients with AD according to the clinical dementia rating score and their caregivers in Spain. This study also gathered data on resource utilization for medical care, social care, caregiver productivity losses, and informal caregiver time reported in the Resource Utilization in Dementia Lite instrument and a complementary questionnaire. The data of 343 patients and their caregivers were collected through the completion of a clinical report form during one visit/assessment at an outpatient center or hospital, where all instruments were administered. The data collected (in addition to clinical measures also included sociodemographic data concerning the patients and their caregivers. Cost analysis was based on resource use for medical care, social care, caregiver productivity losses, and informal caregiver time reported in the Resource Utilization in Dementia Lite instrument and a complementary questionnaire. Resource unit costs were applied to value direct medical-, social-, and indirect-care costs. A replacement cost method was used to value informal care. Patient dependence on others was measured using the Dependence Scale, and the Cumulative Index Rating Scale was administered to the patient to assess multi-morbidity. Multivariate regression analysis was used to model the effects of dependence and other sociodemographic and clinical variables on cost of care. Results: The mean (standard deviation costs per patient

  11. Relationships: empirical contribution. Understanding personality pathology in adolescents: the five factor model of personality and social information processing.

    Hessels, Christel; van den Hanenberg, Danique; de Castro, Bram Orobio; van Aken, Marcel A G

    2014-02-01

    This study seeks to integrate two research traditions that lie at the base of the understanding of personality pathology in adolescents. The first research tradition refers to normal personality according to the Five Factor Model (FFM). The second tradition specifies the key feature of personality disorder as the capacity to mentalize, which can be reflected in Social Information Processing (SIP). In a clinical sample of 96 adolescents, the authors investigated response generation, coping strategy, and memories of past frustrating experiences as part of SIP, as mediator in the relationship between personality and personality pathology, and a possible moderating role of personality on the relationship between SIP and personality pathology. The hypothesized mediation, by which the effects of personality dimensions on personality pathology was expected to be mediated by SIP variables, was found only for the effect of Neuroticism, most specifically on BPD, which appeared to be mediated by memories the patients had about past frustrating conflict situations with peers. Some moderating effects of personality on the relationship between SIP variables and personality pathology were found, suggesting that high Agreeableness and sometimes low Neuroticism can buffer this relationship. These results suggest that personality dimensions and social cognitions both independently and together play a role in adolescents' personality pathology.

  12. The relationship of positive and negative expressiveness to the processing of emotion information.

    Knyazev, Gennady G; Barchard, Kimberly A; Razumnikova, Olga M; Mitrofanova, Larisa G

    2012-06-01

    The tendency to express emotions non-verbally is positively related to perception of emotions in oneself. This study examined its relationship to perception of emotions in others. In 40 healthy adults, EEG theta synchronization was used to indicate emotion processing following presentation of happy, angry, and neutral faces. Both positive and negative expressiveness were associated with higher emotional sensitivity, as shown by cortical responses to facial expressions during the early, unconscious processing stage. At the late, conscious processing stage, positive expressiveness was associated with higher sensitivity to happy faces but lower sensitivity to angry faces. Thus, positive expressiveness predisposes people to allocate fewer attentional resources for conscious perception of angry faces. In contrast, negative expressiveness was consistently associated with higher sensitivity. The effects of positive expressiveness occurred in cortical areas that deal with emotions, but the effects of negative expressiveness occurred in areas engaged in self-referential processes in the context of social relationships. © 2012 The Authors. Scandinavian Journal of Psychology © 2012 The Scandinavian Psychological Associations.

  13. Informal social control of drinking in intimate relationships – a comparative analysis

    Selin, Klara Hradilova; Holmila, Marja; Knibbe, Ronald

    2009-01-01

    A number of studies have shown that pressure from others is an important element in decision making concerning entering treatment and that the pressure most often comes from one's partner. Is has also been found that, besides actual drinking habits, togetherness of drinking, i.e. proportion of drinking occasions spent together with partner, is reversely connected to pressure from partner to drink less. The purpose of this paper was to examine these relationships in a comparative perspective, using GENACIS survey data from 16 countries. The results confirmed that on both individual and aggregated level, there is a relationship between drinking and pressure from partner. There is more pressure reported in ‘dry’ cultures and heavy drinking individuals are more often the object than others – in all cultures studied. In only a few countries with rather different drinking culture, drinking together prevents the pressure, also when controlled for actual consumption. Except for Uganda and UK, men are generally more exposed to pressure to drink less exerted by their female partners and this cannot only be explained by the fact that they actually drink more. PMID:20589234

  14. The relationship between different information sources and disease-related patient knowledge and anxiety in patients with inflammatory bowel disease.

    Selinger, C P; Carbery, I; Warren, V; Rehman, A F; Williams, C J; Mumtaz, S; Bholah, H; Sood, R; Gracie, D J; Hamlin, P J; Ford, A C

    2017-01-01

    Patient education forms a cornerstone of management of inflammatory bowel disease (IBD). The Internet has opened new avenues for information gathering. To determine the relationship between different information sources and patient knowledge and anxiety in patients with IBD. The use of information sources in patients with IBD was examined via questionnaire. Anxiety was assessed with the hospital anxiety and depression scale and disease-related patient knowledge with the Crohn's and colitis knowledge score questionnaires. Associations between these outcomes and demographics, disease-related factors, and use of different information sources were analysed using linear regression analysis. Of 307 patients (165 Crohn's disease, 142 ulcerative colitis) 60.6% were female. Participants used the hospital IBD team (82.3%), official leaflets (59.5%), and official websites (53.5%) most frequently in contrast to alternative health websites (9%). University education (P sex (P = 0.004), clinically active disease (P sources are associated with better knowledge or worse anxiety levels. Face-to-face education and written information materials remain the first line of patient education. Patients should be guided towards official information websites and warned about the association between the use of alternative health websites or random links and anxiety. © 2016 John Wiley & Sons Ltd.

  15. The complementary relationship between the Internet and traditional mass media: the case of online news and information

    An Nguyen

    2006-01-01

    Full Text Available Background. The question whether old media are driven out of existence by new media has been a long concern in academic and industrial research but has received no definitive answer. Aim.This paper goes beyond most previous studies of Internet impact on traditional media, which have placed their relationship within a competition-based framework, to specifically investigate the complementary effect of online news and information usage on traditional sources. Method. Secondary data analysis of a national survey of 4270 Australians conducted in late 2003, employing hypothesis testing for the mean, partial correlations, and a linear regression analysis. Results. Online news and information usage at different usage levels is positively associated with the use of traditional news and information sources, especially those that are more information-intensive. Those who relied on the Internet the most for news and information still used traditional sources substantially. Conclusion. The findings suggest that even if a displacement effect takes place, there will be no replacement (absolute displacement: traditional media will still exist to complement the Internet in serving human beings' news and information needs.

