Design, synthesis, biological evaluation, and docking study of 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

• Published in: Chemical biology & drug design 2018-03, Vol.91 (3), p.756-762
• Main Authors: Wang, Jia, Wang, Chaolei, Wu, Zheng, Li, Xinnan, Xu, Shengtao, Liu, Jie, Lan, Qinying, Zhu, Zheying, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: 4‐isochromanone skeleton; Acetylcholinesterase - metabolism; acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; benzyl pyridine; Cell Line, Tumor; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - metabolism; Phenazopyridine - analogs & derivatives; Phenazopyridine - chemical synthesis; Phenazopyridine - chemistry; Phenazopyridine - pharmacology; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Rats
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13136

A series of novel 4‐isochromanone compounds bearing N‐benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti‐AChE activity with an IC50 value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti‐Alzheimer's disease agents. Twenty‐two 4‐isochromanone hybrids bearing N‐benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors were designed and synthesized, their biological activities were evaluated, and molecular docking study was carried out.