Derivatives of 3-isoxazolecarboxylic acid esters - a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis

Annamaria Lilienkampf, Marco Pieroni, Scott G. Franzblau, William R. Bishai, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC 50's > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3-isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development.

Original languageEnglish (US)
Pages (from-to)729-734
Number of pages6
JournalCurrent topics in medicinal chemistry
Volume12
Issue number7
DOIs
StatePublished - Apr 1 2012

Keywords

  • Drug-resistance
  • Inhibition
  • Isoxazole
  • Mycobacterium
  • Persistence
  • Quinoline
  • Tuberculosis

ASJC Scopus subject areas

  • Drug Discovery

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