Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII.

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (CA) isoforms. All compounds displayed nanomolar potency against the cancer-related CA IX and CA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic CA I and CA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective CA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against CA XII, with single-digit nanomolar values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic CA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.