Synthesis and Biological Evaluation of 4-sulfamoylphenyl/sulfocoumarin carboxamides as selective inhibitors of carbonic anhydrase isoforms hCA II, IX and XII

With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (5a-r and 7a-q) and evaluated for their inhibition profiles against five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), the cytosolic CA I and II as well as transmembrane isozymes CA IV, IX and XII. Compounds 5a-r selectively inhibited the isoform hCA II in nanomolar range, being less effective against the other isoforms. As noticeable from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) act as "prodrug" inhibitor and get hydrolysed by the esterase CA activity to form 2-hydroxyphenyl-vinylsulfonic acid, which thereafter bind to the enzyme in a similar fashion like coumarins and sulfoxocoumarins. All these sulfocoumarins (7a-q) were very weak or ineffective as inhibitors of the housekeeping, off-target isoforms CA I and II, and effectively inhibited transmembrane, tumor associated isoforms hCA IX and XII in high nanomolar to micromolar range. Further structural modifications of these molecules could be useful for the development of effective CA inhibitors that will be used for the treatment of glaucoma, epilepsy and cancer.