Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease

• Published in: Bioorganic & medicinal chemistry 2020-04, Vol.28 (8), p.115400, Article 115400
• Main Authors: Luo, Li, Song, Qing, Li, Yan, Cao, Zhongcheng, Qiang, Xiaoming, Tan, Zhenghuai, Deng, Yong
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Alzheimer Disease; Alzheimer’s disease; Amines - chemistry; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Animals; Anti-Aβ aggregation; Antioxidant; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - pharmacology; DL-3-n-butylphthalide derivatives; Drug Design; Female; Male; Membranes, Artificial; Mice; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Multi-target agents; Permeability; Protein Aggregation, Pathological; Random Allocation; Rats
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115400

[Display omitted] •Phthalide alkyl tertiary amine derivatives were synthesized.•Almost all compounds displayed significant AChE inhibitory and selective activities.•Most compounds exhibited increased self-induced Aβ1-42 aggregation inhibitory activity.•Compound I-8 displayed excellent BBB permeability in vitro.•Compound I-8 significantly reversed scopolamine-induced memory deficit in mice. A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer’s disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ1-42 aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC50 = 2.66 nM), which was significantly better than Donepezil (IC50 = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.