  16. Relationship between information literacy and creativity: a study of students at the isfahan university of medical sciences.

    Raeis, Ahmad Reza; Bahrami, Susan; Yousefi, Mitra

    2013-01-01

    In an era of huge volume of publications and information products, information literacy has become a very important survival tool. Information literacy is an instrument for individual empowerment that leads one to search for the truth and the desired information for decision making with independence. While creativity is the foundation of sciences and innovation, one of the main functions of universities is expanding the frontiers of knowledge and productions of scientific information. Therefore creativity is more vital and necessary for these kinds of institutions than other organizations. In this regard, this paper investigates the relationship between information literacy and creativity of students at the Isfahan University of Medical Sciences. This is a correlation-descriptive study. Statistical population was third year students of Isfahan University of Medical Sciences (1054 individuals) in 2011. Sample size was 250 individuals selected by stratified random Sampling. The instruments for data collection were two questionnaires, an investigator made questionnaire for information literacy and a creativity questionnaire. For questionnaires validity used content validity and for their reliability used Cronbach Alpha Coefficient (r1= 0.95, r2=0.85). SPSS 18 statistical software and descriptive and inferential statistics tests (Frequency distribution tab, Pearson Correlation, T test, Tukey test and ANOVA) were used to analyze data. The results indicate that mean of information literacy was higher than average and mean of creativity was lower than average. There is a significant multiple correlation between 5 dimensions of information literacy (Ability to determine extent and nature of information, effective and efficient access, critical assessment, ability of purposeful application, ability of understanding legal and economic issues) and creativity in level of (p≤ 0.05). Also mean difference of ability of purposeful application based on gender was significant in

  17. Information Adequacy and Communication Relationships: An Empirical Examination of 18 Organizations.

    Spiker, Barry K.; Daniels, Tom D.

    1981-01-01

    Noted that satisfaction with organizational life may be a function of equivocality (uncertainty) reduction rather than participation. Tested the hypothesis that perceived information adequacy is an indicator of equivocality. Results suggest that the equivocality model provides a better explanation of satisfaction than the participation model. (PD)

  18. Examining the Relationship between Online Travel Agency Information and Traveler Destination Transaction Decisions

    Yerby, Dennis

    2012-01-01

    The purpose of this quantitative study was to examine the role that available Online Travel Agency (OTA) destination information may have on a traveler's perceptions and intent in transaction decisions with that respective OTA. Specifically, this research examined a pleasure traveler's transaction perceptions and intentions with an OTA…

  19. What Are the Relationships between Teachers' Engagement with Management Information Systems and Their Sense of Accountability?

    Perelman, Uri

    2014-01-01

    Many public and private sector organizations are supported by Management Information Systems (MIS) for collection, management, analysis, and distribution of the data needed for effective decision-making and enhanced organizational management. The existing body of research on MIS in education focuses on the systems' contribution to achieving…

  20. A Correlational Study Assessing the Relationships among Information Technology Project Complexity, Project Complication, and Project Success

    Williamson, David J.

    2011-01-01

    The specific problem addressed in this study was the low success rate of information technology (IT) projects in the U.S. Due to the abstract nature and inherent complexity of software development, IT projects are among the most complex projects encountered. Most existing schools of project management theory are based on the rational systems…

  1. The Relationship between Chief Information Officer Transformational Leadership and Computing Platform Operating Systems

    Anderson, George W.

    2010-01-01

    The purpose of this study was to relate the strength of Chief Information Officer (CIO) transformational leadership behaviors to 1 of 5 computing platform operating systems (OSs) that may be selected for a firm's Enterprise Resource Planning (ERP) business system. Research shows executive leader behaviors may promote innovation through the use of…

  2. 76 FR 33027 - Agency Information Collection (Statement of Marital Relationship) Activity Under OMB Review

    2011-06-07

    ... collection. Abstract: VA Form 21-4170 is completed by individuals claiming to be common law widows/widowers of deceased veterans and by veterans and their claimed common law spouses to establish marital status. VA uses the information collected to determine whether a common law marriage was valid under the law...

  3. Examining Moral Judgment and Ethical Decision-Making in Information Technology Managers and Their Relationship

    Shahand, Assadullah

    2010-01-01

    Growing incidences of corporate ethical misconducts have revived the debate over ethical reasoning and moral development of corporate managers. The role of information technology (IT) in the ethical dilemmas is becoming more evident as virtual environments become increasingly popular, organizations adopt digital form of record keeping, and the…

  4. The relationship between information prioritization and visual distinctness in two progressive image transmission schemes

    Rodríguez-Sánchez, R.; Fdez-Valdivia, J.; Toet, A.; García, J.A.

    2004-01-01

    The goal of this paper is to analyze the relation between the visual distinctness and the priority assigned to the information in two di2erent progressive transmission schemes: the Set Partitioning in Hierarchical Trees (SPIHT) and the Rational Embedded Wavelet Image Coding (REWIC). SPIHT assigns

  5. Assessment of the Main Indicators' Relationship of Projects of Information and Communication Services' Development

    Chernyavskaya, Yana S.; Kiselev, Sergey V.; Rassolov, Ilya M.; Kurushin, Viktor V.; Chernikova, Lyudmila I.; Faizova, Guzel R.

    2016-01-01

    The relevance of research: The relevance of the problem studied is caused by the acceleration of transition of the Russian economy on an innovative way of development, which depends on the vector of innovative sphere of services and, to a large extent, information and communication services, as well as it is caused by the poor drafting of…

  6. The relationship between organisational climate and employee satisfaction in a South African information and technology organisation

    Monia L. Castro

    2010-05-01

    Research purpose: The objective of this study was to explore the relationship between organisational climate and job satisfaction to determine whether employees’ perceptions of the work environment influence their level of job satisfaction. Motivation for the study: Organisations are facing more challenges than ever before. These challenges are not unique to any specific organisation or industry, but affect all organisations.Organisational climate in particular is constantly challenged by changes impacting organisations today. Research design, approach and method: An organisational climate questionnaire was administered to a convenience sample of 696 employees from a population of 1453 employees working in three regions in which the organisation was operational. Confirmatory and exploratory factor analyses were used to investigate the structure of the climate model. Main findings: The revised 12-factor model (after the confirmatory factor analysis fitted the data best and the researchers therefore decided to proceed with the revised 12-factor model (11 dimensions for further analysis. A stepwise regression was conducted and nine dimensions of organisational climate were found to predict job satisfaction. The results indicated a strong positive correlation (r = 0.813, p< 0.01 between organisational climate and the dependent variable of job satisfaction. Practical implications: This study provided support for the view that line managers and human resource practitioners should be aware that different biographical groups have different needs that can influence their job satisfaction levels and different perceptions of the climate within the organisation and that this impacts on their behaviour. Contribution: The findings of this study indicated a positive relationship between organisational climate scores and job satisfaction scores and thus, regardless of how the dimensions are perceived, organisational climate has an influence on job satisfaction.

