In this study, diverse series of coumarin derivatives were developed as potential carbonic anhydrase inhibitors (CAIs). A "tail" approach was adopted by selecting the coumarin motif as a tail that is connected to the ZBG benzenesulfonamide moiety via a hydrazine (4a,b) or hydrazide (5a,b) linker. Thereafter, an aryl sulfone tail was incorporated to afford the dual tailed coumarin-sulfonamide arylsulfonehydrazones (13a-d) and hydrazides (14a,b). Then, the ZBG were removed from compounds 13 and 14 to furnish coumarin arylsulfonehydrazones (11a-d) and hydrazides (12a,b). Coumarin-sulfonamides 4 and 5 emerged as non-selective CAIs as they displayed good inhibitory activities toward all the examined CA isozymes (I, II, IX and XII) in the nanomolar ranges. Interestingly, the "dual-tail" approach (compounds 13 and 14) succeeded in achieving a good activity and selectivity toward CA IX/XII over the physiologically dominant CA I/II. In particular, compounds 13d and 14a were the most selective coumarin-sulfonamide counterparts. Concerning non-sulfonamide coumarin derivatives, coumarins 8 exhibited excellent activity and selectivity profiles against the target hCA IX/XII, whereas, coumarins 11 and 12 reported excellent selectivity profile, but they barely inhibited hCA IX/XII with KIs spanning in the micromolar ranges. Furthermore, molecular modelling studies were applied to get a deep focus about the feasible affinities and binding interactions for target coumarin-sulfonamides 4, 5, 13 and 14 with the active site for CA II, IX and XII isoforms.
Keywords: Carbonic anhydrase inhibitors; Coumarins; Molecular dynamics; Sulfonamides; Tail approach.
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