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

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds <b>7a</b>-<b>s</b>, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds <b>7a</b>-<b>e</b>, followed by diversification with small hydrophobic groups (<b>7f</b>-<b>m</b>) and hydrophilic heterocyclic secondary amines (<b>7n</b>-<b>s</b>). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative <b>7l</b> exhibited the highest efficacy against CA IX (<i>K</i>_<i>I</i> = 0.317 μM) and ditrifluoromethylated <b>7j</b> against CA XII (<i>K</i>_<i>I</i> = 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially for dimethylated derivative <b>7h</b> (CA IX, <i>K</i>_<i>I</i> = 1.324 μM; CA XII, <i>K</i>_<i>I</i> = 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 <b>7h</b> on CAs IX and XII.