Sulfonamides linked to sulfonate esters via hydrazone functionality: synthesis, human carbonic anhydrase inhibitory activities, and molecular modeling studies

Abstract

In the present study, we synthesized novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors by linking various sulfonate esters to a benzenesulfonamide fragment via hydrazone functionality (SH1–SH14). Following structural characterization using spectral techniques, the obtained molecules were screened for their inhibitory potential against tumor-associated human (h) isoforms hCA IX and XII, along with the physiologically dominant isoforms hCA I and II. Introducing methyl, methoxy or chlorine substituents into the para position of the terminal phenyl ring led to the most effective hCA IX and/or hCA XII inhibitors, with K_i values < 10 nM. Drug-likeness and pharmacokinetic profiles of the selected compounds were predicted using in silico techniques. Finally, molecular docking studies of the most effective inhibitor, 4-((2-(4-sulfamoylbenzoyl)hydrazono)methyl)phenyl 4-methoxybenzenesulfonate (SH3), against the tumor-associated hCA isoforms IX (K_i = 9.4 nM) and XII (K_i = 5.9 nM) were carried out to rationalize the inhibition data.