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.
journal_name
Curr Top Med Chemjournal_title
Current topics in medicinal chemistryauthors
Francisco CS,Javarini CL,de S Barcelos I,Morais PAB,de Paula H,de S Borges W,Neto ÁC,Lacerda Vdoi
10.2174/1568026619666191019105349subject
Has Abstractpub_date
2020-01-01 00:00:00pages
153-160issue
2eissn
1568-0266issn
1873-4294pii
CTMC-EPUB-101652journal_volume
20pub_type
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