Synthesis and Biological Evaluation of 4-Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCAII, IX, and XII

With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (series 5a-r and series 7a-q) and evaluated their inhibition profiles against five isoforms of the zinc-containing human carbonic anhydrase (hCA, EC4.2.1.1): cytosolic hCAI and II, and the transmembrane isozymes hCAIV, IX, and XII. Compounds 5a-r were found to selectively inhibit hCAII in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) acts as a prodrug inhibitor and is hydrolyzed by the esterase activity of hCA to form 2-hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7a-q) were found to be very weak or ineffective as inhibitors of the housekeeping off-target hCA isoforms I and II, and effectively inhibited the transmembrane tumor-associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.