PUBLICATION
Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease
- Authors
- Sang, Z., Wang, K., Bai, P., Wu, A., Shi, J., Liu, W., Zhu, G., Wang, Y., Lan, Y., Chen, Z., Zhao, Y., Qiao, Z., Wang, C., Tan, Z.
- ID
- ZDB-PUB-200403-249
- Date
- 2020
- Source
- European Journal of Medicinal Chemistry 194: 112265 (Journal)
- Registered Authors
- Keywords
- Alzheimer’s disease, Metabolism in vitro, Multi-function agents, O-carbamoyl ferulamide derivatives, PET-CT imaging, Scopolamine-induced cognitive impairment, Zebrafish AD
- MeSH Terms
-
- Alzheimer Disease/drug therapy*
- Alzheimer Disease/metabolism
- Amides/chemical synthesis
- Amides/chemistry
- Amides/pharmacology*
- Amyloid beta-Peptides/antagonists & inhibitors
- Amyloid beta-Peptides/metabolism
- Animals
- Cell Line
- Cell Survival/drug effects
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Design*
- Humans
- Ligands
- Mice
- Mice, Inbred Strains
- Microsomes, Liver/chemistry
- Microsomes, Liver/metabolism
- Molecular Structure
- Peptide Fragments/antagonists & inhibitors
- Peptide Fragments/metabolism
- Positron Emission Tomography Computed Tomography
- Protein Aggregates/drug effects
- Rats
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 32240904 Full text @ Eur. J. Med. Chem.
Citation
Sang, Z., Wang, K., Bai, P., Wu, A., Shi, J., Liu, W., Zhu, G., Wang, Y., Lan, Y., Chen, Z., Zhao, Y., Qiao, Z., Wang, C., Tan, Z. (2020) Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry. 194:112265.
Abstract
A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ1-40. PET-CT imaging demonstrated that [11C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping