Exploring Coumarin‐Triazole Derivatives as Selective Inhibitors of Carbonic Anhydrase IX and XII

Human carbonic anhydrases (hCAs), particularly the cancer-linked isoforms hCA IX and XII, are essential in regulating the abnormal metabolism and pH gradient in cancer cells, facilitating tumor progression, invasiveness, and resistance to chemotherapy. In this study, we designed and synthesized twenty novel 6-functionalized coumarin derivatives bearing 1,2,3-triazole moieties via amide linkers of varying alkyl chain lengths. These molecules were screened for inhibitory effects on hCA isoforms I, II, IX, and XII. The data demonstrated selective inhibition to the cancer-related isoforms hCA IX and XII (K_i values ranging from 79 to 96 nM), with negligible activity against the off-target isoforms hCA I and II (K_i > 100 µM). Among the synthesized compounds, 6d, 7d, and 6f showed the highest potency of K_i 79.5, 81.8, and 94.4 nM against hCA IX and 83.5, 88.3, and 79.5 nM against hCA XII, respectively. Structure-activity relationship analysis highlighted that shorter linkers and electron-withdrawing substituents enhanced potency. Our study confirms the promise of the coumarin-triazole scaffold as a selective and reliable platform for developing anticancer CA inhibitors.