2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ

J Antimicrob Chemother. 2002 Jul;50(1):111-4. doi: 10.1093/jac/dkf075.

Abstract

Compounds originally designed as putative tubulin inhibitors were tested as antitubercular agents for inhibition of the Mycobacterium tuberculosis analogue of tubulin, FtsZ. Initial screening of 200 2-alkoxycarbonylpyridines found several that inhibited M. tuberculosis growth. Two compounds, SRI-3072 and SRI-7614, inhibited FtsZ polymerization and were equipotent against susceptible and single-drug-resistant strains of M. tuberculosis. In addition, SRI-3072 reduced the growth of M. tuberculosis in mouse bone marrow macrophages. Our results suggest that these types of compound might be developed into antitubercular drugs effective against the current multidrug-resistant strains of M. tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Antitubercular Agents / toxicity
  • Azepines / pharmacology*
  • Azepines / therapeutic use
  • Azepines / toxicity
  • Bacterial Proteins / drug effects*
  • Bacterial Proteins / metabolism
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / microbiology
  • Carbamates / pharmacology*
  • Carbamates / therapeutic use
  • Carbamates / toxicity
  • Chlorocebus aethiops
  • Cytoskeletal Proteins*
  • GTP Phosphohydrolases / metabolism
  • Inhibitory Concentration 50
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Mice
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / metabolism
  • Pteridines / pharmacology*
  • Pteridines / therapeutic use
  • Pteridines / toxicity
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Vero Cells

Substances

  • Antitubercular Agents
  • Azepines
  • Bacterial Proteins
  • Carbamates
  • Cytoskeletal Proteins
  • FtsZ protein, Bacteria
  • Pteridines
  • SRI 7614
  • ethyl (8-((4-(diethylamino)-1-methylbutyl)amino)-2,3-diphenylpyrido(2,3-b)pyrazin-6-yl)carbamate
  • GTP Phosphohydrolases