Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design, synthesis and biological evaluation.

Graphical abstract Highlights • Novel salicylamide derivatives were synthesized. • Most compounds showed selective AChE inhibitory and significant antioxidant activities. • Some compounds exhibited good inhibition of self- or Cu2+-induced A β aggregation. • Some compounds exhibited moderate effect on the disaggregation of A β aggregation. • Compound 15b showed good anti-neuroinflammation activity and BBB permeability. Abstract 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 Cu2+-induced A β 1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward Rat AChE and Ee AChE with IC 50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced A β 1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced A β 1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, 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. [ABSTRACT FROM AUTHOR]