Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents

• DOI: 10.1016/j.ejmech.2016.06.022
• Publication Date: 2016-06-15T16:13:12Z
• Authors: Wen Luo; Ting Wang; Chen Hong; Ya–Chen Yang; Ying Chen; Juan Cen; Song–Qiang Xie; Chao–Jie Wang
• Keywords: Flavonoids; 0303 health sciences; Amyloid beta-Peptides; Cell Death; Protein Conformation; Intracellular Space; Chemistry Techniques, Synthetic; Hydrogen Peroxide; PC12 Cells; Peptide Fragments; 3. Good health; Molecular Docking Simulation; Kinetics; Protein Aggregates; 03 medical and health sciences; Alzheimer Disease; Butyrylcholinesterase; Drug Design; Acetylcholinesterase; Animals; Humans; Cholinesterase Inhibitors; Dimethylamines

A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.