Novel -(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches.

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds -, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds -, followed by diversification with small hydrophobic groups (-) and hydrophilic heterocyclic secondary amines (-). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative exhibited the highest efficacy against CA IX ( = 0.317 μM) and ditrifluoromethylated against CA XII ( = 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially for dimethylated derivative (CA IX, = 1.324 μM; CA XII, = 0.435 μM), with GI values ranging from 0.361 to 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions of compound on CAs IX and XII.