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

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 3 beta (GSK-3 beta) 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-3 beta/ DYRK1A inhibitors, we focused on harmine, a natural beta-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-3 beta/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3 beta and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3 beta 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-3 beta 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Harmine derivatives were designed, synthesized, and evaluated as dual GSK-3 beta/DYRK1A inhibitors, showing promising activity against both targets. Compound ZDWX-25 exhibited potent inhibitory effects on GSK-3 beta and DYRK1A, with IC50 values of 71 and 103 nM, respectively. These compounds have the potential to be promising candidates for Alzheimer's disease treatment.