Chen_2026_Bioorg.Med.Chem_142_118765

The pathogenesis of Alzheimer's disease (AD) is closely associated with cholinergic neuronal impairment, which is induced by excessive degradation of acetylcholine (ACh) mediated by acetylcholinesterase (AChE). In this study, a series of novel indole-fused polycyclic derivatives (1-28) were designed, synthesized, and assessed for their AChE inhibitory activities. The biological evaluation results demonstrated that most of the compounds exhibited moderate to excellent AChE inhibitory activities. Among them, compounds 8, 9, 21, and 26 showed leading AChE inhibitory activity with IC(50) values of 0.29 microM, 1.5 microM, 1.2 microM, and 1 microM, respectively, which were superior to the positive control galantamine (IC(50) = 2.2 microM). Furthermore, favorable drug-likeness profiles and optimal pharmacokinetic properties were confirmed for compound 8 through ADME analysis. Stable binding interactions between compound 8 and AChE were validated by the results of 100 ns molecular dynamics simulations. Overall, compound 8 was characterized as a potent and well-qualified AChE inhibitor, and further systematic investigations are warranted for its application in the treatment of AD-related diseases.