Abstract
AIMS: To design, synthesize, and assess novel sulfonamide hydrazone derivatives as selective inhibitors of Mycobacterium tuberculosis carbonic anhydrase. MATERIALS AND METHODS: Two series of 4-(arylidenehydrazinyl)benzenesulfonamides (5a-r) and N-arylidene-4-methylbenzenesulfonohydrazides (6a-h) were synthesized and evaluated against recombinant MtCA isoforms 1 and 3, and human carbonic anhydrase isoforms I and II by enzyme inhibition assays. Molecular docking and molecular dynamics simulations assessed the binding stability and coordination with the active-site zinc ion. Anti-mycobacterial activity was determined by minimum inhibitory concentrations (MICs) against M. tuberculosis. Time-kill kinetics and cytotoxicity assays evaluated the bactericidal potential and selectivity of the compound toward mammalian cells. RESULTS: The compounds showed potent inhibition of MtCA 3 and hCA II, with moderate activity against MtCA 1 and hCA I. Notably, compounds 3e and 3f exhibited K(i) values of 0.0931 µM and 0.0984 µM, respectively, surpassing acetazolamide (K(i) = 0.104 µM). Docking and simulations confirmed stable zinc coordination. MIC values ranged from 4 to 128 µg/mL. Time-kill and cytotoxicity studies confirmed rapid bactericidal activity and low mammalian toxicity. CONCLUSION: These sulfonamide hydrazone derivatives demonstrate potent, selective MtCA inhibition, robust antimycobacterial efficacy, and favorable safety profiles, representing promising scaffolds for novel tuberculosis therapies with a novel mode of action.