Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors

Bioorg Med Chem. 2014 Feb 1;22(3):1016-28. doi: 10.1016/j.bmc.2013.12.057. Epub 2014 Jan 3.

Abstract

The inhibition of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represents a promising strategy to combat infections caused by multidrug-resistant Gram-negative bacteria. In order to elucidate the functional groups being important for the inhibition of LpxC, the structure of our previously reported hydroxamic acid 4 should be systematically varied. Therefore, a series of benzyloxyacetohydroxamic acids was prepared, of which the diphenylacetylene derivatives 28 (Ki=95nM) and 21 (Ki=66nM) were the most potent inhibitors of Escherichia coli LpxC. These compounds could be synthesized in a stereoselective manner employing a Sharpless asymmetric dihydroxylation and a Sonogashira coupling in the key steps. The obtained structure-activity relationships could be rationalized by molecular docking studies.

Keywords: Antibacterials; Enantioselective synthesis; LpxC inhibitors; Molecular docking studies; Phenylethylene glycol derivatives.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Ethylene Glycols / chemistry
  • Hydroxamic Acids / chemistry*
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Ethylene Glycols
  • Hydroxamic Acids
  • styrene glycol
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase