Design, Synthesis and Molecular Modeling of Isothiochromanone Derivatives as Acetylcholinesterase Inhibitors

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.

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Keywords: :

• acetylcholinesterase inhibitor
• Alzheimer's disease
• dual binding site
• isoselenochromanone
• isothiochromanone

Financial & competing interest disclosure

This research was financially supported by the National Natural Science Foundation of China (no. 81874289) and ‘Double First-Class’ University project CPU2018GY04, China Pharmaceutical University. The authors have no other relevant affliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.