Discovery of novel lipophilic inhibitors of OXA-10 enzyme (class D β-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 β-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.

The title compounds have been synthesized by alkylation of glycinate imines with bromoacetates, acrylate or fumarate. Their biochemical activity was evaluated against representative β-lactamases of all classes. Out of these molecules, tested as free acids or esters, 5e and 4e emerged as modest inhibitor of BS3 and good inhibitor of OXA-10 enzymes respectively. This discovery is consistent with the active site hydrophobic character of class D comparatively to class A β-lactamases.Figure optionsDownload as PowerPoint slide