Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer’s Disease

[Image: see text] The pathogenesis of Alzheimer’s disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3β inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3β inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 μM), BACE1 (48.3% at 20 μM), and GSK3β (40.3% at 10 μM). Furthermore, 1c showed good blood–brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aβ-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3β lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.