  7. Information flow between interacting human brains: Identification, validation, and relationship to social expertise.

    Bilek, Edda; Ruf, Matthias; Schäfer, Axel; Akdeniz, Ceren; Calhoun, Vince D; Schmahl, Christian; Demanuele, Charmaine; Tost, Heike; Kirsch, Peter; Meyer-Lindenberg, Andreas

    2015-04-21

    Social interactions are fundamental for human behavior, but the quantification of their neural underpinnings remains challenging. Here, we used hyperscanning functional MRI (fMRI) to study information flow between brains of human dyads during real-time social interaction in a joint attention paradigm. In a hardware setup enabling immersive audiovisual interaction of subjects in linked fMRI scanners, we characterize cross-brain connectivity components that are unique to interacting individuals, identifying information flow between the sender's and receiver's temporoparietal junction. We replicate these findings in an independent sample and validate our methods by demonstrating that cross-brain connectivity relates to a key real-world measure of social behavior. Together, our findings support a central role of human-specific cortical areas in the brain dynamics of dyadic interactions and provide an approach for the noninvasive examination of the neural basis of healthy and disturbed human social behavior with minimal a priori assumptions.

  8. [Internet as an information source for health in primary care patients and its influence on the physician-patient relationship].

    Marin-Torres, Viviana; Valverde Aliaga, Justo; Sánchez Miró, Ignacio; Sáenz Del Castillo Vicente, María Isabel; Polentinos-Castro, Elena; Garrido Barral, Araceli

    2013-01-01

    To describe the use of the Internet by primary care patients to seek health related information, understand how they are influenced by this information, and evaluate its impact on the doctor-patient relationship. Cross sectional study, through self-administered survey. One urban health center in Madrid. A total of 323 questionnaires were collected from patients between 14 and 75 years old who attended a physician's office for any reason, excluding illiterate patients and those with neurological or psychiatric problems preventing them from completing the survey. Internet usage, ability of the internet to clarify doubts regarding health issues, patient lifestyle changes, socio-demographic variables, and physician's receptivity to the use of internet by patients. 61% (CI95%: 56%-67%) of patients used the Internet as a source of health information: Internet queries were able to address health doubts in 92.4% of users, 53.5% reported that the Internet changed their thinking about their health in at least one instance, 30% made behavioral changes (of which 60.1% discussed these changes with their physician), 44.3% had more questions at the physician's office, and 80.8% believe that the doctor would be willing to talk about the information found on the internet. Using the Internet to find information about health is very common, with positive influence on physician-patient relationship. This may be useful for achieving behavioral changes in patients and can be used as a tool in medical practice. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  9. Determination of the Relationship between Information Capacity and Identification by Simulated Aerial Photography.

    1978-06-27

    experiment by Frank Scott, Peter Hollanda , and Albert Harabedian 7 7Scott, F., Hollanda , P. A., and Harabedian, A., Phot. Sci. Eng., 14 1 pp 21-27...photographs of models of military tanks and trucks. The information capacity of these photos was varied by defocussing the taking camera and the simulated...photographic reconnaissance mission. This was done by photographing models of military targets, I processing and duplicating the resulting images, and

  10. Digital Natives Versus Digital Immigrants: Influence of Online Health Information Seeking on the Doctor-Patient Relationship.

    Haluza, Daniela; Naszay, Marlene; Stockinger, Andreas; Jungwirth, David

    2017-11-01

    Ubiquitous Internet access currently revolutionizes the way people acquire information by creating a complex, worldwide information network. The impact of Internet use on the doctor-patient relationship is a moving target that varies across sociodemographic strata and nations. To increase scientific knowledge on the patient-Web-physician triangle in Austria, this study reports findings regarding prevailing online health information-seeking behavior and the respective impact on doctor-patient interactions among a nonprobability convenience sample of Internet users. To investigate digital age group-specific influences, we analyzed whether digital natives and digital immigrants differed in their perspectives. The questionnaire-based online survey collected sociodemographic data and online health information-seeking behavior from a sample of 562 respondents (59% females, mean age 37 ± 15 years, 54% digital natives). Most respondents (79%) referred to the Internet to seek health information, making it the most commonly used source for health information, even more prevalent then the doctor. We found similar predictors for using the Internet as a source for health-related information across digital age groups. Thus, the overall generational gap seems to be small among regular Internet users in Austria. However, study participants expressed a rather skeptical attitude toward electronic exchange of health data between health care professionals and patients, as well as toward reliability of online health information. To improve adoption of electronic doctor-patient communication and patient empowerment, public education and awareness programs are required to promote consumer-centered health care provision and patient empowerment.

  11. Ontology lexicalization: Relationship between content and meaning in the context of Information Retrieval

    Marcelo SCHIESSL

    Full Text Available Abstract The proposal presented in this study seeks to properly represent natural language to ontologies and vice-versa. Therefore, the semi-automatic creation of a lexical database in Brazilian Portuguese containing morphological, syntactic, and semantic information that can be read by machines was proposed, allowing the link between structured and unstructured data and its integration into an information retrieval model to improve precision. The results obtained demonstrated that the methodology can be used in the risco financeiro (financial risk domain in Portuguese for the construction of an ontology and the lexical-semantic database and the proposal of a semantic information retrieval model. In order to evaluate the performance of the proposed model, documents containing the main definitions of the financial risk domain were selected and indexed with and without semantic annotation. To enable the comparison between the approaches, two databases were created based on the texts with the semantic annotations to represent the semantic search. The first one represents the traditional search and the second contained the index built based on the texts with the semantic annotations to represent the semantic search. The evaluation of the proposal was based on recall and precision. The queries submitted to the model showed that the semantic search outperforms the traditional search and validates the methodology used. Although more complex, the procedure proposed can be used in all kinds of domains.

