Novel benzenesulfonamide-bearing pyrazoles and 1,2,4-thiadiazoles as selective carbonic anhydrase inhibitors

Two series comprising 20 novel benzenesulfonamides bearing thioureido-linked pyrazole 8 and amino-1,2,4-thiadiazole 10 were synthesized and assayed as human carbonic anhydrase (hCA) inhibitors against isoforms I and II as well as the tumor-associated isoforms IX and XII. Molecular modeling studies of some potent derivatives (8a, 8c, 10a, and 10c) were also performed against isoforms hCA I, II, and XII. Both the promising series of compounds were synthesized by using commercially available mtethyl ketones and sulfanilamide as the starting materials. Interestingly, this paper also reports a novel methodology for the synthesis of amino-1,2,4-thiadiazoles 10 using 3-amino isoxazoles and 4-isothiocyanatobenzenesulfonamide as reactants. The activity profile of all the newly synthesized compounds reveals that amino-linked 1,2,4-thiadiazoles 10 were better inhibitors of the cytosolic isoform, hCA I, as compared to thioureido-linked pyrazoles 8. Further, hCA II was strongly inhibited by nearly all the newly synthesized sulfonamides, while all the compounds were less effective as hCA IX and XII inhibitors compared to the standard drug acetazolamide. However, in terms of selectivity, compound 8e was found to be the most selective inhibitor of hCA II, which is the isoform associated with glaucoma, edema, altitude sickness, and epilepsy.

Automated summary

Two series of novel benzenesulfonamides were synthesized and tested as hCA inhibitors, with amino-linked 1,2,4-thiadiazoles showing better inhibition of hCA I compared to thioureido-linked pyrazoles. Most of the newly synthesized sulfonamides exhibited strong inhibition of hCA II, while compound 8e was found to be the most selective inhibitor of hCA II.