Peptide deformylase inhibitors with retro-amide scaffold: synthesis and structure-activity relationships

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4317-9. doi: 10.1016/j.bmcl.2010.06.088. Epub 2010 Jun 19.

Abstract

Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins. Thus inhibition of PDF activity is considered to be one of the most effective antibiotic strategies. Reported herein are the synthesis and structure-activity relationship studies of retro-amide inhibitors based on actinonin, a naturally occurring PDF inhibitor. Analysis of the structure-activity relationships led to the discovery of 7a, which exhibits potent enzyme inhibition and antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hydroxamic Acids / pharmacology
  • Microbial Sensitivity Tests
  • Structure-Activity Relationship

Substances

  • Amides
  • Anti-Bacterial Agents
  • Cyclopentanes
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Amidohydrolases
  • peptide deformylase
  • actinonin