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

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 IC ₅₀ values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC ₅₀ = 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.