  12. Relationship between firewood usage and urinary Cr, Cu and As in informal areas of Cape Town.

    Dalvie, Mohamed Aqiel; Africa, Algernon; Naidoo, Sivapregasen

    2013-09-03

    The study investigated whether wood usage by informal food vendors and household residents in Cape Town results in the absorption of arsenic (As), chromium (Cr) and copper (Cu) owing to release of these metals in the burning of chromated copper arsenate (CCA)-treated wood. The participants (N=78) selected included an equal number of food vendors and non-vendors from 2 informal settlements. All participants answered a questionnaire concerning exposure and were tested for urinary Cr, Cu and As, while the urine of 29 participants was also tested for toxic As (As(tox)). Multivariate analysis showed that the time spent in close proximity to the wood, as well as the quantity of wood used for cooking and for household use, was weakly positively associated with urinary levels of As, Cr and the sum of As, Cr and Cu. The study provides evidence that use of wood likely to contain CCA as a fuel for informal food outlets and household purposes may increase the absorption of inorganic As, Cu and Cr.

  13. Formation of cognitive structures in conditioned-reflex behavior in monkeys: Relationship with type of visual information.

    Dudkin, K N; Chueva, I V

    2009-02-01

    The characteristics of learning processes and long-term memory (LTM) were studied in rhesus macaques discriminating visual stimuli (geometrical figures of different shapes, sizes, and orientations, and with different spatial relationships between image components). Trained monkeys were tested for the ability to perform invariant recognition after stimulus transformation, i.e., changes in size, shape, number of objects, and spatial relationships. Analysis of behavioral characteristics (correct solutions, refusals to decide, motor response times) revealed differences associated with the type of visual information. When monkeys discriminated between black and white geometrical figures of different shapes and orientations, as well as black-and-white figures with different shapes or orientations, the learning time was short and transformation of the stimuli had no effect on correct solutions: there was complete transfer of learning. When monkeys discriminated figures of different sizes or complex images with different spatial relationships, the learning time was significantly greater. Changes in the size and shape of figures led to significant reductions in correct solutions and significant increases in refusals to solve the task and in motor reaction times. Invariance of discrimination in this case appeared after additional training. The results obtained here showed that in conditioned reflex learning, the sensory processing of stimuli has the result that discriminatory features are formed in LTM, i.e., cognitive structures (functional neurophysiological mechanisms), these supporting the classification of visual images. The temporal conditioned link of the executive reaction is established with these. Their formation is determined by the type of sensory information and the existence in LTM of separate subsystems for spatial and non-spatial information.

  14. The potential for using information systems to enhance information flows and relationships in the intellectual property sector: The case of Kennedys Patent

    Barlow, A.

    2007-01-01

    Full Text Available This paper investigates the potential use of information systems (IS for enhancing the supply chains of organisations positioned in the intellectual property (IP sector. Exploratory research has been conducted through the lens of a patent and trade mark agent who is involved in advising on a range of IP issues. The research highlights the opportunities offered by IS (including online technologies for generally improving the provision of business services e.g. automating supply chain processes. More specifically, though, it investigates the potential IS have for integrating information flows and providing timely, in-depth and better presented information and the options for online filing. It also explores the capabilities for improving interactions with clients and enhancing relationships with key stakeholders in the supply chain e.g. government agencies, overseas patent agents and lawyers. The paper additionally outlines key challenges that are at the forefront and need to be addressed when using IS within the IP sector such as identity management, security and authentication. The key findings of the research will be of value to researchers and practitioners in the IP field but many of the issues and challenges faced will also be applicable to other sectors.

  15. Relationship between early and late stages of information processing: an event-related potential study

    Claudio Portella

    2012-11-01

    Full Text Available The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP components, including P200, N200, premotor potential (PMP and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2, N200 (electrode O2, PMP (electrode C3, P300 (electrode PZ and the reaction time (RT. In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2, PMP (electrode C3, P300 (electrode PZ was found. Therefore, we propose that if the secondary processing of visual input (P200 latency occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency, motor response processing (PMP latency, reorganization of attention and working memory update (P300 latency, and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude.

  16. Public Attitudes about Health Information Technology, and Its Relationship to Health Care Quality, Costs, and Privacy

    Gaylin, Daniel S; Moiduddin, Adil; Mohamoud, Shamis; Lundeen, Katie; Kelly, Jennifer A

    2011-01-01

    Objective To understand Americans' attitudes concerning health information technology's (IT's) potential to improve health care and differences in those attitudes based on demographics and technological affinity. Data Sources/Study Setting A random-digit-dial sample with known probability of selection for every household in the United States with a telephone, plus a supplemental sample of cell phone users. Telephone interviews were conducted from August 2009 through November 2009. Study Design Data were analyzed to present univariate estimates of Americans' opinions of health IT, as well as multivariate logistic regressions to assess hypotheses relating individuals' characteristics to their opinions. Characteristics used in our model include age, race, ethnicity, gender, income, and affinity to technology. Findings A large majority (78 percent) favor use of electronic medical records (EMRs); believe EMRs could improve care and reduce costs (78 percent and 59 percent, respectively); believe benefits of EMR use outweigh privacy risks (64 percent); and support health care information sharing among providers (72 percent). Regression analyses show more positive attitudes among those with higher incomes and greater comfort using electronic technologies. Conclusion The findings suggest that American's believe that health IT adoption is an effective means to improve the quality and safety of health care. PMID:21275986

  17. Controversial hypotheses on the relationship between researcher and informant in qualitative research.

    Wilde, V

    1992-02-01

    This paper addresses methodological issues that emerged unexpectedly during a qualitative study set up to explore nurses' descriptions of difficult, challenging and satisfying experiences at work. The purpose of the study had been to look for critical factors influencing nurses' perceptions of their performance in specific situations, and their labelling of each event. Ten nurses were asked to describe in detail three events; a difficult situation in which they had coped well, a difficult situation in which they would like to have coped better, and a satisfying or rewarding situation. The critical incident technique was used. Rich descriptions were obtained, tape recorded, transcribed verbatum, and analysed by constant comparative analysis, following the principles of grounded theory. Some suprising hypotheses emerged regarding the methodology of the informal interview in qualitative research. This paper addresses these hypotheses, which focus on the interaction between the researcher and informant, the role conflict facing the nurse researcher, the effect of the researcher's past experience on the interaction, the use of counselling strategies and the principle of self-disclosure. These hypotheses were incidental to the original area of study and were more exciting in their emergence because of this.

  18. Enacting trust: contract, law and informal economic relationships in a Spanish border enclave in Morocco

    Brian Campbell

    2012-01-01

    Full Text Available Small and removed from the Spanish mainland, the Enclave of Ceuta has always depended on flows of goods and labour out of the Moroccan hinterland, with individuals from different ethnic and religious groups forming informal, flexible and personal economic bonds based on mutual ‘confianza’ (trust. Since its entry into the European Union in 1986,the Spanish government has erected a border-wall around the enclave, and introduced new migration policies branding many informal workers within its borders as a threat to Spanish society. Based on my preliminary months of research, this paper compares the Ceutancontext with other research recently conducted on the topics of migration and borders in the Mediterranean region. It brings into focus key theoretical issues and assumptions that constantly emerge in such literature, particularly regarding the role of ‘a-cultural’ personal ties between migrants and locals in undermining State categories and ideology. This paper observes how the Ceutan case encourages us to expand our focuses and consequently problematise our understanding of crucial concepts such as ‘trust’ and ‘integration’.

  19. Relationship between early and late stages of information processing: an event-related potential study

    Portella, Claudio; Machado, Sergio; Arias-Carrión, Oscar; Sack, Alexander T.; Silva, Julio Guilherme; Orsini, Marco; Leite, Marco Antonio Araujo; Silva, Adriana Cardoso; Nardi, Antonio E.; Cagy, Mauricio; Piedade, Roberto; Ribeiro, Pedro

    2012-01-01

    The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude). PMID:23355929

  20. Geographical Information System (GIS) for Relationship Between Dengue Disease and Climatic Factors at Cheras, Malaysia

    Ahmad Dasuki Mustafa; Azman Azid; Hafizan Juahir; Kamaruzzaman Yunus; Ismail Zainal Abidin; Nur Hishaam Sulaiman; Mohammad Azizi Amran; Mohamad Romizan Osman; Mohd Khairul Amri Kamarudin; Muhammad Barzani Gasim; Mohd Khairul Amri Kamarudin

    2015-01-01

    The Geographical Information System (GIS) was utilized to generate dengue distribution cases and its correlation to the climatic factors in Cheras, Kuala Lumpur, Malaysia. The data were provided by Dewan Bandaraya Kuala Lumpur (DBKL). The data was integrated with Kuala Lumpur map to graphically present information about the areas which been hit by the dengue outbreak through a graphic display. The analysis using focused on overlay, buffer creating, and query builder. The statistical analysis such as linear regression is undertaken to show the correlation between dengue diseases with the climatic factors that is rainfall, temperature and relative humidity for the year 2008, 2009, 2010, and 2011. The study found that there is no correlation between disease incidence and total rainfall (R"2=0.057). Thus, it can be concluded that the climatic factors were not contributed to the dengue cases. Through this research, highly expect that the dengue distribution map had been developed and can be used by the authorities to analyzing the dengue disease pattern by related with the climatic factors. (author)

  1. The Relationship of Health Beliefs with Information Sources and HPV Vaccine Acceptance among Young Adults in Korea.

    Kim, Jarim

    2018-04-04

    Despite the HPV vaccine’s efficacy in preventing cervical cancer, its coverage rates among Asians are very low. To increase immunization coverage among these populations, understanding the psychological factors that affect HPV acceptability is critical. To this end, this study examined the relationships between multidimensional health beliefs and HPV vaccine acceptance, and what information sources effectively foster HPV vaccination-related health beliefs. Data were collected using a survey of 323 undergraduate students in Korea. Results showed that perceived susceptibility, perceived severity, perceived benefits, and perceived vaccine safety concerns predicted vaccine acceptance. Multiple dimensions of perceived barriers showed differing impacts on vaccine acceptance. In addition, interpersonal information sources were effective in boosting various health beliefs for HPV vaccination. The Internet also was effective in reducing social barriers, but the effects were opposite to those of social media. Theoretical and practical implications are discussed.

  2. The Relationship of Health Beliefs with Information Sources and HPV Vaccine Acceptance among Young Adults in Korea

    Jarim Kim

    2018-04-01

    Full Text Available Despite the HPV vaccine’s efficacy in preventing cervical cancer, its coverage rates among Asians are very low. To increase immunization coverage among these populations, understanding the psychological factors that affect HPV acceptability is critical. To this end, this study examined the relationships between multidimensional health beliefs and HPV vaccine acceptance, and what information sources effectively foster HPV vaccination-related health beliefs. Data were collected using a survey of 323 undergraduate students in Korea. Results showed that perceived susceptibility, perceived severity, perceived benefits, and perceived vaccine safety concerns predicted vaccine acceptance. Multiple dimensions of perceived barriers showed differing impacts on vaccine acceptance. In addition, interpersonal information sources were effective in boosting various health beliefs for HPV vaccination. The Internet also was effective in reducing social barriers, but the effects were opposite to those of social media. Theoretical and practical implications are discussed.

  3. The value of private patient information in the physician-patient relationship: a game-theoretic account.

    De Jaegher, Kris

    2012-01-01

    This paper presents a game-theoretical model of the physician-patient relationship. There is a conflict of interests between physician and patient, in that the physician prefers the patient to always obtain a particular treatment, even if the patient would not consider this treatment in his interest. The patient obtains imperfect cues of whether or not he needs the treatment. The effect of an increase in the quality of the patient's private information is studied, in the form of an improvement in the quality of his cues. It is shown that when the patient's information improves in this sense, he may either become better off or worse off. The precise circumstances under which either result is obtained are derived.

  4. Appraisal Skills, Health Literacy and the Patient-Provider Relationship: Considerations as the Health Care Consumer Turns to the Internet to Inform their Care.

    O'Dell, Rosann

    2012-01-01

    Health care consumers increasingly obtain health information from the Internet to inform their health care; the health care consumer, who also has the role of patient, maintains the right to access information from sources of their choosing for this purpose. However, noteworthy considerations exist including information appraisal skills, health literacy and the patient-provider relationship. Awareness and education are warranted to assist the health care consumer in achieving proficiency as they turn to the Internet for health information.

  5. The physician-patient relationship as a game of strategic information transmission.

    De Jaegher, K; Jegers, M

    2001-10-01

    We show that the intuition underlying the supplier-induced demand (SID) hypothesis is reflected in the cheap-talk literature from game theory, and in the credence-good literature from the economics of information. Applying these theories, we conclude that a neoclassical version of the SID hypothesis is only relevant for treatment decisions involving an expensive treatment that is equally effective in curing several states, but efficient in curing only some of these states (in that a cheaper treatment is efficient otherwise). For a simple game involving such a treatment decision, we show that a Nash equilibrium exists where the patient is able to constrain the physician in inducing demand, without the market for the potentially induced treatment failing. This equilibrium allows us to derive comparative statistics and welfare results. Copyright 2001 John Wiley & Sons, Ltd.

