Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents
Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents
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DOI：
10.1016/j.ejmech.2016.06.022
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发表时间：
2016-10-21
影响因子：
6.7
通讯作者：
Wang, Chao-Jie
中科院分区：
文献类型：
--
作者：
Luo, Wen;Wang, Ting;Wang, Chao-Jie
设计并合成了一系列4-二甲胺类黄酮衍生物，作为潜在的多功能抗阿尔茨海默病药物。研究了这些衍生物对胆碱酯酶活性、自诱导β-淀粉样蛋白（A β）聚集和抗氧化活性的抑制作用。大多数化合物具有较强的乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制活性。Lineweaver-Burk作图和分子模拟研究表明，这些化合物同时靶向AChE的催化活性位点（CAS）和外周阴离子位点（PAS）。衍生物显示出有效的自诱导A β聚集抑制和过氧自由基吸收活性。此外，化合物6d在低浓度下显著保护PC12神经元免受H2O2诱导的细胞死亡。因此，这些化合物可能成为多功能药物，用于进一步开发治疗AD。(C)2016 Elsevier Masson SAS。All rights reserved.
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 beta-amyloid (A beta) 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 A beta 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. (C) 2016 Elsevier Masson SAS. All rights reserved.