Synthesis of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides and evaluation of their antitubercular activity
Abstract
The rise of drug-resistant tuberculosis (TB) has created an urgent need to discover and develop new anti-mycobacterial agents. Herein, we report the synthesis and evaluation of a library of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides as promising anti-TB agents. In preliminary screening, 10 out of 26 compounds displayed potent in vitro inhibition against Mtb H37Rv with a MIC value of 0.03 μg/mL, which is 17-fold more potent than the first-line TB drug streptomycin, 33-fold more potent than ethambutol, and equipotent with isoniazid and rifampicin. Encouragingly, most of these compounds exhibited a selectivity index (SI) >3333.3 and CC₅₀ values >100 μg/mL against Vero cells, indicating they are over 3000 times more toxic to M. tuberculosis than to mammalian cells and demonstrate absence of cytotoxicity at concentrations effective against TB (MIC = 0.03 μg/mL). Among them, 12a, 14a, and 14d demonstrated remarkable activity against drug-resistant strains of Mtb with an MIC of 0.03 μM. Time-kill kinetic studies revealed that 12a, 14a, and 14d exhibited bacteriostatic properties. Furthermore, 12a, 14a, and 14d demonstrated synergistic effects with the FDA-approved anti-TB drugs rifampicin (ƩFIC 0.093), ethambutol (ƩFIC 0.061), and moxifloxacin (ƩFIC 0.154-0.281), exhibiting bactericidal time-kill properties in combination with these drugs. Additionally, 12a, 14a, and 14d exhibited acceptable metabolic stability (CLint 11.49-14.62 μL/min/mg microsomal…
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