Novel benzenesulfonamide-Thiourea derivatives as potent carbonic anhydrase inhibitors with anticancer activity

Carbonic anhydrases are metalloenzymes that reversibly catalyze the hydration of carbon dioxide to a proton and bicarbonate and are implicated in the pathophysiology of many diseases. In the quest for novel carbonic anhydrase inhibitors with prospective therapeutic effects, a series of benzenesulfonamides-thiourea derivatives was synthesized. The compounds were further assessed for their inhibitory activity against human carbonic anhydrases hCA I, hCA II, hCA IX, and hCA XII, and subsequently evaluated for their in vitro anticancer activity against cancer cell lines overexpressing hCA IX and hCA XII, such as endometrial (ECC-1), lung (A549), colon (Caco-2, HT-29), breast (MCF-7), and glioblastoma (U118-MG) cancer cells. The compounds generally show nanomolar inhibition of all four isoforms, with compound 8a showing the best activity against hCA I (K_i: 2.05 nM) and hCA II (K_i: 0.39 nM), compound 8h against hCA IX (K_i: 17 nM), and compound 8c against hCA XII (K_i: 7.3 nM). In silico studies were conducted to rationalize the hCA inhibition data, revealing that tail modifications contribute to both potency and isoform selectivity. Among the series, compound 8h, which has the most potent hCA IX inhibition, outperformed 5-fluorouracil against MCF-7 and U118-MG cells.  .