Novel <i>N</i>-(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

Abstract

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds 7a–s, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds 7a–e, followed by diversification with small hydrophobic groups (7f–m) and hydrophilic heterocyclic secondary amines (7n–s). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative 7l exhibited the highest efficacy against CA IX (KI = 0.317 μM) and ditrifluoromethylated 7j against CA XII (KI = 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially for dimethylated derivative 7h (CA IX, KI = 1.324 μM; CA XII, KI = 0.435 μM), with GI50 values ranging from 0.361 to 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions of compound 7h on CAs IX and XII.