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Development of naringenin- O -alkylamine derivatives as multifunctional agents for the treatment of Alzheimer's disease.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2022 Dec; Vol. 37 (1), pp. 792-816. - Publication Year :
- 2022
-
Abstract
- In this study, a series of naringenin- O -alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3 eq and 1.2 eq , respectively. Compounds 5f and 7k were reversible and excellent hu AChE inhibitors with IC <subscript>50</subscript> values of 0.91 μM and 0.57 μM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced A β <subscript>1-42</subscript> aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited hu AChE-A β <subscript>1-40</subscript> aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu <superscript>2+</superscript> -induced A β <subscript>1-42</subscript> aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.
- Subjects :
- Acetylcholinesterase metabolism
Alzheimer Disease metabolism
Amines chemical synthesis
Amines chemistry
Amyloid beta-Peptides antagonists & inhibitors
Amyloid beta-Peptides metabolism
Animals
Antioxidants chemical synthesis
Antioxidants chemistry
Blood-Brain Barrier drug effects
Blood-Brain Barrier metabolism
Butyrylcholinesterase metabolism
Cell Line
Cell Survival drug effects
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Dose-Response Relationship, Drug
Drug Development
Flavanones chemical synthesis
Flavanones chemistry
Humans
Mice
Molecular Structure
Neuroprotective Agents chemical synthesis
Neuroprotective Agents chemistry
Protein Aggregates drug effects
Rats
Structure-Activity Relationship
Alzheimer Disease drug therapy
Amines pharmacology
Antioxidants pharmacology
Cholinesterase Inhibitors pharmacology
Flavanones pharmacology
Neuroprotective Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 37
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35193434
- Full Text :
- https://doi.org/10.1080/14756366.2022.2041627