Exploration of 2-phenylquinoline-4-carboxamide linked benzene sulfonamide derivatives as isoform selective inhibitors of transmembrane human carbonic anhydrases

A novel series of 32 sulfonamide containing quinolines (5a-j, 7a-k and 9a-k) were synthesized using tail approach and assayed for their carbonic anhydrase inhibitory potency against four human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX and XII. Most of these newly synthesized compounds exhibited interesting inhibition potency against hCA I, II, IX and XII, in the nanomolar range with some derivatives being more potent than the standard drug acetazolamide (AAZ). The most effective ones on hCA I were 9b (91.8 nM), on hCA II: 5b (7.1 nM), 9c (9.6 nM) and on hCA IX: 5b (6.5 nM), 5g (21.4 nM), 5i (9.1 nM), 9a (22.8 nM), 9b (9.7 nM). Compounds 5h (8.8 nM), 7a (9.6 nM), 9d (6.9 nM), 9e (6.7 nM) were found highly effective against hCA XII. These 4-functionalized benzenesulfonamides (5a-5j, 9a-9k) were found to be more potent than the corresponding 3-functionalized derivatives (7a-k). These compounds may emerge as potential leads for the development of isoform selective hCA IX and XII inhibitors.