Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3β (GSK-3β) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3β/DYRK1A inhibitors, we focused on harmine, a natural β-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3β/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3β and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3β and DYRK1A with IC50 values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3β and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.

• Authors: Wenwu Liu, Xin Liu, Liting Tian, Yaping Gao, Wenjie Liu, Huanhua Chen, Xiaowen Jiang, Zihua Xu, Huaiwei Ding, Qingchun Zhao
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 222 Pg. 113554 (Oct 15 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 34098466 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Neuroprotective Agents
• Protein Kinase Inhibitors
• Harmine
• Dyrk kinase
• Protein-Tyrosine Kinases
• Glycogen Synthase Kinase 3 beta
• Protein Serine-Threonine Kinases

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, metabolism)
• Harmine (chemical synthesis, chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship