Synthesis and Biological Evaluation of Indole‐Benzene Sulfonamides as Carbonic Anhydrase II, IX, and XII Inhibitors

Human carbonic anhydrases (hCAs) are zinc‐bound enzymes that play a critical role in pH regulation and ion balance. Among them, isoforms hCA IX and XII are overexpressed in tumor hypoxia and are implicated in tumor progression. In this study, new indole‐benzenesulfonamide derivatives with hydrazide and amide linkers were synthesized and evaluated against hCA I, II, IX, and XII. Among them, compounds 5c and 5o showed potent inhibition against hCA IX with K i values of 22.4 and 22.7 nM, respectively, while compound 5h showed potent inhibition against hCA XII ( K i = 22.6 nM). Halogenation at C 5 /C 6 and N ‐substitution on the indole moiety played significant roles in improving the potency and selectivity toward hCA IX and XII. Molecular docking studies revealed that the most active compounds formed stable coordination with Zn 2+ , hydrogen bonding with Thr199, Thr200, and Gln92, and pi–pi stacking with His residues. ADMET predictions indicated that the lead compounds possess favorable drug‐likeness and safety profiles. Together, these results identify 5c , 5o , 5f , and 5h as promising leads for further structural modifications to develop anticancer agents that selectively target hCA IX and XII isoforms.