Ninhydrins inhibit carbonic anhydrases directly binding to the metal ion

• Published in: European journal of medicinal chemistry Vol. 209; p. 112875
• Main Authors: Bouzina, Abdeslem, Berredjem, Malika, Nocentini, Alessio, Bua, Silvia, Bouaziz, Zouhair, Jose, Joachim, Le Borgne, Marc, Marminon, Christelle, Gratteri, Paola, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2021; Elsevier
• Subjects: Binding mode; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - chemistry; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrases; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Chemical Sciences; Chemistry, Medicinal; Humans; Inhibitors; Life Sciences; Life Sciences & Biomedicine; Medication; Medicinal Chemistry; Microwave synthesis; Molecular Docking Simulation; Ninhydrin - analogs & derivatives; Ninhydrin - pharmacology; Ninhydrins; Pharmaceutical sciences; Pharmacology; Pharmacology & Pharmacy; Science & Technology; Zinc - chemistry; Zinc - metabolism; Zinc binder; Ninhydrins; Binding mode; Zinc binder; Microwave synthesis; Inhibitors; Carbonic anhydrases; DESIGN; ACID; ANALOGS; TAIL; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112875

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. [Display omitted] •Ninhydrins act as human carbonic anhydrase inhibitors.•Ninhydrins most effectively inhibit CA II and CA VII, targets for CNS diseases.•Up to low nanomolar inhibition constants were measured against CA VII.•Ninhydrin coordinates the Zn(II) ion by one or two OH moieties.•The most putative binding mode in CA II and VII was pointed out in silico.