RESUMEN
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3ß isoforms is likely to represent an effective strategy against AD. OBJECTIVE: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3ß kinase inhibitors. METHODS: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3ß activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3ß complex [Protein Data Bank (PDB) code: 1Q3D]. RESULTS: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3ß inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3ß enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. CONCLUSION: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3ß inhibitors.