Synthesis, biological evaluation, and molecular docking studies of deoxygenated C-glycosides as LpxC inhibitors

Bioorg Chem. 2021 Dec:117:105403. doi: 10.1016/j.bioorg.2021.105403. Epub 2021 Oct 6.

Abstract

The bacterial deacetylase LpxC is a promising target for the development of novel antibiotics being selectively active against Gram-negative bacteria. In chiral pool syntheses starting from d- and l-ribose, a series regio- and stereoisomeric monohydroxytetrahydrofuran derivatives was synthesized and tested for LpxC inhibitory and antibacterial activities. Molecular docking studies were performed to rationalize the obtained structure-activity relationships. The (2S,3R,5R)-configured 3-hydroxytetrahydrofuran derivative ent-8 ((2S,3R,5R)-N,3-Dihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Ki = 3.5 µM) of the synthesized series of monohydroxytetrahydrofuran derivatives and to exhibit the highest antibacterial activity against E. coli BL21(DE3) and the D22 strain.

Keywords: Antibiotics; C-glycosides; LpxC inhibitors; Molecular docking studies; Monohydroxytetrahydrofuran derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / drug effects
  • Amidohydrolases / metabolism
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli Infections / drug therapy
  • Glycosides / chemical synthesis
  • Glycosides / chemistry*
  • Glycosides / pharmacology*
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Gram-Negative Bacterial Infections / drug therapy
  • Humans
  • Molecular Docking Simulation

Substances

  • Anti-Bacterial Agents
  • C-glycoside
  • Enzyme Inhibitors
  • Glycosides
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase