Piperazine Derivatives Carrying an Imidazole Ring as Selective Modulators of Human Carbonic Anhydrase Isozymes.

A small library of piperazine and piperazinone derivatives carrying an imidazole ring was synthesized, with the aim to find selective carbonic anhydrase (CA) modulators. These compounds can be regarded as reduced-flexibility analogues of histamine and histidine, two well-known CA activators. Their activating properties were evaluated against human CA I, II, VA, VII, and XIII. Activity was observed exclusively on CA VA and CA XIII, with KA values in the medium and low micromolar range, respectively. Among the tested molecules, compound (R)-2 emerged as a promising lead compound for the development of selective CA XIII activators. Conversely, introduction of a 4-sulfamoylbenzoyl group on the piperazine nitrogen atom switched the activity from activation to inhibition, yielding compound 6 as a potent inhibitor of hCA II.