Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.

Biomedical Research Center University Hospital Hradec Králové Sokolská 581 50005 Hradec Kralové Czech Republic

CZ OPENSCREEN National Infrastructure for Chemical Biology Department of Informatics and Chemistry Faculty of Chemical Technology University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

Department of Biotechnology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

Department of Toxicology and Military Pharmacy University of Defense Třebešská 1575 50005 Hradec Králové Czech Republic

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

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