Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Eur J Med Chem. 2021 Jul 5;219:113426. doi: 10.1016/j.ejmech.2021.113426. Epub 2021 Apr 3.
The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against HO (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by HO (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by HO. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.
阿尔茨海默病（AD）的复杂发病机制已成为其治疗的主要障碍。一种有效的方法是开发多功能药物，同时针对多种病理过程。在这里，设计、合成了一系列薯蓣皂苷元-吲哚类化合物，并评价了它们对 HO（过氧化氢）、6-OHDA（6-羟多巴胺）和 Aβ（β淀粉样蛋白）损伤的神经保护作用。初步的构效关系研究表明，在吲哚环 C-5 位引入吲哚片段和供电子基团有利于提高神经保护活性。结果表明，化合物 5b 是对抗 HO（52.9±1.9%）、6-OHDA（38.4±2.4%）和 Aβ（54.4±2.7%）诱导的细胞损伤最有前途的候选药物。分子对接研究表明，5b 与 Aβ 的结合亲和力为-40.59 kcal/mol，表明 5b 与 Aβ 具有很强的结合亲和力。脑/血分配系数（-0.733）和极性表面积（85.118 Å）的预测值表明 5b 具有良好的 BBB 渗透和吸收能力。此外，5b 能显著降低 HO 诱导的 ROS（活性氧）生成。在随后的体内实验中，5b 明显减轻了 Aβ 注射小鼠的记忆和学习障碍。总之，化合物 5b 可被认为是一种有前途的抗 AD 双功能神经保护剂。
