Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.