Derivatives of 3-isoxazolecarboxylic acid esters: a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis |
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Authors: | Lilienkampf Annamaria Pieroni Marco Franzblau Scott G Bishai William R Kozikowski Alan P |
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Institution: | Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. |
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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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