橙皮素
神经保护
丁酰胆碱酯酶
化学
胆碱酯酶
药理学
神经毒性
三唑
IC50型
抗氧化剂
生物化学
阿切
体外
乙酰胆碱酯酶
医学
酶
毒性
有机化学
类黄酮
作者
Min Wang,Longji Fang,Tongtong Liu,Xuejie Chen,Yan Zheng,Yilong Zhang,Shiming Chen,Zeng Li
标识
DOI:10.1016/j.cbi.2021.109489
摘要
The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 μM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 μM concentration. Furthermore, possessing significant self-mediated Aβ1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood–brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.
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