Synthesis of Hydrazidoureidobenzensulfonamides Incorporating a Nicotinoyl Tail and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity

<b>Background</b>: Carbonic anhydrases (CAs) are known to play important roles in several physiological and pathological processes; among them, CAs IX and XII are of particular relevance in cancer therapy due to their involvement in tumor growth and progression. <b>Methods</b>: In this study, a novel series of benzenesulfonamides incorporating a hydrazinocarbonyl-ureido linker alongside a 6-arylpyridine tail was synthesized and evaluated for inhibitory activity through a stopped-flow CO₂ hydrase assay on four hCA isoforms. <b>Results</b>: Some of the new compounds exhibited great activity and selectivity toward the tumor-expressed CA XII isoform over the off-target isoforms CA I and CA II. Based on these results, they were selected for ADME prediction studies, showing favorable drug-like properties. To further investigate their binding mode, these compounds were docked into the four hCA isoforms. <b>Conclusions</b>: Overall, the results underscore the potential of compounds bearing a 6-arylpyridine tail along with a hydrazinocarbonyl-ureido linker as a foundation for further inhibitor development.