The lack of an effective treatment for Alzheimer’ disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD.

缺乏针对阿尔茨海默氏病（AD）的有效疗法，患病率增加和严重的神经退行性病变促使药物化学家寻找新药。当前，仅乙酰胆碱酯酶（AChE）抑制剂和谷氨酸拮抗剂已被批准用于AD的姑息治疗。尽管它们具有短期症状上的益处，但其临床应用显示出AChE的重要非胆碱能功能，例如其伴侣蛋白在β-淀粉样蛋白毒性中的作用。我们在这里提出通过茚满酮和喹啉杂环支架杂交的无毒双结合位点AChEIs的设计，合成和评估。出乎意料的是，我们发现了一种有效的AChE变构调节剂，可通过修复特定的AChE构象来靶向胆碱能和非胆碱能功能，由STD-NMR和分子模型研究证实。此外，从人类神经母细胞瘤SH-SY5Y细胞测定中获得的新的变构杂种有希望的生物学数据14，使我们提出将其作为研究AChE的非胆碱能功能的有价值的药理学工具，并作为针对AD的新型疾病改良剂的新重要线索。