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6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease
- Source :
- ChemMedChem. 10:1863-1874
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
Abstract
- Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain.
- Subjects :
- Models, Molecular
Pyrimidine
Stereochemistry
Mice, Transgenic
Peptide
Crystallography, X-Ray
Biochemistry
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Alzheimer Disease
Drug Discovery
Animals
Humans
Structure–activity relationship
General Pharmacology, Toxicology and Pharmaceutics
Uracil
Bifunctional
Butyrylcholinesterase
Cholinesterase
Pharmacology
chemistry.chemical_classification
Behavior, Animal
Dose-Response Relationship, Drug
Molecular Structure
biology
Organic Chemistry
Brain
Active site
Acetylcholinesterase
Disease Models, Animal
chemistry
biology.protein
Molecular Medicine
Cholinesterase Inhibitors
Subjects
Details
- ISSN :
- 18607179
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- ChemMedChem
- Accession number :
- edsair.doi.dedup.....d228ac7106a086903aa92974b963d10a