title: 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
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.
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia. sve@iopc.ru.
authors.forename: Vyacheslav E
authors.initials: VE
authors.lastname: Semenov
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.|Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zueva
authors.affiliation: Kazan State Medical University, Butlerov str. 49, Kazan, 420012, Russia.
authors.forename: Marat A
authors.initials: MA
authors.lastname: Mukhamedyarov
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.|N.M. Emanuel Institute of Biochemical Physics, Kosygin str. 4, Moscow, 119991, Russia.
authors.forename: Sofya V
authors.initials: SV
authors.lastname: Lushchekina
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Kharlamova
authors.affiliation: Kazan State Medical University, Butlerov str. 49, Kazan, 420012, Russia.
authors.forename: Elena O
authors.initials: EO
authors.lastname: Petukhova
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Anatoly S
authors.initials: AS
authors.lastname: Mikhailov
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Podyachev
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Lilya F
authors.initials: LF
authors.lastname: Saifina
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.|Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.|Kazan Institute of Biochemistry & Biophysics, Russian Academy of Sciences, Lobachevsky str. 2/31, Kazan, 420111, Russia.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Petrov
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Oksana A
authors.initials: OA
authors.lastname: Minnekhanova
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.|Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Zobov
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.|Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.|Kazan State Medical University, Butlerov str. 49, Kazan, 420012, Russia.|Kazan Institute of Biochemistry & Biophysics, Russian Academy of Sciences, Lobachevsky str. 2/31, Kazan, 420111, Russia.
authors.forename: Evgeny E
authors.initials: EE
authors.lastname: Nikolsky
authors.affiliation: Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Masson
authors.affiliation: A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Reznik
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D014498:Uracil; C008378:6-methyluracil; D000110:Acetylcholinesterase
keywords: 6-methyluracil; Alzheimer's disease; acetylcholinesterase; molecular modeling; reversible inhibitors