- Azole-based non-peptidomimetic plasmepsin inhibitors
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The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases – plasmepsins (Plms) – are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.
- Kinena, Linda,Leitis, Gundars,Kanepe-Lapsa, Iveta,Bobrovs, Raitis,Jaudzems, Kristaps,Ozola, Vita,Suna, Edgars,Jirgensons, Aigars
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- Role of the CAI-1 fatty acid tail in the Vibrio cholerae quorum sensing response
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Quorum sensing is a mechanism of chemical communication among bacteria that enables collective behaviors. In V. cholerae, the etiological agent of the disease cholera, quorum sensing controls group behaviors including virulence factor production and biofilm formation. The major V. cholerae quorum-sensing system consists of the extracellular signal molecule called CAI-1 and its cognate membrane bound receptor called CqsS. Here, the ligand binding activity of CqsS is probed with structural analogues of the natural signal. Enabled by our discovery of a structurally simplified analogue of CAI-1, we prepared and analyzed a focused library. The molecules were designed to probe the effects of conformational and structural changes along the length of the fatty acid tail of CAI-1. Our results, combined with pharmacophore modeling, suggest a molecular basis for signal molecule recognition and receptor fidelity with respect to the fatty acid tail portion of CAI-1. These efforts provide novel probes to enhance discovery of antivirulence agents for the treatment of V. cholerae.
- Perez, Lark J.,Ng, Wai-Leung,Marano, Paul,Brook, Karolina,Bassler, Bonnie L.,Semmelhack, Martin F.
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p. 9669 - 9681
(2013/01/16)
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- Making a difference on excited-state chemistry by controlling free space within a nanocapsule: Photochemistry of 1-(4-alkylphenyl)-3-phenylpropan-2-ones
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The free space within a reaction cavity plays a determining role during the excited-state reaction of 1-(4-alkylphenyl)-3-phenylpropan-2-ones included within a capsule formed by two molecules of a deep cavity cavitand. By controlling the free space within the reaction cavity through remote alkyl substitution on the reactant ketone it is possible to control the yield of the rearrangement product shown above.
- Sundaresan, Arun Kumar,Ramamurthy
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p. 3575 - 3578
(2008/02/12)
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- FUNGAL CELL WALL SYNTHESIS GENE
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A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed.Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.
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- Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships
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Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.
- Koide, Yuuki,Hasegawa, Takeshi,Takahashi, Atsuo,Endo, Akira,Mochizuki, Naoki,Nakagawa, Masako,Nishida, Atsushi
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p. 4629 - 4638
(2007/10/03)
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- Phenacenes: A family of graphite ribbons. 2. Syntheses of some [7]phenacenes and an [11]phenacene by stilbene-like photocyclizations
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It is proposed that members of the family of polycyclic aromatic compounds with an extended phenanthrene-like structural motif be designated as [n]phenacenes, where n is the number of fused benzene rings. [n]Phenacene molecules are related to layers of gr
- Mallory, Frank B.,Butler, Kelly E.,Evans, Amanda C.,Brondyke, Emilie J.,Mallory, Clelia W.,Yang, Changqing,Ellenstein, Aviva
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p. 2119 - 2124
(2007/10/03)
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- Phenacenes: A family of graphite ribbons. 1. Syntheses of some [7]phenacenes by stilbene-like photocyclizations
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The largest previously reported phenacene, the name we propose for the family of polycyclic aromatic compounds having fused benzene rings in an extended phenanthrene-like structural motif, contains only six rings ([6]phenacene). We have employed stilbene-like photocyclizations to synthesize the unsubstituted [7]phenacene, an extremely insoluble compound, as well as 2,13-di-n-pentyl[7]phenacene and 2,13-di-tert-butyl[7]phenacene, two alkyl-substituted derivatives with greatly improved solubilities.
- Mallory, Frank B.,Butler, Kelly E.,Evans, Amanda C.,Mallory, Clelia W.
