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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-05, Vol.27 (10), p.3090
• Main Authors: Li, Xinnan, Jia, Yilin, Li, Junda, Zhang, Pengfei, Li, Tiantian, Lu, Li, Yao, Hequan, Liu, Jie, Zhu, Zheying, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: (±)-7,8-dihydroxy-3-methyl-isochroman-4-one; Acetylcholinesterase; Acetylcholinesterase - metabolism; acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; antioxidant activity; Antioxidants; Binding sites; Blood-brain barrier; Catalysis; Cholinesterase Inhibitors - chemistry; Cognitive ability; Cytotoxicity; High temperature; Humans; Hydrocarbons; Hypotheses; Models, Molecular; molecular docking; Molecular modelling; Natural products; Neurodegenerative Diseases - drug therapy
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27103090

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 [( )-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 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 exhibited low cytotoxicity and moderate anti-A 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 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.