Ommi Ojaswitha, Bhalerao Harshada Anil, Malik Pradip, Ali Juned, Saxena Deepanshi, Nanduri Srinivas, Sonti Rajesh, Dasgupta Arunava, Chopra Sidharth, Yaddanapudi Venkata Madhavi
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Telangana, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Telangana, India.
Bioorg Med Chem. 2025 Nov 1;129:118341. doi: 10.1016/j.bmc.2025.118341. Epub 2025 Aug 6.
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 (CL 11.49-14.62 μL/min/mg microsomal protein), indicating effective drug levels and bioavailability. Also, 12a, 14a, and 14d showed stable interactions with QcrB in docking studies. These findings highlight 12a, 14a, and 14d as potential candidates for in vivo evaluation and further development as novel anti-tubercular drugs.
耐多药结核病（TB）的出现迫切需要发现和开发新的抗分枝杆菌药物。在此，我们报告了一系列基于1,3 - 二芳基取代吡唑的咪唑并[1,2 - a]吡啶羧酰胺的合成与评估，这些化合物有望成为抗结核药物。在初步筛选中，26种化合物中有10种对结核分枝杆菌H37Rv表现出强效的体外抑制作用，MIC值为0.03μg/mL，比一线抗结核药物链霉素强17倍，比乙胺丁醇强33倍，与异烟肼和利福平相当。令人鼓舞的是，这些化合物中的大多数对Vero细胞的选择性指数（SI）>3333.3，CC₅₀值>100μg/mL，表明它们对结核分枝杆菌的毒性比对哺乳动物细胞高3000倍以上，并且在有效抗结核浓度（MIC = 0.03μg/mL）下无细胞毒性。其中，12a、14a和14d对耐多药结核分枝杆菌菌株表现出显著活性，MIC为0.03μM。时间 - 杀菌动力学研究表明，12a、14a和14d具有抑菌特性。此外，12a、14a和14d与FDA批准的抗结核药物利福平（ƩFIC 0.093）、乙胺丁醇（ƩFIC 0.061）和莫西沙星（ƩFIC 0.154 - 0.281）表现出协同作用，与这些药物联合使用时具有杀菌时间 - 杀菌特性。此外，12a、14a和14d表现出可接受的代谢稳定性（CL 11.49 - 14.62μL/min/mg微粒体蛋白），表明药物水平和生物利用度有效。此外，在对接研究中，12a、14a和14d与QcrB显示出稳定的相互作用。这些发现突出了12a、14a和14d作为体内评估的潜在候选物以及作为新型抗结核药物进一步开发的潜力。
