Synthesis and Biological Evaluation of Novel Chromone+Donepezil Hybrids for Alzheimer's Disease Therapy.
Alzheimer disease
ORAC
antioxidants
cholinesterase
chromone
donepezil
passerini reaction.
Journal
Current Alzheimer research
ISSN: 1875-5828
Titre abrégé: Curr Alzheimer Res
Pays: United Arab Emirates
ID NLM: 101208441
Informations de publication
Date de publication:
2019
2019
Historique:
received:
30
04
2019
revised:
10
07
2019
accepted:
16
08
2019
pubmed:
30
10
2019
medline:
4
9
2020
entrez:
30
10
2019
Statut:
ppublish
Résumé
Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development. The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.
Sections du résumé
BACKGROUND
Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets.
OBJECTIVE
We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals.
METHODS
We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed.
RESULTS
Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development.
CONCLUSION
The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.
Identifiants
pubmed: 31660831
pii: CAR-EPUB-101361
doi: 10.2174/1567205016666191011112624
doi:
Substances chimiques
Cholinesterase Inhibitors
0
Chromones
0
Free Radical Scavengers
0
Donepezil
8SSC91326P
Acetylcholinesterase
EC 3.1.1.7
Butyrylcholinesterase
EC 3.1.1.8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
815-820Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.