Design, synthesis, and carbonic anhydrase inhibition activity of benzenesulfonamide-linked novel pyrazoline derivatives

Abstract

Carbonic anhydrases (CA, EC 4.2.1.1) are Zinc metalloenzymes and are present throughout most living organisms. Among the catalytically active isoforms are the cytosolic CA I and II, and tumor-associated CA IX and CA XII. The carbonic anhydrase (CA) inhibitory activities of newly synthesized pyrazoline-linked benzenesulfonamides 18-33 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared with that of acetazolamide (AAZ), a standard inhibitor. Potent inhibitory activity against hCA I was exerted by compounds 18-25, with inhibition constant (K_I) values of 87.8-244.1 nM, which were greater than that of AAZ (K_I, 250.0 nM). Compounds 19, 21, 22, 29, 30, and 32 were proven to have inhibitory activities against hCA IX with K_I values (5.5-37.0 nM) that were more effective than or nearly equal to that of AAZ (K_I, 25.0 nM). Compounds 20-22, and 30 exerted potent inhibitory activities (K_Is, 7.1-10.1 nM) against hCA XII, in comparison with AAZ (K_I, 5.7 nM).

Keywords: Acetazolamide; Benzenesulfonamide; Carbonic anhydrase; Enzyme inhibition; Pyrazoline scaffolds; Synthesis.