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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 (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, showed the most promising profile as a nanomolar inhibitor on bothAChE (IC = 6.5 nM) and GSK-3β kinase activity (IC = 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 inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. studies confirmed that 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.

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Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC 50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar K D value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aβ 1−42 . The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.