Dual GSK-3?/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-3? (GSK-3?) and human acetylcholinesterase (hAChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3?/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) and hGSK-3? kinase activity (IC50 = 66 nM). It also showed good inhibitory effect on ?-amyloid self-aggregation (inhibitory rate = 46%) at 20 ?M. Western blot analysis revealed that compound 2f inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed that 2f significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3? and AChE pathway dual inhibition as a promising strategy for AD treatment.

SUBMITTER: Jiang XY 

PROVIDER: S-EPMC5846044 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature