Abstract：
Alzheimer\'s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a β-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro, using tacrine (hAChE, IC50 = 305.78 nM; hBuChE, IC50 = 56.72 nM) and donepezil (hAChE, IC50 = 89.32 nM; hBuChE, IC50 = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC50 = 30.68 nM) and BuChE (IC50 = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H2O2-induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 μM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H2O2-induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment.
摘要：
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性记忆丧失和认知领域的缺陷。低胆碱水平,氧化应激，和神经炎症是涉及AD进展的主要机制。单分子同时抑制乙酰胆碱酯酶（AChE）和活性氧（ROS）的产生可能为AD治疗提供新的希望。这里,我们将多奈哌齐-他克林杂种描述为AChE和ROS的抑制剂。设计并合成了四个系列的带有β-氨基醇接头的衍生物。在这项研究中,评价目标化合物体外抑制AChE和丁酰胆碱酯酶(BuChE)的能力,使用他克林(hAChE，IC50=305.78nM;hBuChE,IC50=56.72nM）和多奈哌齐（hAChE，IC50=89.32nM;hBuChE,IC50=9137.16nM)作为阳性对照。化合物B19对AChE(IC50=30.68nM)和BuChE(IC50=124.57nM)表现出优异且平衡的抑制效力。细胞毒性实验表明，化合物B19的PC12细胞存活率（84.37％）接近他克林（87.73％）和多奈哌齐（79.71％）。使用化合物对H2O2诱导的毒性的神经保护作用来评估AD的潜在治疗作用。和化合物B19（68.77%）在25μM的浓度下表现出明显的神经保护活性，与模型组相比(30.34%)。此外，化合物B19保护PC12细胞免受H2O2诱导的凋亡和ROS产生。化合物B19的这些性质表明它是一种具有AChE抑制作用的多功能药物，抗氧化，抗炎活性，低毒性，值得进一步研究作为一种有前途的AD治疗药物。
