Development of New Donepezil Analogues: Synthesis, Biological Screening and In Silico Study Rational

Abstract Fifteen new benzothiophene-based compounds were designed, synthesized, and evaluated as potential anti-Alzheimer agents. Most of the synthesized compounds exhibited remarkable AChE inhibitory activity and effectively inhibited self-mediated β-amyloid protein in vitro. Compound 3g (IC50 = 72.488 ± 3.69 µM) showed a significant β-amyloid inhibitory effect exceeding that of donepezil (IC50 = 87.414 ± 4.46 µM). Furthermore, compound 3j (IC50 = 0.498 ± 0.02 µM) showed the best inhibitory activity comparable to that of donepezil (IC50 = 0.404 ± 0.03µM). The in vivo evaluation of the promising compounds (3g and 3j) confirmed a significant memory improvement in scopolamine-induced memory impairment model in mice. The molecular docking simulation of compounds 3g and 3j in Torpedo californica-AChE (TcAChE) active site showed a good agreement with the obtained screening results. The in silico ADMET and other physicochemical parameters were also reported.