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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis

Author(s): Annamaria Lilienkampf, Marco Pieroni, Scott G. Franzblau, William R. Bishai and Alan P. Kozikowski

Volume 12, Issue 7, 2012

Page: [729 - 734] Pages: 6

DOI: 10.2174/156802612799984544

Price: $65


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 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.

Keywords: Isoxazole, Tuberculosis, mycobacterium, inhibition, drug-resistance, persistence, quinoline, micromolar activity, Vero cells, isoniazid (INH), rifampin (RMP), anti-TB chemotype, 3-isoxazolecarboxylic acid, Mefloquine

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