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

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