Structural insights into Arylidenehydrazinyl Benzenesulfonamides as potent mycobacterial carbonic anhydrase inhibitors.

AIMS: To design, synthesize, and assess novel sulfonamide hydrazone derivatives as selective inhibitors ofcarbonic anhydrase.

MATERIALS AND METHODS: Two series of 4-(arylidenehydrazinyl)benzenesulfonamides () and N-arylidene-4-methylbenzenesulfonohydrazides () 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, compoundsandexhibited Kvalues of 0.0931 µM and 0.0984 µM, respectively, surpassing acetazolamide (K = 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.