Song_2018_Bioorg.Chem_84_137

A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu(2+)-induced Abeta1-42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4muM and 15.2muM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu(2+)-induced Abeta1-42 aggregation inhibitory potency (42.5% and 31.4% at 25.0muM, respectively) and moderate disaggregation ability to self- and Cu(2+)-induced Abeta1-42 aggregation fibrils (23.4% and 27.0% at 25muM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.