-Benzyl Benzamide Derivatives as Selective Sub-Nanomolar Butyrylcholinesterase Inhibitors for Possible Treatment in Advanced Alzheimer's Disease.

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel -benzyl benzamide scaffold, inhibited BChE with IC from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar 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 and was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg or exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aβ. The pharmacokinetics studies characterized the metabolic stability of . Thus, -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.