Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a-t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with K-i = 0.246 mu M and 5p with K-i = 0.376 mu M against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with K-i = 0.493 and 0.4 mu M, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.

Automated summary

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives were synthesized and showed selective inhibition against human carbonic anhydrase isoforms. Some compounds displayed potent inhibitory activity, indicating their potential as lead compounds for designing enzyme-selective CA inhibitors.