Design, synthesis and evaluation of novel ferulic acid derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease
Design, synthesis and evaluation of novel ferulic acid derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease
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新型阿魏酸衍生物的设计、合成和评估作为治疗阿尔茨海默病的多靶点配体
DOI：
10.1016/j.bioorg.2019.103413
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发表时间：
2020
影响因子：
5.1
通讯作者：
Zhang Tong
中科院分区：
文献类型：
--
作者：
Lan Jin-Shuai;Zeng Rui-Feng;Jiang Xiao-Yi;Hou Jian-Wei;Liu Yun;Hu Zheng-Hao;Li Hong-Xin;Li Yin;Xie Sai-Sai;Ding Yue;Zhang Tong
设计、合成并评价了一系列新的阿魏酸衍生物作为阿尔茨海默病多靶点抑制剂，体外研究表明，大多数化合物对自身诱导的β-淀粉样蛋白（Aβ）聚集和乙酰胆碱酯酶（AChE）有明显的抑制作用，并具有良好的抗氧化活性。化合物4g对胆碱酯酶（ChE）有较强的抑制作用（IC 50，hAChE为19.7 nM，hBuChE为0.66 μM），对Aβ聚集有较好的抑制作用（20 μM时抑制率为49.2%），同时也是一种较好的抗氧化剂（1.26 trolox当量）。动力学和分子模拟研究表明，化合物4g是一种混合型抑制剂，能同时与AChE的催化阴离子位点（CAS）和外周阴离子位点（PAS）相互作用。此外，化合物4g还能显著提高过氧化氢诱导的PC 12细胞氧化损伤和Aβ诱导的细胞损伤的存活率。最后，使用PAMPA-BBB测定，化合物4g具有良好的穿过BBB的能力。这些结果表明，化合物4g是一种很有潜力的多功能胆碱酯酶抑制剂。
A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer’s disease.In vitrostudies indicated that most compounds showed significant potency to inhibit self-inducedβ-amyloid (Aβ) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound4gexhibited the potent ability to inhibit cholinesterase (ChE) (IC50, 19.7 nM forhAChE and 0.66 μM forhBuChE) and the good Aβaggregation inhibition (49.2% at 20 μM), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound4gwas a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound4gcould remarkably increase PC12 cells viability in hydrogen peroxide–induced oxidative cell damage and Aβ-induced cell damage. Finally, compound4ghad good ability to cross the BBB using the PAMPA–BBB assay. These results suggested that compound4gwas a promising multifunctional ChE inhibitor for the further investigation.