Exploration of New Pyrazole–Hydrazone–Benzenesulfonamide Conjugates as Potent Mycobacterial Carbonic Anhydrase Inhibitors: Design, Synthesis, and Biological Evaluation

The growing threat of multidrug-resistant tuberculosis highlights the need for new agents with alternative mechanisms of action. Herein, a series of pyrazole-sulfonamide derivatives are synthesized and evaluated for inhibition of Mycobacterium tuberculosis β-carbonic anhydrases (MtCA 1 and MtCA 3). N-substituted analogues (6a–6i) are inactive, while compounds bearing a free sulfonamide group (SO2NH2) (5a–5s) exhibit potent inhibitory activity, with Ki values of 0.2154–0.7542 µM for MtCA 1 and 0.0548–0.3241 µM for MtCA 3. Molecular docking studies support their binding interactions and selectivity. Antitubercular screening of all synthesized compounds reveals minimum inhibitory concentration (MIC) values in the range of 4–128 µg mL−1. Among them, compound 5p emerges as the most potent derivative, with a Ki of 0.07 µM against MtCA 3 and an MIC of 8 µg mL−1, outperforming the reference inhibitor acetazolamide. It exhibits no cytotoxicity in THP-1 cells, showing no toxicity against human cell lines, and demonstrates a favorable selectivity index. Furthermore, compound 5p retains activity against rifampicin-resistant M. tuberculosis. In silico ADMET predictions indicate acceptable pharmacokinetic and safety profiles. These findings suggest that compound 5p is a promising lead for the development of novel antitubercular agents, potentially acting through MtCA inhibition.