Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors

Abstract

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc‐anchoring group has been designed. The structures of the synthesized derivatives 5a‐l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benznesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for invitro cytotoxicity. Most of them act as effective inhibitors of the tumor‐linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5d, 5g, and 5l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX, compounds 5d, 5g, 5h and 5l Ki: 46.7, 45.9, 15.5 and 20.1 nM, respectively) showed the best inhibitory profile. In‐vitro screening of all derivatives against a full sixty‐cell‐lined from NCI at a single dose of 10 μM offered growth inhibition of up to 45 %. Compound 5b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor‐related hCAs IX/XII suppression.