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Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one

Li, Xinnan; Jia, Yilin; Li, Junda; Zhang, Pengfei; Li, Tiantian; Lu, Li; Yao, Hequan; Liu, Jie; Zhu, Zheying; Xu, Jinyi

Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one Thumbnail


Authors

Xinnan Li

Yilin Jia

Junda Li

Pengfei Zhang

Tiantian Li

Li Lu

Hequan Yao

Jie Liu

ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu



Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (±)-7,8-dihydroxy-3-methyl-isochroman-4-one [(±)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound 10a [(Z)-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyri-din-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 10a was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound 10a exhibited low cytotoxicity and moderate anti-Aβ aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood–brain barrier with high penetration. These findings show that compound 10a was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD.

Citation

Li, X., Jia, Y., Li, J., Zhang, P., Li, T., Lu, L., …Xu, J. (2022). Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one. Molecules, 27(10), Article 3090. https://doi.org/10.3390/molecules27103090

Journal Article Type Article
Acceptance Date May 9, 2022
Online Publication Date May 11, 2022
Publication Date May 11, 2022
Deposit Date May 14, 2022
Publicly Available Date May 17, 2022
Journal Molecules
Electronic ISSN 1420-3049
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 27
Issue 10
Article Number 3090
DOI https://doi.org/10.3390/molecules27103090
Public URL https://nottingham-repository.worktribe.com/output/8049796
Publisher URL https://www.mdpi.com/1420-3049/27/10/3090

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