Discovery of novel lipophilic inhibitors of OXA-10 enzyme (class D beta-lactamase) by screening amino analogs and homologs of citrate and isocitrate.

TitleDiscovery of novel lipophilic inhibitors of OXA-10 enzyme (class D beta-lactamase) by screening amino analogs and homologs of citrate and isocitrate.
Publication TypeJournal Article
Year of Publication2009
AuthorsBeck, J., L. Vercheval, C. Bebrone, A. Herteg-Fernea, P. Lassaux, and J. Marchand-Brynaert
JournalBioorg Med Chem Lett
Volume19
Issue13
Pagination3593-7
Date Published2009 Jul 1
ISSN1464-3405
KeywordsAcylation, 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.

DOI10.1016/j.bmcl.2009.04.149
Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID19467869