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

Abstract

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 K_i 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 K_i 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.