Sang Zhipei, Bai Ping, Ban Yujuan, Wang Keren, Wu Anguo, Mi Jing, Hu Jiaqi, Xu Rui, Zhu Gaofeng, Wang Jianta, Zhang Jiquan, Wang Changning, Tan Zhenghuai, Tang Lei
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China; College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China; School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Bioorg Chem. 2022 Oct;127:106007. doi: 10.1016/j.bioorg.2022.106007. Epub 2022 Jul 7.
Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC = 0.87 μM) and huBuChE (IC = 3.3 μM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated Aβ aggregation (60.6%) and huAChE-mediated induced Aβ aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Aβ-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.
阿尔茨海默病（AD）是一种慢性进行性脑神经退行性疾病。到目前为止，尚无有效的药物来阻止或逆转AD的进展。鉴于AD发病机制复杂，多靶点导向配体（MTDLs）策略被认为是一种有前景的治疗方法。在此，通过融合多奈哌齐、查隆和卡巴拉汀，合理设计并合成了一系列新型多奈哌齐-查隆-卡巴拉汀杂合物。体外生物活性结果表明，化合物10c是一种可逆的人乙酰胆碱酯酶（IC = 0.87 μM）和人丁酰胆碱酯酶（IC = 3.3 μM）抑制剂。它还通过抑制白细胞介素-6和肿瘤坏死因子-α的产生水平呈现出显著的抗炎作用，并显著抑制自身介导的Aβ聚集（60.6%）和人乙酰胆碱酯酶介导的诱导Aβ聚集（46.2%）。此外，10c对Aβ诱导的PC12细胞损伤显示出显著的神经保护作用，并激活HT22细胞中的UPS途径以降解tau蛋白和淀粉样前体蛋白（APP）。此外，化合物10c在体外人工胃肠液和肝微粒体中表现出良好的稳定性。药代动力学研究表明，化合物10c在大鼠体内胃内给药后迅速吸收并分布于大鼠脑内。PET-CT成像表明，[C]10c可迅速进入脑内并在体内逐渐清除。此外，5 mg/kg剂量的化合物10c改善了东莨菪碱诱导的记忆障碍，值得进一步研究。
