Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

A series of 1-(4-sulfamoyl-benzoyl)-piperidine-4-carbox-amides deriving from substituted piperazines/ benzyl-amines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfon-amides was analyzed using acetazol-amide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfon-amides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzene-sulfon-amido carbox-amides 11 and 15 were the most potent of the piperazino- and benzyl-amino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound 11 toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.