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 <b>EMC-4f</b>, and obtained the potential selective BChE inhibitor <b>12a</b> (<i>eq</i>BChE, IC₅₀ = 1.3 μM; <i>hu</i>BChE, IC₅₀ = 0.95 μM). The <i>in vitro</i> results exhibited that <b>12a</b> showed good BBB permeability. Moreover, <b>12a</b> demonstrated significant neuroprotective effects on l-Glu/Aβ_25-35-induced HT22 cells injury. Further, the <i>in vivo</i> tests suggested that <b>12a</b> remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that <b>12a</b> is a promising BChE inhibitor against AD.