Title | Discovery of novel lipophilic inhibitors of OXA-10 enzyme (class D beta-lactamase) by screening amino analogs and homologs of citrate and isocitrate. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Beck, J., L. Vercheval, C. Bebrone, A. Herteg-Fernea, P. Lassaux, and J. Marchand-Brynaert |
Journal | Bioorg Med Chem Lett |
Volume | 19 |
Issue | 13 |
Pagination | 3593-7 |
Date Published | 2009 Jul 1 |
ISSN | 1464-3405 |
Keywords | Acylation, Anti-Bacterial Agents, beta-Lactamases, Catalytic Domain, Citrates, Computer Simulation, Crystallography, X-Ray, Drug Discovery, Enzyme Inhibitors, Isocitrates |
Abstract | Aminocitrate (and homolog) derivatives have been prepared by bis-alkylation of glycinate Schiff bases with bromoacetates (and ethyl acrylate), followed by N-acylation and esters (partial or complete) deprotection. Aminoisocitrate was similarly obtained by mono-alkylation with diethyl fumarate. Evaluation against representative beta-lactamases revealed that the free acid derivatives are modest inhibitors of class A enzymes, whilst their benzyl esters showed a good inhibition of OXA-10 (class D enzyme). A docking experiment featured hydrophobic interactions in the active site. |
DOI | 10.1016/j.bmcl.2009.04.149 |
Alternate Journal | Bioorg. Med. Chem. Lett. |
PubMed ID | 19467869 |
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