Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease
Электронный научный архив УРФУ
Информация об архиве | Просмотр оригинала| Поле | Значение | |
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Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease
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| Автор |
Makhaeva, G. F.
Kovaleva, N. V. Rudakova, E. V. Boltneva, N. P. Lushchekina, S. V. Astakhova, T. Y. Timokhina, E. N. Serebryakova, O. G. Shchepochkin, A. V. Averkov, M. A. Utepova, I. A. Demina, N. S. Radchenko, E. V. Palyulin, V. A. Fisenko, V. P. Bachurin, S. O. Chupakhin, O. N. Charushin, V. N. Richardson, R. J. |
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| Тематика |
9-PHOSPHORYL-9,10-DIHYDROACRIDINES
9-PHOSPHORYLACRIDINES ACETYLCHOLINESTERASE ALZHEIMER’S DISEASE BUTYRYLCHOLINESTERASE 9 PHOSPHORYL 9,10 DIHYDROACRIDINES 9 PHOSPHORYLACRIDINES ACETYLCHOLINESTERASE ACRIDINE DERIVATIVE AMYLOID BETA PROTEIN ANTIOXIDANT CARBOXYLESTERASE CHOLINESTERASE CHOLINESTERASE INHIBITOR UNCLASSIFIED DRUG ABTS RADICAL SCAVENGING ASSAY ALZHEIMER DISEASE ANTIOXIDANT ACTIVITY ARTICLE ASSAY BLOOD BRAIN BARRIER CARDIOTOXICITY DRUG PENETRATION ENZYME ACTIVITY ENZYME INHIBITION FERRIC REDUCING ANTIOXIDANT POWER FERRIC REDUCING ANTIOXIDANT POWER ASSAY FLUORESCENCE INTENSITY HIGH TEMPERATURE PROCEDURES HUMAN IN VITRO STUDY INTESTINE ABSORPTION LIPOPHILICITY MOLECULAR DOCKING MOLECULAR DYNAMICS MOLECULAR INTERACTION NONHUMAN NUCLEAR MAGNETIC RESONANCE PROTEIN AGGREGATION QUANTITATIVE STRUCTURE ACTIVITY RELATION QUANTUM CHEMISTRY SYNTHESIS THIOFLAVIN TEST WATER SOLUBILITY X RAY CRYSTALLOGRAPHY |
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| Описание |
We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations. Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.
122041400110-4; FFSN-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, РФФИ: 19-29-08037; Russian Science Foundation, RSF This research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan. |
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| Дата |
2024-04-05T16:32:10Z
2024-04-05T16:32:10Z 2023 |
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| Тип |
Article
Journal article (info:eu-repo/semantics/article) |info:eu-repo/semantics/publishedVersion |
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| Идентификатор |
Makhaeva, G, Kovaleva, N, Rudakova, E, Boltneva, N, Lushchekina, S, Astakhova, T, Timokhina, E, Serebryakova, O, Shchepochkin, A, Averkov, M, Utepova, I, Demina, N, Radchenko, E, Palyulin, V, Fisenko, VP, Bachurin, S, Chupakhin, O, Charushin, V & Richardson, R 2023, 'Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease', Frontiers in Pharmacology, Том. 14, 1219980. https://doi.org/10.3389/fphar.2023.1219980
Makhaeva, G., Kovaleva, N., Rudakova, E., Boltneva, N., Lushchekina, S., Astakhova, T., Timokhina, E., Serebryakova, O., Shchepochkin, A., Averkov, M., Utepova, I., Demina, N., Radchenko, E., Palyulin, V., Fisenko, V. P., Bachurin, S., Chupakhin, O., Charushin, V., & Richardson, R. (2023). Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease. Frontiers in Pharmacology, 14, [1219980]. https://doi.org/10.3389/fphar.2023.1219980 1663-9812 Final All Open Access, Gold, Green https://www.scopus.com/inward/record.uri?eid=2-s2.0-85169578072&doi=10.3389%2ffphar.2023.1219980&partnerID=40&md5=e5a9703fe921a2849ee1d5766d8a9381 https://www.frontiersin.org/articles/10.3389/fphar.2023.1219980/pdf http://elar.urfu.ru/handle/10995/130756 10.3389/fphar.2023.1219980 85169578072 001057900600001 |
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| Язык |
en
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| Связанные ресурсы |
info:eu-repo/grantAgreement/RSF//22-13-00298
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| Права |
Open access (info:eu-repo/semantics/openAccess)
cc-by https://creativecommons.org/licenses/by/4.0/ |
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| Формат |
application/pdf
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| Издатель |
Frontiers Media SA
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| Источник |
Frontiers in Pharmacology
Frontiers in Pharmacology |
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