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p. 7173 - 7176
(2007/10/03)
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- Influence of substrate structure on the catalytic efficiency of hydroxysteroid sulfotransferase STa in the sulfation of alcohols
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Sulfotransferase a (STa) is an isoform of hydroxysteroid (alcohol) sulfotransferase that catalyzes the formation of sulfuric acid esters from both endogenous and xenobiotic alcohols. Among its various functions in toxicology, STa is the major form of hepatic sulfotransferase in the rat that catalyzes the formation of genotoxic and carcinogenic sulfuric acid esters from hydroxymethyl polycyclic aromatic hydrocarbons. The goal of the present study was to elucidate fundamental quantitative relationships between substrate structure and catalytic activity of STa that would be applicable to these and other xenobiotics. We have modified previous procedures for purification of STa in order to obtain sufficient amounts of homogeneous enzyme for determination of k(cat)/K(m) values, a quantitative measure of catalytic efficiency. We determined the catalytic efficiency of STa with benzyl alcohol and eight benzylic alcohols that were substituted with n- alkyl groups (C(n)H(2n+1), where n = 1-8) in the para position, and the optimum value for k(cat)/K(m) in these reactions was obtained with n- pentylbenzyl alcohol. Correlations between logarithms of k(cat)/K(m) values and logarithms of partition coefficients revealed that hydrophobicity of the substrate was a major factor contributing to the catalytic efficiency of STa. Primary n-alkanols (C(n)H(2n+1)OH, where n = 3-16) exhibited an optimum k(cat)/K(m) for C9-C11 and a linear decrease in v(max) of the reaction for C3-C14; 15- and 16-carbon n-alkanols were not substrates for STa. These results indicated limits to the length of the extended carbon chain in substrates. Such limits may also apply to hydroxysteroids, since cholesterol was inactive as either substrate or inhibitor of STa. Furthermore, the importance of steric effects on the catalytic efficiency of STa was also evident with a series of linear, branched, and cyclic seven-carbon aliphatic alcohols. In conclusion, our results provide fundamental quantitative relationships between substrate structure and catalytic efficiency that yield insight into the specificity of STa for both endogenous and xenobiotic alcohols.
- Chen, Guangping,Banoglu, Erden,Duffel, Michael W.
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- Synthesis of 4-Alkyl-2-iodosobenzoic Acids: Potent Catalysts for the Hydrolysis of Phosphorous Esters
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The syntheses of five new 4-alkyl-2-iodosobenzoic acids (3) are described.The iodine atom was introduced by ortho-directed lithiation of 4-alkylbenzyl alcohols followed by treatment with I2.The catalytic effectiveness of each of the products in the hydrolysis of 4-nitrophenyl diphenyl phosphate in microemulsions was studied.The 4-methyl- and 4-ethyl-substituted products were each found to be significantly better catalysts than the standard nonalkylated 2-iodosobenzoic acid (3, R=H).These results would indicate that microemulsions of these materials may find use in detoxification procedures.
- Panetta, Charles A.,Garlick, Stephanie M.,Durst, H. Dupont,Longo, Frederick R.,Ward, J. Richard
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p. 5202 - 5205
(2007/10/02)
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- The Properties of Liquid Crystal Materials Incorporating the -CH2O- Inter-ring Linkage
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To establish more securely the influence of the -CH2O- inter-ring linkage upon the properties of mesogens of both high and low dielectric anisotropy, a range of ethers with the following general structure has been prepared and their properties examined. The thermal and electro-optic properties of the compounds are discussed, and comparisons made where possible with analogous materials incorporating the -CH2CH2- linkage.
- Carr, N.,Gray, G. W.
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- KETONES-NEMATOGENS WITH MODERATE NEGATIVE DIELECTRIC ANISOTROPY AND HIGH CLEARING POINTS.
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Anisotropic ketones whose rigid cores contain phenyl and cyclohexyl units were synthesized. The carbonyl group was incorporated either in the terminal substituents or in the link between the core units. The mesomorphic behavior of these ketones is described and correlated with their chemical structure. The 1-(4-alkanoylphenyl)-4-trans-alkylcyclohexanes as well as the 1-(4-alkanoylphenyl)-4-trans-alkanoylcyclohexanes show nematic phases. In contrast to laterally substituted compounds, these ketones have clearing points which are higher than those of the corresponding hydrocarbons. Another advantage of these nematogens is the ease of synthesis.
- Osman,Huynh-Ba
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p. 141 - 152
(2007/10/02)
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- 1-(TRANS-4 prime -N-ALKYLCYCLOHEXYL)-2-(4 double prime -CYANOPHENYL)ETHANES - A NEW SERIES OF STABLE NEMATOGENS OF POSITIVE DIELECTRIC ANISOTROPY.
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The synthesis and some important properties of the 1-(trans-4 prime -n-alkylcyclohexyl)-2-(4 double prime -cyanophenyl)ethanes - where n-alkyl equals C//1 to C//7 - are described.
- Carr,Gray,McDonnell
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