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6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
ChemMedChem. 2015 Nov; 10(11):1863-74.C

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+Show Affiliations

A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia. sve@iopc.ru.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.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.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.Kazan State Medical University, Butlerov str. 49, Kazan, 420012, Russia.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.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.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.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.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.Kazan Federal University, Kremlevskaya str. 18, Kazan, 420008, Russia.A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26412714

Citation

Semenov, Vyacheslav E., et al. "6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease." ChemMedChem, vol. 10, no. 11, 2015, pp. 1863-74.
Semenov VE, Zueva IV, Mukhamedyarov MA, et al. 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease. ChemMedChem. 2015;10(11):1863-74.
Semenov, V. E., Zueva, I. V., Mukhamedyarov, M. A., Lushchekina, S. V., Kharlamova, A. D., Petukhova, E. O., Mikhailov, A. S., Podyachev, S. N., Saifina, L. F., Petrov, K. A., Minnekhanova, O. A., Zobov, V. V., Nikolsky, E. E., Masson, P., & Reznik, V. S. (2015). 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease. ChemMedChem, 10(11), 1863-74. https://doi.org/10.1002/cmdc.201500334
Semenov VE, et al. 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease. ChemMedChem. 2015;10(11):1863-74. PubMed PMID: 26412714.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease. AU - Semenov,Vyacheslav E, AU - Zueva,Irina V, AU - Mukhamedyarov,Marat A, AU - Lushchekina,Sofya V, AU - Kharlamova,Alexandra D, AU - Petukhova,Elena O, AU - Mikhailov,Anatoly S, AU - Podyachev,Sergey N, AU - Saifina,Lilya F, AU - Petrov,Konstantin A, AU - Minnekhanova,Oksana A, AU - Zobov,Vladimir V, AU - Nikolsky,Evgeny E, AU - Masson,Patrick, AU - Reznik,Vladimir S, Y1 - 2015/09/28/ PY - 2015/07/27/received PY - 2015/9/29/entrez PY - 2015/9/29/pubmed PY - 2016/5/11/medline KW - 6-methyluracil KW - Alzheimer's disease KW - acetylcholinesterase KW - molecular modeling KW - reversible inhibitors SP - 1863 EP - 74 JF - ChemMedChem JO - ChemMedChem VL - 10 IS - 11 N2 - 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. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/26412714/6_Methyluracil_Derivatives_as_Bifunctional_Acetylcholinesterase_Inhibitors_for_the_Treatment_of_Alzheimer's_Disease_ L2 - https://doi.org/10.1002/cmdc.201500334 DB - PRIME DP - Unbound Medicine ER -