Novel benzenesulfonamide-Thiourea derivatives as potentcarbonic anhydrase inhibitors with anticancer activity

Abstract

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