Owning to the promising neuroprotective profile and the ability to cross the blood–brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure–activity relationship studies for Alzheimer’s disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aβ_1–42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs.

由于有希望的神经保护作用和穿越血脑屏障的能力，雷公藤甲素引起了广泛的关注。尽管雷公藤内酯醇有限的溶解度和毒性极大地阻碍了临床翻译，但雷公藤内酯醇已成为阿尔茨海默氏病结构-活性关系研究的有希望的候选者。在本研究中，设计和合成了一系列雷公藤内酯类似物，然后使用细胞培养模型测试了它们的神经保护作用和抗神经炎作用。在测试的雷公藤甲素衍生物中，美金刚共轭物化合物8对_Aβ1–42表现出显着的神经保护作用在亚纳摩尔浓度下，对原代皮层神经元培养物的毒性以及对LPS诱导的BV2细胞中TNF-α产生的抑制作用。我们的发现提供了对雷公藤甲素在中枢神经系统中的多功能作用负责的不同药效团的见解。我们的研究应有助于开发基于雷公藤甲素的多功能抗阿尔茨海默病药物。