Design and Synthesis of Bis-Triazole-Linked Benzenesulfonamides as Selective Carbonic Anhydrase IX/XII Inhibitors with Chemosensitizing Activity

Carbonic anhydrase hCA IX and hCA XII are cancer-associated enzymes involved in tumor pH regulation, hypoxia-driven survival, and therapeutic resistance. Here, we report the rational design, synthesis, and biological evaluation of bis-triazole-linked benzenesulfonamides as novel carbonic anhydrase inhibitors. Several compounds exhibited potent and selective inhibition of hCA IX/XII, with compounds 2g and 4g showing nanomolar activity (hCA IX K I = 25.1 and 28.1 nM; hCA XII K I = 35.2 and 11.6 nM, respectively) and reduced activity against off-target isoforms hCA I/II, indicating favorable selectivity profiles. Lead compounds 2g and 4g significantly enhanced the antiproliferative effects of azacitidine and sorafenib in breast and pancreatic cancer cells under both normoxic and hypoxic conditions. Molecular modeling and simulation studies further supported productive zinc coordination and stable active-site interactions. Overall, these findings highlight bis-triazole benzenesulfonamides as promising scaffolds for targeting hCA IX/XII-expressing tumors and improving chemosensitivity to conventional chemotherapeutics to overcome cancer resistance.