Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3685-8. doi: 10.1016/j.bmcl.2003.08.015.

Abstract

Analogues of the antibiotic thiolactomycin, with biphenyl-based 5-substituents, were found to have excellent in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-(4'-benzyloxy-biphen-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited approximately a 4-fold increased potency against this key condensing enzyme involved in M. tuberculosis mycolic acid biosynthesis, compared to thiolactomycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Acetyltransferases / antagonists & inhibitors
  • Alkylation
  • Anti-Bacterial Agents / pharmacology*
  • Fatty Acid Synthase, Type II
  • Fatty Acid Synthases / antagonists & inhibitors
  • Multienzyme Complexes / antagonists & inhibitors
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / metabolism
  • Mycolic Acids / metabolism
  • Recombinant Proteins / metabolism
  • Thiophenes / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Multienzyme Complexes
  • Mycolic Acids
  • Recombinant Proteins
  • Thiophenes
  • thiolactomycin
  • Acetyltransferases
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
  • Fatty Acid Synthases
  • Fatty Acid Synthase, Type II