  6. [Relationship between organisational structure and worksite health management in the information technology and communications sector].

    Ansmann, L; Jung, J; Nitzsche, A; Pfaff, H

    2012-05-01

    Worksite health management (WHM) can positively influence employee health and performance. However, it has not yet been comprehensively implemented in companies. This study aims to identify the role of organisational structures in the implementation of WHM. In this cross-sectional study, data were collected on the companies' WHM and the organisational structure. Out of 522 randomly selected companies within the German information technology and communication (ITC) sector, one managing director for each company was being questioned through telephone interviews. Bivariate and multivariate logistic regression analyses were conducted. The results of the study reveal that the implementation of WHM is positively correlated with a large company size (OR 2.75; 95%-CI 1.10-6.88) and with the existence of an employee representation (OR 2.48; 95%-CI 1.54-3.98). Other structural characteristics, such as the employment of a company physician, the percentage of temporary workers as well as the staff's age and sex distribution do not seem to have a significant impact on the implementation of WHM. The results indicate that the implementation of WHM can only be explained to a certain degree by organisational structures. However, the findings highlight the fact that companies with few structural resources are in particular need of tailored support when implementing WHM. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Social Information Processing in Dating Conflicts: Reciprocal Relationships With Dating Aggression in a One-Year Prospective Study.

    Calvete, Esther; Orue, Izaskun; Gamez-Guadix, Manuel; López de Arroyabe, Elena

    2016-04-01

    The aim of this study was to assess the reciprocal associations among social information processing (SIP) in dating conflicts and the perpetration of dating aggression. A first step involved the development of a measure (The Social Information Processing Questionnaire in Dating Conflicts, SIPQ-DC) to assess social information in scenarios of conflict with dating partners. A sample of 1,272 adolescents (653 girls, 619 boys; Mage = 14.74 years, SD = 1.21) completed measures of SIP and dating aggression perpetration in two different times, which were spaced 1 year apart. Confirmatory factor analyses provided support for a model with five correlated factors for the SIPQ-DC, namely, hostile attribution, anger, aggressive response access, anticipation of positive consequences for oneself, and anticipation of negative consequences for partners. Although the perpetration of dating aggression at T1 was cross-sectionally associated with all the SIP components, anger was the only component that predicted the residual increase in dating aggression behavior over time. The perpetration of dating aggression predicted a worsening of cognitive-emotional processes involved in dating conflicts. Some longitudinal paths were significant only in male adolescents. In conclusion, relationships among SIP and aggression are reciprocal. Gender differences in longitudinal paths can contribute to explaining men's higher perpetration of violence in adulthood. © The Author(s) 2014.

  8. Relationship between parenting stress and informant discrepancies on symptoms of ADHD/ODD and internalizing behaviors in preschool children

    Ni, Hsing-Chang; Liang, Sophie Hsin-Yi; Lin, Hsiang-Yuan; Lin, Chiao-Fan; Tseng, Yu-Han

    2017-01-01

    Parent and teacher ratings of child behaviors are often discrepant, and these discrepancies may be correlated with parenting stress. The present study explored whether various parenting stress factors are associated with discrepancies between parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder (ODD) as well as internalizing symptoms in preschool children. We recruited 299 Taiwanese preschool children (aged 4–6 years) from the community or via clinical referrals. A structural equation modeling was used to analyze the relationships among three factors derived from the Parenting Stress Index-Short Form and informant discrepancies on symptoms of inattention, hyperactivity/impulsivity, ODD, and internalizing behaviors. Scores reported by parents were higher for each of the symptoms examined than those reported by teachers, and the degree of agreement between informants ranged from low to moderate. The parental distress factor of parenting stress was associated only with parent ratings, whereas other factors of parenting stress—parent-child dysfunctional interaction and parents’ stress resulted from their child’s temperament—were correlated with both parent and teacher ratings. Only parental distress factor predicted informant discrepancies for all behavioral symptoms assessed. Our findings suggest that parental distress should be considered when parent rating scores show significant discrepancies from that of teacher rating scores. PMID:29016602

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

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

    2009-05-01

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

  10. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian

    2013-01-01

    Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine...... about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure...... but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure...

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

    Monika Wujec

    2014-04-01

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

  12. Side effects of anabolic androgenic steroids: pathological findings and structure-activity relationships.

    Büttner, Andreas; Thieme, Detlef

    2010-01-01

    Side effects of anabolic steroids with relevance in forensic medicine are mainly due to life-threatening health risks with potential fatal outcome and cases of uncertain limitations of criminal liability after steroid administration. Both problems are typically associated with long-term abuse and excessive overdose of anabolic steroids. Side effects may be due to direct genomic or nongenomic activities (myotrophic, hepatotoxic), can result from down-regulation of endogenous biosynthesis (antiandrogenic) or be indirect consequence of steroid biotransformation (estrogenic).Logically, there are no systematic clinical studies available and the number of causally determined fatalities is fairly limited. The following compilation reviews typical abundant observations in cases where nonnatural deaths (mostly liver failure and sudden cardiac death) were concurrent with steroid abuse. Moreover, frequent associations between structural characteristics and typical side effects are summarized.

  13. General approaches to structure-activity relationships illustrated by recent data on angiotensin II

    Fromageot, P.; Fermandjian, S.; Greff, D.; Meyer, P.

    1975-01-01

    Molecular conformations of angiotensin in trifluoroethanol and hexafluoroisopropanol solutions were studied by circular dichroism. The molecule is organized by intramolecular forces, which implies doubling-up of the molecule onto itself. Hence the definition cross-beta proposed for this model. Examination of the peptide fragments of the hormone shows that those belonging to the C-terminal series play a capital part in the establishment of the beta conformation of angiotensin. The ratio of the intramolecular forces varies with any disturbance of the medium, leading to conformational changes. Increasing the polarity of the solvent, and/or its acidity modifies the balance of forces. The C-terminal fragments of the molecule is that containing the functional groups essential to the biological activity [fr

  14. Structure-activity relationship of CART (cocaine- and amphetamine-regulated transcript) peptide fragments

    Maixnerová, Jana; Hlaváček, Jan; Blokešová, Darja; Kowalczyk, W.; Elbert, Tomáš; Šanda, Miloslav; Blechová, Miroslava; Železná, Blanka; Slaninová, Jiřina; Maletínská, Lenka

    2007-01-01

    Roč. 28, č. 10 (2007), s. 1945-1953 ISSN 0196-9781 R&D Projects: GA ČR GA303/05/0614 Institutional research plan: CEZ:AV0Z40550506 Keywords : CART peptide * fragments * binding * PC12 cells Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.368, year: 2007

  15. Negative inotropism of terpenes on guinea pig left atrium: structure-activity relationships.

    Vasconcelos, Carla M L; Oliveira, Ingrid S N; Santos, José N A; Souza, Américo A; Menezes-Filho, José E R; Silva Neto, Júlio A; Lima, Tamires C; de Sousa, Damião P

    2018-06-01

    The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC 50 and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism.

  16. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    Prouillac, Caroline, E-mail: c.prouillac@vetagro-sup.fr [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Rodriguez, Frédéric; Baltas, Michel [Université Paul Sabatier, SPCMIB-UMR5068, Laboratoire de Synthèse et de Physicochimie des Molécules d' Intérêt Biologique, 118 route de Narbonne, 31062 TOULOUSE cedex 9 (France); Lecoeur, Sylvaine [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France)

    2012-03-15

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

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

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

    2009-01-15

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

  18. Structure-Activity Relationships of Lipopolysaccharide Sequestration in Guanylhydrazone-bearing Lipopolyamines

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

    2008-01-01

    The toxicity of Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of Gram-negative sepsis. We had previously identified in rapid-throughput screens several guanylhydrazones as potent LPS binders. We were desirous of examining ...

  19. Investigation of structure-activity relationships of Oxyntomodulin (Oxm) using Oxm analogs.

    Druce, Maralyn R; Minnion, James S; Field, Benjamin C T; Patel, Sejal R; Shillito, Joyceline C; Tilby, Michael; Beale, Kylie E L; Murphy, Kevin G; Ghatei, Mohammad A; Bloom, Stephen R

    2009-04-01

    Oxyntomodulin (Oxm) is an intestinal peptide that inhibits food intake and body weight in rodents and humans. These studies used peptide analogs to study aspects of structure and function of Oxm, and the sensitivity of parts of the Oxm sequence to degradation. Analogs of Oxm were synthesized and studied using receptor binding and degradation studies in vitro. Their effects on food intake and conditioned taste avoidance were measured in vivo in rodents. Oxm breakdown by the enzyme dipeptidyl peptidase IV (DPPIV) was demonstrated in vitro and in vivo. In vitro degradation was reduced and in vivo bioactivity increased by inhibitors of DPPIV. Modifications to the N terminus of Oxm modulated binding to the glucagon-like peptide (GLP)-1 receptor and degradation by DPPIV. Modifications to the midsection of Oxm modulated binding to the GLP-1 receptor and degradation by neutral endopeptidase. These modifications also altered bioactivity in vivo. The C-terminal octapeptide of Oxm was shown to contribute to the properties of Oxm in vitro and in vivo but was not alone sufficient for the effects of the peptide. Elongation and acylation of the C terminus of Oxm altered GLP-1 receptor binding and duration of action in vivo, which may be due to changes in peptide clearance. An Oxm analog was developed with enhanced pharmaceutical characteristics, with greater potency and longevity with respect to effects on food intake. These studies suggest that Oxm is a potential target for antiobesity drug design.

  20. Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship

    Agarwal, Ch.; Wadhwa, R.; Deep, G.; Biedermann, David; Gažák, Radek; Křen, Vladimír; Agarwal, R.

    2013-01-01

    Roč. 8, č. 3 (2013), e00074 E-ISSN 1932-6203 R&D Projects: GA MŠk(CZ) ME10027 Institutional support: RVO:61388971 Keywords : Silybin * silibinin * anti-cancer efficacy Subject RIV: CE - Biochemistry Impact factor: 3.534, year: 2013

  1. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

    Bach, Anders

    2015-01-01

    be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We...... examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic...

  2. Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis

    Nielsen, S F; Christensen, S B; Cruciani, G

    1998-01-01

    of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots......) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models...

  3. In vitro structure-activity relationship of Re-cyclized octreotide analogues

    Dannoon, Shorouk F. [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Bigott-Hennkens, Heather M. [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Ma Lixin [Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); International Institute of Nano and Molecular Medicine, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Gallazzi, Fabio [Structural Biology Core, University of Missouri, Columbia, MO 65211 (United States); Lewis, Michael R., E-mail: lewismic@missouri.ed [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Jurisson, Silvia S., E-mail: jurissons@missouri.ed [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States)

    2010-07-15

    Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods: Various octreotide analogue sequences and coordination systems (e.g., S{sub 2}N{sub 2} and S{sub 3}N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with {sup 111}In-DOTA-Tyr{sup 3}-octreotide in AR42J rat pancreatic tumor cells yielded IC{sub 50} values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr{sup 3}-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr{sup 3}-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS{sub 3} and N{sub 2}S{sub 2} coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of {sup 99m}Tc-cyclized analogue 4.

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

    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 an...

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

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

    2011-09-05

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

  6. Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors.

    Yamaki, Susumu; Yamada, Hiroyoshi; Nagashima, Akira; Kondo, Mitsuhiro; Shimada, Yoshiaki; Kadono, Keitaro; Yoshihara, Kosei

    2017-11-01

    Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.

    La Regina, Giuseppe; Edler, Michael C; Brancale, Andrea; Kandil, Sahar; Coluccia, Antonio; Piscitelli, Francesco; Hamel, Ernest; De Martino, Gabriella; Matesanz, Ruth; Díaz, José Fernando; Scovassi, Anna Ivana; Prosperi, Ennio; Lavecchia, Antonio; Novellino, Ettore; Artico, Marino; Silvestri, Romano

    2007-06-14

    The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241.

  8. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    Prouillac, Caroline; Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle; Rodriguez, Frédéric; Baltas, Michel; Lecoeur, Sylvaine

    2012-01-01

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

  9. Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents

    Pramod K. Sahu

    2017-07-01

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

  10. Immunological evaluation of lipopeptide group A streptococcus (GAS vaccine: structure-activity relationship.

    Mehfuz Zaman

    Full Text Available Streptococcus pyogenes (group A streptococcus, GAS is a Gram-positive bacterial pathogen responsible for a wide variety of diseases. To date, GAS vaccine development has focused primarily on the M-protein. The M-protein is highly variable at the amino (N-terminus (determining serotype but is conserved at the carboxyl (C-terminus. Previously a 29 amino acid peptide (named J14 from the conserved region of the M-protein was identified as a potential vaccine candidate. J14 was capable of eliciting protective antibodies that recognized many GAS serotypes when co-administered with immuno-stimulants. This minimal epitope however showed no immunogenicity when administered alone. In an attempt overcome this immunological non-responsiveness, we developed a self-adjuvanting vaccine candidate composed of three components: the B-cell epitope (J14, a universal helper T-cell epitope (P25 and a lipid moiety consisting of lipoamino acids (Laas which target Toll-like receptor 2 (TLR2. Immunological evaluation in B10.BR (H-2k mice demonstrated that the epitope attachment to the point of lipid moiety, and the length of the Laa alkyl chain have a profound effect on vaccine immunogenicity after intranasal administration. It was demonstrated that a vaccine featuring C-terminal lipid moiety containing alkyl chains of 16 carbons, with P25 located at the N-terminus, and J14 attached to the side chain of a central lysine residue was capable of inducing optimal antibody response. These findings have considerable relevance to the development of a broad spectrum J14-based GAS vaccine and in particular provided a rational basis for peptide vaccine design based on this self-adjuvanting lipopeptide technology.

  11. Total Synthesis of (-)-Doliculide, Structure-Activity Relationship Studies and Its Binding to F-Actin

    Matcha, Kiran; Madduri, Ashoka V. R.; Roy, Sayantani; Ziegler, Slava; Waldmann, Herbert; Hirsch, Anna K. H.; Minnaard, Adriaan J.

    2012-01-01

    Actin, an abundant protein in most eukaryotic cells, is one of the targets in cancer research. Recently, a great deal of attention has been paid to the synthesis and function of actin-targeting compounds and their use as effective molecular probes in chemical biology. In this study, we have

  12. Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives

    Virapong Prachayasittikul

    2010-01-01

    Full Text Available Nicotinic acid, known as vitamin B3, is an effective lipid lowering drug and intense cutaneous vasodilator. This study reports the effect of 2-(1-adamantylthionicotinic acid (6 and its amide 7 and nitrile analog 8 on phenylephrine-induced contraction of rat thoracic aorta as well as antioxidative activity. It was found that the tested thionicotinic acid analogs 6-8 exerted maximal vasorelaxation in a dose-dependent manner, but their effects were less than acetylcholine (ACh-induced nitric oxide (NO vasorelaxation. The vasorelaxations were reduced, apparently, in both NG-nitro-L-arginine methyl ester (L-NAME and indomethacin (INDO. Synergistic effects were observed in the presence of L-NAME plus INDO, leading to loss of vasorelaxation of both the ACh and the tested nicotinic acids. Complete loss of the vasorelaxation was noted under removal of endothelial cells. This infers that the vasorelaxations are mediated partially by endothelium-induced NO and prostacyclin. The thionicotinic acid analogs all exhibited antioxidant properties in both 2,2-diphenyl-1-picrylhydrazyl (DPPH and superoxide dismutase (SOD assays. Significantly, the thionicotinic acid 6 is the most potent vasorelaxant with ED50 of 21.3 nM and is the most potent antioxidant (as discerned from DPPH assay. Molecular modeling was also used to provide mechanistic insights into the vasorelaxant and antioxidative activities. The findings reveal that the thionicotinic acid analogs are a novel class of vasorelaxant and antioxidant compounds which have potential to be further developed as promising therapeutics.

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

    André Luiz Lourenço

    2015-04-01

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

  14. Inhibition of [gamma]-endorphin generating endopeptidase activity of rat brain by peptides: Structure activity relationship

    Lebouille, J.L.M.; Visser, W.H.; Hendriks, R.W.; Nispen, J.W. van; Greven, H.M.; Burbach, J.P.H.

    1985-01-01

    Gamma-Endorphin generating endopeptidase (gammaEGE) activity is an enzyme activity which converts beta-endorphin into gamma-endorphin and beta-endorphin-(18–31). The inhibitory potency on gammaEGE activity of neuropeptides and analogues or fragments of neuropeptides was tested. Dynorphin-(1–13)

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

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

    2009-04-01

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

  16. Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors.

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

    2016-02-04

    PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N-terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N-terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Structure Activity Relationships of N-linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids

    Makanjuola Ogunsina

    2013-12-01

    Full Text Available 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (1 was previously reported to show potent in vitro antitumor activity on a range of cancer cell lines derived from breast, pancreas and prostate cancer. This compound was not toxic to mice and was inactive against breast tumor xenografts in mice. This inactivity was attributed to hydrolysis of the glycosidic linkage by glycosidases. Here three N-linked (glycosylamide analogs 2–4, one triazole-linked analog 5 of 1 as well as two diglycosylated analogs 6 and 7 with different stereochemistry at the C2-position of the glycerol moiety were synthesized and their antitumor activity against breast (JIMT-1, BT-474, MDA-MB-231, pancreas (MiaPaCa2 and prostrate (DU145, PC3 cancer cell lines was determined. The diglycosylated analogs 1-O-hexadecyl-2(R-, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (7 and the 1:1 diastereomeric mixture of 1-O-hexadecyl-2(R/S, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (6 showed the most potent cytotoxic activity at CC50 values of 17.5 µM against PC3 cell lines. The replacement of the O-glycosidic linkage by a glycosylamide or a glycosyltriazole linkage showed little or no activity at highest concentration tested (30 µM, whereas the replacement of the glycerol moiety by triazole resulted in CC50 values in the range of 20 to 30 µM. In conclusion, the replacement of the O-glycosidic linkage by an N-glycosidic linkage or triazole-linkage resulted in about a two to three fold loss in activity, whereas the replacement of the methoxy group on the glycerol backbone by a second glucosamine moiety did not improve the activity. The stereochemistry at the C2-position of the glycero backbone has minimal effect on the anticancer activities of these diglycosylated analogs.

  18. A Relational Learning Approach to Structure-Activity Relationships in Drug Design Toxicity Studies

    Camacho Rui

    2011-12-01

    Full Text Available It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current “target-rich, lead-poor” scenario.

  19. In-silico structure activity relationship study of toxicity endpoints by QSAR modeling (SOT)

    Several thousand chemicals were tested in 700 toxicity-related in-vitro HTS bioassays through the EPA’s ToxCast and Tox21 projects. This chemical set only covers a portion of the chemical space of interest for environmental exposure, leading to a need to fill data gaps with alter...

  20. Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study

    Hendriks, Jerome J. A.; de Vries, Helga E.; van der Pol, Susanne M. A.; van den Berg, Timo K.; van Tol, Eric A. F.; Dijkstra, Christine D.

    2003-01-01

    Demyelination is a characteristic hallmark of the neuro-inflammatory disease multiple sclerosis. During demyelination, macrophages phagocytose myelin and secrete inflammatory mediators that worsen the disease. Here, we investigated whether flavonoids, naturally occurring immunomodulating compounds,