阿尔茨海默病(AD)是一种病因复杂的神经退行性疾病，设计能同时作用于乙酰胆碱酯酶(AChE)和其它AD相关靶标的多靶点分子是目前抗AD药物研究的主要方法。然而，目前所选取的这些靶标只能针对AD病因中的一个方面，由于AD病因复杂多样，以这样的靶标设计多靶点分子，仍不能有效的治疗AD。Nrf2是近年发现的可以同时调控AD多个病理因素的关键转录因子，激活Nrf2能更全面的实现对AD的有效治疗。基于此，本项目拟从具有良好Nrf2激活活性的查尔酮结构出发，运用药物化学手段，首次设计具有Nrf2激活和AChE抑制活性的多靶点分子。通过对这些分子的合成及多层次的活性评价，以期得到的多靶点候选化合物不仅能快速的缓解AD症状同时也能通过激活Nrf2发挥对AD多种病理因素的全面调节，最终阻止AD病理进程的发展。本项目的研究不仅为AD的多靶点治疗提供了新的突破也为基于天然产物的药物开发提供了新的策略。

Alzheimer’s disease (AD) is a complex neurodegenerative disease. Currently, development of multi-target compounds possessing AChE (Acetylcholinesterase) inhibition and additional activities related to AD treatment is the main strategy to treat this disease. However, the therapeutic effects of such compounds are still not satisfactory because the causes leading to AD are very complex while the selected target for designing these compounds can only play a single role in AD treatment. Nrf2 (Nuclear factor erythroid 2-ralated factor 2) is key transcription factor associated with many pathological factors of AD. Activation of Nrf2 is found to simultaneously modulate numerous pathways involved in AD pathogenesis, which may be more beneficial for AD treatment. Based on the above finding, this project will select the safe and potent Nrf2 activator, chalcone scaffold, for first time to design novel multi-target compounds with Nrf2 activation and AChE inhibitory activity. After synthesizing and evaluating these compounds in different biological levels, we hope the obtained multi-target molecules can not only quickly relieve symptoms of AD but also can realize the comprehensive treatment of AD through regulating Nrf2. Finally, the research of this project can offer new ideals of developing multi-target molecules for treating AD and provide new strategy for drug discovery based on natural products.