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 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
Current Topics in Medicinal Chemistry
Title:Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis
Volume: 12 Issue: 7
Author(s): Annamaria Lilienkampf, Marco Pieroni, Scott G. Franzblau, William R. Bishai and Alan P. Kozikowski
Affiliation:
Keywords: Isoxazole, Tuberculosis, mycobacterium, inhibition, drug-resistance, persistence, quinoline, micromolar activity, Vero cells, isoniazid (INH), rifampin (RMP), anti-TB chemotype, 3-isoxazolecarboxylic acid, Mefloquine
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 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.
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Lilienkampf Annamaria, Pieroni Marco, G. Franzblau Scott, R. Bishai William and P. Kozikowski Alan, Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis, Current Topics in Medicinal Chemistry 2012; 12 (7) . https://dx.doi.org/10.2174/156802612799984544
DOI https://dx.doi.org/10.2174/156802612799984544 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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