The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
Chem Biol Interact. 2021 Jun 1;342:109489. doi: 10.1016/j.cbi.2021.109489. Epub 2021 Apr 24.
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 (IC = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC = 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 Aβ 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.
多靶点导向配体（MTDLs）的开发可能会改善阿尔茨海默病（AD）等复杂的中枢神经系统疾病。在这里，评估了一系列 7-O-1,2,3-三唑橙皮苷衍生物对胆碱酯酶、抗神经炎症和神经保护活性的抑制作用。在橙皮苷衍生物中，化合物 a8（7-O-（（1-（3-氯苄基）-1H-1,2,3-三唑-4-基）甲基）橙皮苷）具有出色的丁酰胆碱酯酶抑制活性（IC = 3.08 ± 0.29 μM），并通过显著阻断 NF-κB 信号通路和抑制 P65 的磷酸化，表现出良好的抗神经炎症活性（IC = 2.91 ± 0.47 μM），对 NO 产生。此外，a8 表现出显著的神经保护作用，在高达 50 μM 的浓度下没有神经毒性。此外，在化合物 a8 中发现具有显著的自介导 Aβ 聚集抑制活性、螯合生物金属和减少 ROS 产生。在双向转运测定中，a8 表现出穿过血脑屏障的能力。在这项研究中，Morris 水迷宫任务表明，化合物 a8 显著改善了东莨菪碱诱导的 AD 小鼠模型的学习和记忆障碍。结果突出了化合物 a8 作为潜在的多靶点导向配体用于开发抗 AD 药物的潜力。
