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*

*Corresponding author for this work

Research output: Contribution to journalLiterature reviewpeer-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 (IC50's > 128 mu M). 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
Pages (from-to)729-734
Number of pages6
JournalCurrent Topics in Medicinal Chemistry
Volume12
Issue number7
Publication statusPublished - Apr 2012

Keywords

  • Tuberculosis
  • mycobacterium
  • inhibition
  • drug-resistance
  • persistence
  • quinoline
  • isoxazole
  • MEFLOQUINE-BASED LIGANDS
  • ANTITUBERCULOSIS AGENTS
  • DESIGN
  • METABOLISM
  • MECHANISMS
  • INHIBITORS
  • GROWTH
  • SERIES
  • DRUGS

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