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

• Published in: European journal of medicinal chemistry Vol. 222; pp. 113554 - 113571
• Main Authors: Liu, Wenwu, Liu, Xin, Tian, Liting, Gao, Yaping, Liu, Wenjie, Chen, Huanhua, Jiang, Xiaowen, Xu, Zihua, Ding, Huaiwei, Zhao, Qingchun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.10.2021; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Cell Line; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Dyrk Kinases; DYRK1A; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; GSK-3β; Harmine; Harmine - chemical synthesis; Harmine - chemistry; Harmine - pharmacology; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Science & Technology; Structure-Activity Relationship; Tau pathology; β-carboline alkaloid; β-carboline alkaloid; DYRK1A; GSK-3β; Tau pathology; Harmine; Alzheimer's disease; PHOSPHORYLATION; ANALOGS; KINASE; BETA-CARBOLINE; DISCOVERY; MEMORY; ACETYLCHOLINESTERASE; beta-carboline alkaloid; GSK-3 beta; ALKALOIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113554

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. [Display omitted] •Synthesis of novel harmine derivatives as kinase inhibitors for the treatment of AD.•ZDWX-25 inhibits GSK-3β (IC50 = 71 nM) and DYRK1A (IC50 = 103 nM).•Effects of ZDWX-25 on the protein expression levels in okadaic acid-induced SH-SY5Y cells.•ZDWX-25 ameliorates the impaired learning and memory in APP/PS1/Tau transgenic mice.