1,4-Naphthoquinone–Nheterocycle Hybrids As Potent and Selective Acetylcholinesterase Inhibitors Against Alzheimer’S Disease Publisher



Mohammadi Mehr E ; Radmoghadam K ; Mahmoodi NO ; Mahdavi M ; Iraji A
Source: Journal of Molecular Structure Published:2026

Abstract

This study presents the design, synthesis, and evaluation of a novel series of 1,4-naphthoquinone–N-heterocycle hybrids as potential acetylcholinesterase and butyrylcholinesterase inhibitors for the treatment of Alzheimer’s disease. Among the synthesized derivatives, compound 4i bearing pyrrolidine moiety was the most potent, with an IC50 of 0.11 ± 0.02 µM against AChE and >245-fold selectivity against BChE. Enzyme kinetics validated competitive inhibition with a Ki value of 0.12 µM. Furthermore, molecular docking and 100 ns molecular dynamics simulations demonstrated a stable dual binding site interaction, characterized by hydrogen bonds with Glu202 and His447, and π–π stacking with Tyr124 and Tyr341. The in silico ADMET profiling was also performed. Importantly, 4i exhibited no significant neurotoxicity in SH-SY5Y cells following a 72-hour treatment at the tested concentrations. These results identify 4i as a promising drug candidate against Alzheimer's disease. © 2026 Published by Elsevier B.V.