6‐Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease |
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| Authors: | Dr. Vyacheslav E. Semenov Irina V. Zueva Dr. Marat A. Mukhamedyarov Dr. Sofya V. Lushchekina Dr. Alexandra D. Kharlamova Elena O. Petukhova Dr. Anatoly S. Mikhailov Dr. Sergey N. Podyachev Dr. Lilya F. Saifina Dr. Konstantin A. Petrov Oksana A. Minnekhanova Prof. Vladimir V. Zobov Prof. Evgeny E. Nikolsky Prof. Patrick Masson Prof. Vladimir S. Reznik |
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| Affiliation: | 1. A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russia;2. Kazan Federal University, Kazan, Russia;3. Kazan State Medical University, Kazan, Russia;4. N.M. Emanuel Institute of Biochemical Physics, Moscow, Russia;5. Kazan Institute of Biochemistry & Biophysics, Russian Academy of Sciences, Kazan, Russia |
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| 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. |
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| Keywords: | 6-methyluracil acetylcholinesterase Alzheimer's disease molecular modeling reversible inhibitors |
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