A series of benzensulfonamide derivatives as new potent carbonic anhydrase IX and XII inhibitors

Aim: Human carbonic anhydrases (hCAs) are involved in many physiological processes including respiration, pH control, ion transport, bone resorption, and gastric fluid secretion. Recently, CA IX and CA XII have been studied for their role in Cancer diseases, motivating the design of inhibitors of these isoforms.

Material and method: Here, we used the tail approach to design a new series of monoaryl (1a-i) and bicyclic (1j-n) benzensulfonamide derivatives CA IX and CA XII inhibitors. All synthesized compounds were investigated toward a panel of hCAs, and most of them exhibited potent CA inhibitory activity for CA II, CA IX and CA XII with K_i values. In silico studies were performed to investigate the binding mode between inhibitors and CA.

Results and conclusion: The best compound was 1i that showed a low nanomolar range of K_i value as CA Inhibitor (K_i = 9.4, 5.6 and 6.3 nM hCA II, IX and XII, respectively).

Carbonic anhydrase IX, XII; Carbonic anhydrase inhibitors (CAIs); benzensulfonamide derivatives; enzyme inhibition; metalloenzymes.