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

Bioorg Med Chem Lett. 2004 Jan 19;14(2):373-6. doi: 10.1016/j.bmcl.2003.10.061.

Abstract

Analogues of the natural antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-[3-(4-acetyl-phenyl)-prop-2-ynyl]-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited more than an 18-fold increased potency, compared to thiolactomycin, against this key condensing enzyme, involved in M. tuberculosis mycolic acid biosynthesis. Analogues of the antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded activity against cloned mtFabH condensing enzyme.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylene / analogs & derivatives*
  • Acetylene / pharmacology
  • Acetyltransferases / antagonists & inhibitors
  • Acetyltransferases / metabolism
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Fatty Acid Synthase, Type II
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / metabolism
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology*
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • Bacterial Proteins
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Thiophenes
  • thiolactomycin
  • Acetyltransferases
  • Fatty Acid Synthases
  • Fatty Acid Synthase, Type II
  • fatty acid synthase I, mycobacteria
  • Acetylene