Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer's disease.
Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer's disease.
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带有 N-苄基吡啶鎓部分的新型肉桂酸衍生物作为阿尔茨海默病多功能胆碱酯酶抑制剂的设计、合成和评价
DOI：
10.1080/14756366.2016.1256883
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发表时间：
2017-12
影响因子：
5.6
通讯作者：
Zhang T
中科院分区：
文献类型：
--
作者：
Lan JS;Hou JW;Liu Y;Ding Y;Zhang Y;Li L;Zhang T
摘要通过N-苄基吡啶与不同取代的肉桂酸类化合物的融合，合成了一类新的抗AD的多功能胆碱酯酶抑制剂。体外研究表明，大多数化合物具有显著的抑制胆碱酯酶、自诱导Aβ（1-42）聚集和螯合金属离子的能力。其中化合物51对乙酰胆碱酯酶的抑制活性（IC_（50）分别为eeAChE 12.1 nM、hAChE 8.6 nM、eqBuChE 2.6 μM和hBuChE 4.4 μM），对乙酰胆碱酯酶的选择性最高。它还显示出良好的Aβ（1-42）聚集抑制（20 μM时为64.7%）和对淀粉样蛋白诱导的PC 12细胞毒性的良好神经保护作用。最后，化合物51可以穿透血脑屏障，如PAMPA-BBB测定所预测的，并通过离体实验在OF 1小鼠中证明。总体而言，化合物5l似乎是用于治疗阿尔茨海默病的有希望的先导化合物。
Abstract A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1–42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC50, 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 μM for eqBuChE and 4.4 μM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aβ (1–42) aggregation (64.7% at 20 μM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer’s diseases.
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影响因子：
7.3
作者：
Isabel Fernandez-Bachiller, Maria;Perez, Concepcion;Isabel Rodriguez-Franco, Maria
通讯作者：
Isabel Rodriguez-Franco, Maria
影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
3.5
作者：
Fang, Lei;Chen, Mohao;Chen, Li
通讯作者：
Chen, Li
影响因子：
7.3
作者：
Fernandez-Bachiller, Maria Isabel;Perez, Concepcion;Rodriguez-Franco, Maria Isabel
通讯作者：
Rodriguez-Franco, Maria Isabel
影响因子：
7.3
作者：
Galdeano, Caries;Viayna, Elisabet;Munoz-Torrero, Diego
通讯作者：
Munoz-Torrero, Diego