PUBLICATION
The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease
- Authors
- Sang, Z., Wang, K., Shi, J., Liu, W., Cheng, X., Zhu, G., Wang, Y., Zhao, Y., Qiao, Z., Wu, A., Tan, Z.
- ID
- ZDB-PUB-200305-12
- Date
- 2020
- Source
- European Journal of Medicinal Chemistry 192: 112180 (Journal)
- Registered Authors
- Keywords
- Alzheimer’s disease, Blood-brain barrier permeability, Metabolism, Multi-function agents, Scopolamine-induced memory impairment, Transcriptome sequencing, Zebrafish AD model
- MeSH Terms
-
- Acetylcholinesterase/metabolism
- Aluminum Chloride
- Alzheimer Disease/chemically induced
- Alzheimer Disease/drug therapy*
- Alzheimer Disease/metabolism
- Amyloid beta-Peptides/antagonists & inhibitors
- Amyloid beta-Peptides/metabolism
- Animals
- Butyrylcholinesterase/metabolism
- Cholinesterase Inhibitors/chemical synthesis
- Cholinesterase Inhibitors/chemistry
- Cholinesterase Inhibitors/pharmacology*
- Donepezil/chemical synthesis
- Donepezil/chemistry
- Donepezil/pharmacology*
- Dose-Response Relationship, Drug
- Drug Development*
- Humans
- Ligands
- Molecular Structure
- Neuroprotective Agents/chemical synthesis
- Neuroprotective Agents/chemistry
- Neuroprotective Agents/pharmacology*
- Oxidative Stress/drug effects
- Peptide Fragments/antagonists & inhibitors
- Peptide Fragments/metabolism
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 32131034 Full text @ Eur. J. Med. Chem.
Citation
Sang, Z., Wang, K., Shi, J., Liu, W., Cheng, X., Zhu, G., Wang, Y., Zhao, Y., Qiao, Z., Wu, A., Tan, Z. (2020) The development of advanced structural framework as multi-target-directed ligands for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry. 192:112180.
Abstract
In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC50 = 0.36 μM) and huBChE (IC50 = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ1-42 aggregation (IC50 = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu2+-induced Aβ aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl3-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ1-40-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping