Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease

Abstract

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ_1-42 aggregation, Cu²⁺-induced Aβ_1-42 aggregation, human AChE-induced Aβ_1-40 aggregation and disassembled Cu²⁺-induced aggregation of the well-structured Aβ_1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H₂O₂-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.

Keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Antioxidant agents; Aβ aggregation inhibitors; Multifunctional agents; Scutellarein-O-acetamidoalkylbenzylamines.