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.
