Single molecule, dual actions: GSK-3β/AChE dual inhibition for Alzheimer's disease

The optimal compound AJ-4 showed potent GSK-3β inhibitor activity with an IC 50 value of 4.7 nM. • AJ-4 exerted superior AChE inhibitor with an IC 50 value of 2.97 μM. • AJ-4 exhibited favorable selectivity against selected serine/threonine and tyrosine kinases. • AJ-4 presented favorable pharmacokinetic characteristics and tissue distribution. • AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments in AD mice. The pathogenesis of Alzheimer's disease (AD) is closely related with glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3β inhibitory and neuroprotective activities relative to Tideglusib. Accordingly, a molecular hybridization strategy was applied to design and synthesize a series of dual target inhibitors against GSK-3β and AChE by conjugating GL10a and carbamate fragment of Rivastigmine's pharmacophore. After in vitro evaluations, the compound AJ-4 was screened as the most remarkable compound with potent inhibitory activities against GSK-3β (IC 50 : 4.7 nM) and AChE (IC 50 : 2.97 μM). Meanwhile, in vitro and in vivo data revealed that the optimal compound AJ-4 with excellent enzyme selectivity could decrease amyloid precursor protein (APP) and phosphorylated Tau expressions and increase phosphorylated GSK-3β levels. With favorable pharmacokinetic characteristics and tissue distribution, AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments and alleviated hippocampal neuronal injury in AD mice. In conclusion, GSK-3β/AChE dual inhibitors represent a promising strategy for developing multi-target anti-AD drugs. Download: Download high-res image (495KB) Download: Download full-size image