A novel thiazole-sulfonamide hybrid molecule as a promising dual tubulin/carbonic anhydrase IX inhibitor with anticancer activity.

INTRODUCTION: Multitargeted anticancer agents can overcome resistance by simultaneously modulating key pathways. This study reports a novel thiazole -chalcone/sulfonamide hybrid (compound 7) designed to inhibit both tubulin polymerization and carbonic anhydrase IX (CA IX). METHODS: Compound 7 was synthesized through a five-step sequence and characterized by NMR and elemental analysis. Its cytotoxicity was assessed against cancer (HT-29, A549, 786-O, MCF-7) and normal (WI-38) cell lines. Tubulin polymerization and CA isoform inhibition (I, II, IX, XII) were evaluated. Apoptosis induction was confirmed by measuring p53, Bax, Bcl-2, and caspases 3 and 9. Molecular docking, ADMET, and DFT studies supported mechanistic insights. RESULTS AND DISCUSSION: Compound 7 showed potent activity against HT-29 cells (IC(50) = 0.98 μM) and low toxicity toward WI-38 cells. It inhibited tubulin polymerization (IC(50) = 2.72 μM) and selectively targeted CA IX (IC(50) = 0.021 μM) and CA XII, while sparing CA I and II. Apoptotic effects were confirmed by increased p53 and Bax, reduced Bcl-2, and activation of caspases. Docking studies revealed key interactions within the colchicine-binding site of tubulin and CA IX's zinc-binding pocket. ADMET and DFT results supported its drug-like properties and electronic suitability. These findings suggest that compound 7 is a promising lead for dual-targeted anticancer therapy with selective cytotoxicity and mechanistic efficacy.