Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer’s Disease Drug Discovery

Abstract

Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase (<i>h</i>AChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, <b>2f</b> showed the most promising profile as a nanomolar inhibitor on both <i>h</i>AChE (IC₅₀ = 6.5 nM) and <i>h</i>GSK-3β kinase activity (IC₅₀ = 66 nM). It also showed good inhibitory effect on β-amyloid self-aggregation (inhibitory rate = 46%) at 20 μM. Western blot analysis revealed that compound <b>2f</b> inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. <i>In vivo</i> studies confirmed that <b>2f</b> significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3β and AChE pathway dual inhibition as a promising strategy for AD treatment.