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

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3593-7. doi: 10.1016/j.bmcl.2009.04.149. Epub 2009 May 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Catalytic Domain
  • Citrates / chemical synthesis
  • Citrates / chemistry*
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Isocitrates / chemical synthesis
  • Isocitrates / chemistry*
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Citrates
  • Enzyme Inhibitors
  • Isocitrates
  • beta-Lactamase Inhibitors
  • beta-lactamase PSE-2
  • beta-Lactamases