Xue-Yang Jiang

A facile one-pot synthetic method of building aryloxyalkyl esters was developed using various types of phenolic esters with halogenated alcohols. The ready availability of both starting materials, coupled with the required simple experimental technique, enables the current synthetic method of producing aryloxyalkyl esters in a fast and efficient way. It is noteworthy that acyl transfer was demonstrated in this reaction.

Designing multi-target-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 nov-el family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most prom-ising profile as a nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) and 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 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-3β and AChE pathway dual inhibiton as a promising strategy for AD treatment.