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 (hAChE), 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, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC₅₀ = 6.5 nM) and hGSK-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 t

SUBMITTER: Jiang XY 

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

REPOSITORIES: biostudies-literature