PUBLICATION
Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer's disease
- Authors
- Wang, K., Shi, J., Zhou, Y., He, Y., Mi, J., Yang, J., Liu, S., Tang, X., Liu, W., Tan, Z., Sang, Z.
- ID
- ZDB-PUB-210430-15
- Date
- 2021
- Source
- Bioorganic chemistry 112: 104879 (Journal)
- Registered Authors
- Keywords
- AlCl(3)-induced zebrafish, Alzheimer’s disease, Cinnamic acid hybrids, Multi-function agents, Scopolamine-induced memory impairment, Stability study
- MeSH Terms
-
- Alzheimer Disease/drug therapy*
- Alzheimer Disease/metabolism
- Amyloid beta-Peptides/antagonists & inhibitors
- Amyloid beta-Peptides/metabolism
- Antioxidants/chemical synthesis
- Antioxidants/chemistry
- Antioxidants/pharmacology*
- Butyrylcholinesterase/metabolism
- Cholinesterase Inhibitors/chemical synthesis
- Cholinesterase Inhibitors/chemistry
- Cholinesterase Inhibitors/pharmacology*
- Cinnamates/chemical synthesis
- Cinnamates/chemistry
- Cinnamates/pharmacology*
- Dose-Response Relationship, Drug
- Drug Design
- Humans
- Molecular Structure
- Monoamine Oxidase/metabolism
- Monoamine Oxidase Inhibitors/chemical synthesis
- Monoamine Oxidase Inhibitors/chemistry
- Monoamine Oxidase Inhibitors/pharmacology*
- Neuroprotective Agents/chemical synthesis
- Neuroprotective Agents/chemistry
- Neuroprotective Agents/pharmacology*
- Peptide Fragments/antagonists & inhibitors
- Peptide Fragments/metabolism
- Protein Aggregates/drug effects
- Reactive Oxygen Species/metabolism
- Structure-Activity Relationship
- PubMed
- 33915461 Full text @ Bioorg. Chem.
Citation
Wang, K., Shi, J., Zhou, Y., He, Y., Mi, J., Yang, J., Liu, S., Tang, X., Liu, W., Tan, Z., Sang, Z. (2021) Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer's disease. Bioorganic chemistry. 112:104879.
Abstract
Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible huBuChE inhibitor (IC50 = 2.5 μM) and good MAO-B inhibition activity (IC50 = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated Aβ1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood-brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping