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

• Published in: European journal of medicinal chemistry 2015-04, Vol.94, p.348-366
• Main Authors: Sang, Zhipei, Qiang, Xiaoming, Li, Yan, Yuan, Wen, Liu, Qiang, Shi, Yikun, Ang, Wei, Luo, Youfu, Tan, Zhenghuai, Deng, Yong
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer's disease; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Apigenin - chemical synthesis; Apigenin - chemistry; Apigenin - pharmacology; Aβ aggregation inhibitors; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - pharmacology; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Metal-chelating agents; Mice; Models, Molecular; Molecular Structure; Multifunctional agents; PC12 Cells; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Rats; Scopolamine Hydrobromide; Scutellarein-O-alkylamines; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.02.063

A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study. A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). Compound 16d was shown to be an interesting multifunctional lead compound for AD treatment. [Display omitted] •Novel scutellarein derivatives with carbon spacer-linked alkylamines were synthesized.•Compound 16d exhibited good acetylcholinesterase inhibitory and antioxidant activity.•Compound 16d exhibited excellent inhibitory effects on Aβ aggregation.•Compound 16d markedly disassembled the Cu2+-induced Aβ aggregation.•16d showed neuroprotective effects and reversed scopolamine-induced memory deficit in mice.