Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors
Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors
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带有N-苄基吡啶部分的新型多奈哌齐衍生物的设计、合成和生物活性，作为有效的双结合位点乙酰胆碱酯酶抑制剂
DOI：
10.1016/j.ejmech.2017.02.045
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发表时间：
2017-06-16
影响因子：
6.7
通讯作者：
Ding, Yue
中科院分区：
文献类型：
--
作者：
Lan, Jin-Shuai;Zhang, Tong;Ding, Yue
设计、合成并评价了一系列新型多奈哌齐类多功能胆碱酯酶抑制剂，用于治疗阿尔茨海默病(AD)。体外研究表明，它们中的大多数都显示出显著的抑制乙酰胆碱酯酶和自身诱导的(β-淀粉样蛋白)聚集的活性，并具有中等的抗氧化活性。尤其是化合物5b对胆碱酯酶的抑制能力最强(IC50，eeAChE为1.9 nM，HAChE为0.8 nM)，对Aβ聚集的抑制作用(20mM时为53.7%)，以及良好的抗氧化活性(相当于0.54 trolox当量)。动力学和分子模拟研究表明，化合物5b是一种混合型抑制剂，同时与AChE的催化活性中心(CAS)和外周阴离子中心(PAS)结合。此外，化合物5b还可减轻氧化应激和Aβ(1-42)诱导的PC12细胞死亡。此外，体内实验表明，化合物5b无毒，耐受性高达2000 mg/kg。这些结果表明，化合物5b可能是治疗AD的一种很好的多功能药物。(C)2017年爱思唯尔·马森公司。版权所有。
A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced (beta-amyloid (A beta) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of A beta aggregation (53.7% at 20 mu M) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and A beta (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment. (C) 2017 Elsevier Masson SAS. All rights reserved.