Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold

Bioorg Med Chem. 2011 Jan 15;19(2):852-60. doi: 10.1016/j.bmc.2010.12.017. Epub 2010 Dec 9.

Abstract

Compounds inhibiting LpxC in the lipid A biosynthetic pathway are promising leads for novel antibiotics against multidrug-resistant Gram-negative pathogens. We report the syntheses and structural and biochemical characterizations of LpxC inhibitors based on a diphenyl-diacetylene (1,4-diphenyl-1,3-butadiyne) threonyl-hydroxamate scaffold. These studies provide a molecular interpretation for the differential antibiotic activities of compounds with a substituted distal phenyl ring as well as the absolute stereochemical requirement at the C2, but not C3, position of the threonyl group.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / metabolism
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase