Abstract |
The natural product harmine, a representative β- carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti- acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC50 = 0.27 μM) and selective BChE inhibition (IC50 = 20.82 μM), as well as acceptable glycogen synthase kinase-3 (GSK-3β) inhibition (IC50 = 6.78 μM). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3β. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3β over multi- kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.
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Authors | Wenwu Liu, Xin Liu, Wenjie Liu, Yaping Gao, Limeng Wu, Yaoguang Huang, Huanhua Chen, Deping Li, Lijun Zhou, Nan Wang, Zihua Xu, Xiaowen Jiang, Qingchun Zhao |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 229
Pg. 114095
(Feb 05 2022)
ISSN: 1768-3254 [Electronic] France |
PMID | 34995924
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Carbolines
- Cholinesterase Inhibitors
- Protein Kinase Inhibitors
- Glycogen Synthase Kinase 3 beta
- Acetylcholinesterase
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Topics |
- Acetylcholinesterase
(metabolism)
- Alzheimer Disease
(drug therapy)
- Antineoplastic Agents
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Carbolines
(chemical synthesis, pharmacology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cholinesterase Inhibitors
(chemical synthesis, pharmacology)
- Drug Design
- Glycogen Synthase Kinase 3 beta
(antagonists & inhibitors)
- Humans
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- Protein Binding
- Protein Kinase Inhibitors
(chemical synthesis, pharmacology)
- Signal Transduction
- Structure-Activity Relationship
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