Development of new donepezil analogs: synthesis, biological screening and in silico study rational

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 (IC 50 = 72.488 ± 3.69 μM) showed a significant β-amyloid inhibitory effect exceeding that of donepezil (IC 50 = 87.414 ± 4.46 μM). Furthermore, compound 3j (IC 50 = 0.498 ± 0.02 μM) showed the best inhibitory activity comparable to that of donepezil (IC 50 = 0.404 ± 0.03 μM). 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 ( Tc AChE) active site showed a good agreement with the obtained screening results. The in silico ADMET and other physicochemical parameters were also reported.