A series of multifunctional 3-piperazinecarboxylate sarsasapogenin derivatives were designed and synthesized against Alzheimer's disease (AD). The protection against H₂O₂-triggered oxidative stress in PC12 cells, and inhibition on LPS-induced NO production in RAW264.7 cell lines in vitro by these derivatives were firstly evaluated. Most of the compounds showed better antioxidant and antiinflammatory activities compared with sarsasapogenin, especially AA34 and AA36. Structure-activity relationships revealed that benzyl group, electron-donating group and intramolecular hydrogen bond might be beneficial to enhancing their neuroprotective activities. Moreover, Aβ42 was the optimum predicted target based on the high 3D molecular similarity between compound AA36 and caprospinol. In the following experiments, AA36 significantly protected PC12 cells from Aβ-induced damage and improved learning and memory impairments in Aβ-injected mice. Thus AA36 is regarded as a potent anti-AD agent and N-substituted piperazinecarboxylate can be served as a promising structural unit for anti-AD drug design.

设计并合成了一系列针对阿尔茨海默氏病（AD）的多功能3-哌嗪羧酸盐sarsasapogenin衍生物。首先评估了这些衍生物对PC12细胞中H ₂ O ₂触发的氧化应激的保护作用，以及它们在体外对RAW264.7细胞系中LPS诱导的NO产生的抑制作用。与sarsasapogenin相比，大多数化合物表现出更好的抗氧化和抗炎活性，尤其是AA34和AA36。构效关系表明，苄基，给电子基团和分子内氢键可能有利于增强它们的神经保护活性。此外，基于化合物AA36与己内酯之间的3D分子高度相似性，Aβ42是最佳的预测靶标。在以下实验中，AA36显着保护了PC12细胞免受Aβ诱导的小鼠损害，并改善了注射Aβ的小鼠的学习和记忆障碍。因此，AA36被认为是有效的抗AD药物，N-取代的哌嗪羧酸酯可以用作抗AD药物设计的有前途的结构单元。