Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

Automated summary

A series of novel benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with bulky moieties were synthesized and investigated for their inhibitory effects on various human carbonic anhydrase isoforms. Isoform-selective inhibitors were obtained, with a computational approach employed to explain the observed selectivity, potentially useful in drug design for developing inhibitors with pharmacological applications such as antiglaucoma, diuretic, antitumor, or anti-cerebral ischemia drugs.