Discovery of novel lipophilic inhibitors of OXA-10 enzyme (class D beta-lactamase) by screening amino analogs and homologs of citrate and isocitrate.
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.
Beck
Joséphine
J
Unité de Chimie Organique et Médicinale, Université Catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium.
Vercheval
Lionel
L
Bebrone
Carine
C
Herteg-Fernea
Adriana
A
Lassaux
Patricia
P
Marchand-Brynaert
Jacqueline
J
D000215:Acylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002951:Citrates / Q000138:chemical synthesis / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007523:Isocitrates / Q000138:chemical synthesis / Q000737:chemistry*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D002951:Citrates; D004791:Enzyme Inhibitors; D007523:Isocitrates; D065093:beta-Lactamase Inhibitors; C055187:beta-lactamase PSE-2; D001618:beta-Lactamases