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6‐Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease
Author(s) -
Semenov Vyacheslav E.,
Zueva Irina V.,
Mukhamedyarov Marat A.,
Lushchekina Sofya V.,
Kharlamova Alexandra D.,
Petukhova Elena O.,
Mikhailov Anatoly S.,
Podyachev Sergey N.,
Saifina Lilya F.,
Petrov Konstantin A.,
Minnekhanova Oksana A.,
Zobov Vladimir V.,
Nikolsky Evgeny E.,
Masson Patrick,
Reznik Vladimir S.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500334
Subject(s) - butyrylcholinesterase , acetylcholinesterase , chemistry , bifunctional , aché , in vivo , stereochemistry , enzyme , alkyl , pyrimidine , pharmacology , biochemistry , organic chemistry , biology , microbiology and biotechnology , catalysis
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.