Design, synthesis and molecular modeling of isothiochromanone derivatives as acetylcholinesterase inhibitors.

Wen Shuai,Wenlong Li,Jinyi Xu,Limei Yang,Feijie Xu,Hequan Yao,Zheying Zhu,Ying Yin,Shengtao Xu

doi:10.4155/fmc-2019-0125

Wen Shuai, Wenlong Li + Show 7 more

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https://doi.org/10.4155/fmc-2019-0125

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Journal: Future medicinal chemistry	Publication Date: Oct 1, 2019
Citations: 5	License type: cc-by

Affiliation: China Pharmaceutical University

Abstract

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.

Highlights

A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors
The intermediates 10a and 10b were hydrolyzed to give the corresponding acids 11a and 11b, which were cyclized via Friedel-crafts reactions to give isothiochromanone 12a and isoselenochromanone 12b
The results revealed that all target compounds bearing N-benzyl pyridinium moiety exhibit significant inhibitory activity towards AChE with IC50 values in the nanomolar range, indicating that these compounds are potent AChE

Summary

Introduction

A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. The kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bound to PAS and CAS of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment

Methods

Results

Conclusion