Ninhydrins inhibit carbonic anhydrases directly binding to the metal ion

Ninhydrins show extensive application in organic chemistry and agriculture whereas they have been poorly investigated as bioactive molecules for medicinal chemistry purposes. A series of ninhydrin derivatives was here investigated for the inhibition of human carbonic anhydrases (CAs, EC 4.2.1.1), based on earlier evidence that gem diols are able to coordinate the metal ion from the CA active site. Ninhydrins demonstrated a micromolar inhibitory action against CA I and IX (KIs in the range 0.57–68.2 μM) and up to a nanomolar efficacy against CA II and VII (KIs in the range 0.025–78.2 μM), validated isoforms as targets in several CNS-related diseases. CA IV was instead weakly or poorly inhibited. A computational protocol based on docking, MM-GBSA and metadynamics calculations was used to elucidate the putative binding mode of this type of inhibitors to CA II and CA VII. The findings of this study testify that such pharmacologically underestimated ligands may represent interesting lead compounds for the development of CA inhibitors possessing an innovative mechanism of action, i.e., mono- or bis-coordination to the zinc ion through the diol moiety.