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 (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA 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.
Keywords: carbonic anhydrase inhibitor; coumarins; docking; metalloenzymes; molecular modeling.