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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3β Enzyme Inhibition

Author(s): Carla S. Francisco, Clara L. Javarini, Iatahanderson de S. Barcelos , Pedro A.B. Morais, Heberth de Paula, Warley de S. Borges, Álvaro Cunha Neto and Valdemar Lacerda*

Volume 20, Issue 2, 2020

Page: [153 - 160] Pages: 8

DOI: 10.2174/1568026619666191019105349

Price: $65

Abstract

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-3β 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-3β kinase inhibitors.

Methods: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β 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-3β complex [Protein Data Bank (PDB) code: 1Q3D].

Results: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β 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-3β inhibitors.

Keywords: Coumarin, Coumarin derivatives, Biological activity, GSK-3β, Enzymatic inhibition, Molecular docking.

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