| Summary: | No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer’s disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer’s disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound <b>PS-10</b> was found to have potent AChE inhibitory activity (IC<sub>50</sub> = 15.3 nM), even more than the standard drug (IC<sub>50</sub> = 15.68 nM). Further, the in vivo evaluation of <b>PS-10</b> against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, <b>PS-10</b> inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the <b>PS-10</b> and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer’s molecules.
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