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

Jie Liu,Jia Wang,Xinnan Li,Jinyi Xu,Chaolei Wang,Zheying Zhu,Shengtao Xu,Qinying Lan,Zheng Wu

doi:10.1111/cbdd.13136

Abstract

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 0.15nm 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.

Highlights

A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors
Compound 1q showed the most potent activity against AChE with IC50 of 0.15 nM, which was 250 and 160 times higher compared to the positive drug donepezil and the lead compound 1, respectively
As to compounds 1o-1r, the number and position of the methoxy group on 4-isochromanone skeleton had a significant influence on the anticholinesterase activity

Summary

Introduction

A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. In our previous studies, using donepezil as a template[11], a series of dual-site AChE inhibitors were synthesized by introducing N-benzyl pyridinium moiety into the natural product XJP (Figure 1). Among these compounds, the most potent compound 1 showed good AChE inhibitory activity (IC50 value : 8.9 nM) and excellent AChE/BuChE selectivity (SI >230)[11]. Target compounds 1a-1r were obtained after the nucleophilic substitution of compound 9

Methods

Results

Conclusion