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 evalua...

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Published in:European journal of medicinal chemistry Vol. 219; pp. 113426 - 113442
Main Authors: Zhou, Li-Cheng, Liang, Ying-Fan, Huang, Yi, Yang, Gui-Xiang, Zheng, Lu-Lu, Sun, Jia-Min, Li, Yang, Zhu, Fu-Li, Qian, He-Wen, Wang, Rui, Ma, Lei
Format: Journal Article
Language:English
Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.07.2021
Elsevier
Subjects:
Alzheimer’s disease
Anti-beta amyloid
Antioxidant
Chemistry, Medicinal
Diosgenin
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Diosgenin
Alzheimer’s disease
Antioxidant
Anti-beta amyloid
PATHOLOGIES
OXIDATIVE STRESS
MELATONIN
TAU
DIRECTED LIGANDS
NEUROTOXICITY
AMYLOID-BETA
A-BETA
SIMULATIONS
Alzheimer's disease
ISSN:0223-5234, 1768-3254, 1768-3254
Online Access:Get full text
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Summary: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 H2O2 (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 H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was −40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (−0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. 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. [Display omitted] •Design and synthesis of diosgenin-indole derivatives.•Biological evaluation and structure-activity relationships of these compounds.•H2O2, 6-OHDA and Aβ models were used to evaluate neuroprotective activity in vitro.•5b effectively ameliorated memory and learning impairments of Aβ-damaged mice.•5b is a new potential candidate for AD treatment.
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ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2021.113426