Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease.

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.