PUBLICATION
Design, synthesis and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease
- Authors
- Sang, Z., Wang, K., Xue, H., Cao, M., Tan, Z., Liu, W.
- ID
- ZDB-PUB-181213-2
- Date
- 2018
- Source
- ACS Chemical Neuroscience 10(2): 1008-1024 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Alzheimer Disease/drug therapy*
- Alzheimer Disease/metabolism
- Animals
- Animals, Genetically Modified
- Cholinesterase Inhibitors/administration & dosage
- Cholinesterase Inhibitors/chemical synthesis
- Coumaric Acids/administration & dosage*
- Coumaric Acids/chemical synthesis*
- Coumaric Acids/metabolism
- Dose-Response Relationship, Drug
- Drug Delivery Systems/methods*
- Drug Design*
- Female
- Ligands
- Male
- Mice
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Treatment Outcome
- Zebrafish
- PubMed
- 30537804 Full text @ ACS Chem. Neurosci.
Citation
Sang, Z., Wang, K., Xue, H., Cao, M., Tan, Z., Liu, W. (2018) Design, synthesis and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease. ACS Chemical Neuroscience. 10(2):1008-1024.
Abstract
A novel series of ferulic acid-donepezil hybrids were designed and synthesized based on multitarget-directed ligands (MTDLs) strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective BuChE inhibitors, in particular, compound TM-10 showed the best BuChE inhibitory activity with IC50 value of 0.0089μM, remarkable MAO-A and MAO-B inhibitory potency with IC50 value of 6.3μM and 8.6μM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced Aβ aggregation. In addition, compound TM-10 exhibited potent antioxidant activity (ORAC = 0.52 eq) and neuroprotective effect against Aβ1-42-mediated SH-SY5Y neurotoxicity, as well as acted as an autophagic activator. TM-10 also showed good blood-brain barrier (BBB) penetration. Furthermore, compound TM-10 exhibited favorable dyskinesia recovery rate and response efficiency on AlCl3-induced zebrafish AD model, and potent neuroprotective effect on Aβ1-40-induced zebrafish vascular injury. Further, in vivo assay demonstrated that compound TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study evidently displayed that compound TM-10 is a potent multi-functional agent against Alzheimer's disease and could act as promising lead candidate for anti-Alzheimer drug development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping