Semenov_2015_ChemMedChem_10_1863

Reference

Title : 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease - Semenov_2015_ChemMedChem_10_1863
Author(s) : Semenov VE , Zueva IV , Mukhamedyarov MA , Lushchekina SV , Kharlamova AD , Petukhova EO , Mikhailov AS , Podyachev SN , Saifina LF , Petrov KA , Minnekhanova OA , Zobov VV , Nikolsky EE , Masson P , Reznik VS
Ref : ChemMedChem , 10 :1863 , 2015
Abstract : Novel 6-methyluracil derivatives with omega-(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 beta-amyloid peptide plaques in the brain.
ESTHER : Semenov_2015_ChemMedChem_10_1863
PubMedSearch : Semenov_2015_ChemMedChem_10_1863
PubMedID: 26412714

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Semenov VE, Zueva IV, Mukhamedyarov MA, Lushchekina SV, Kharlamova AD, Petukhova EO, Mikhailov AS, Podyachev SN, Saifina LF, Petrov KA, Minnekhanova OA, Zobov VV, Nikolsky EE, Masson P, Reznik VS (2015)
6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease
ChemMedChem 10 :1863

Semenov VE, Zueva IV, Mukhamedyarov MA, Lushchekina SV, Kharlamova AD, Petukhova EO, Mikhailov AS, Podyachev SN, Saifina LF, Petrov KA, Minnekhanova OA, Zobov VV, Nikolsky EE, Masson P, Reznik VS (2015)
ChemMedChem 10 :1863