Antibacterial activity of xylose-derived LpxC inhibitors - Synthesis, biological evaluation and molecular docking studies

Bioorg Chem. 2021 Feb:107:104603. doi: 10.1016/j.bioorg.2020.104603. Epub 2020 Dec 31.

Abstract

LpxC inhibitors represent a promising class of novel antibiotics selectively combating Gram-negative bacteria. In chiral pool syntheses starting from D- and L-xylose, a series of four 2r,3c,4t-configured C-furanosidic LpxC inhibitors was obtained. The synthesized hydroxamic acids were tested for antibacterial and LpxC inhibitory activity, the acquired biological data were compared with those of previously synthesized C-furanosides, and molecular docking studies were performed to rationalize the observed structure-activity relationships. Additionally, bacterial uptake and susceptibility to efflux pump systems were investigated for the most promising stereoisomers.

Keywords: Antibiotics; Bacterial uptake; C-glycosides; LpxC inhibitors; Molecular docking studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Molecular Docking Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • Xylose / chemical synthesis
  • Xylose / chemistry
  • Xylose / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Xylose
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase