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.
Method:
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.
