Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease
Электронный научный архив УРФУ
Информация об архиве | Просмотр оригинала| Поле | Значение | |
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Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease
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| Автор |
Makhaeva, G. F.
Kovaleva, N. V. Rudakova, E. V. Boltneva, N. P. Grishchenko, M. V. Lushchekina, S. V. Astakhova, T. Y. Serebryakova, O. G. Timokhina, E. N. Zhilina, E. F. Shchegolkov, E. V. Ulitko, M. V. Radchenko, E. V. Palyulin, V. A. Burgart, Y. V. Saloutin, V. I. Bachurin, S. O. Richardson, R. J. |
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| Тематика |
ACETYLCHOLINESTERASE
ADMET PREDICTION ALZHEIMER’S DISEASE ANTIOXIDANT ACTIVITY AΒ42 SELF-AGGREGATION BUTYRYLCHOLINESTERASE METAL CHELATION PROPIDIUM DISPLACEMENT SALICYLIC ACID DERIVATIVES TACRINE CONJUGATES 2 METHYL N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)BUTYL]BENZAMIDE 2 METHYL N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)HEXYL]BENZAMIDE 2 METHYL N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)OCTYL]BENZAMIDE 2 [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)BUTYLIMINOMETHYL]PHENOL 2 [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)HEXYLIMINOMETHYL]PHENOL 2 [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)OCTYLIMINOMETHYL]PHENOL 4,5 DIFLUORO 2 HYDROXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)BUTYL]BENZAMIDE 4,5 DIFLUORO 2 HYDROXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)HEXYL]BENZAMIDE 4,5 DIFLUORO 2 HYDROXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)OCTYL]BENZAMIDE 4,5 DIFLUORO 2 METHOXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)BUTYL]BENZAMIDE 4,5 DIFLUORO 2 METHOXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)HEXYL]BENZAMIDE 4,5 DIFLUORO 2 METHOXY N [4 (1,2,3,4 TETRAHYDROACRIDIN 9 YLAMINO)OCTYL]BENZAMIDE ACETYLCHOLINESTERASE AMYLOID BETA PROTEIN[1-42] ANTIOXIDANT ASCORBIC ACID CHELATING AGENT CHOLINESTERASE CHOLINESTERASE INHIBITOR COPPER DONEPEZIL IRON MYRICETIN NOOTROPIC AGENT PROPIDIUM IODIDE SALICYLAMIDE DERIVATIVE SALICYLIC ACID TACRINE TACRINE DERIVATIVE THIOFLAVINE TROLOX C UNCLASSIFIED DRUG ZINC ABTS RADICAL SCAVENGING ASSAY ALZHEIMER DISEASE ANIMAL CELL ANIMAL EXPERIMENT ANTIOXIDANT ACTIVITY ARTICLE ARTIFICIAL NEURAL NETWORK BLOOD BRAIN BARRIER CARDIOTOXICITY CHELATION CHOLINESTERASE INHIBITION COMPARATIVE STUDY CONJUGATE CONTROLLED STUDY CYTOTOXICITY DRUG ABSORPTION DRUG DISTRIBUTION DRUG ELIMINATION DRUG METABOLISM DRUG SELECTIVITY DRUG SOLUBILITY DRUG STRUCTURE DRUG SYNTHESIS FERRIC REDUCING ANTIOXIDANT POWER ASSAY HYDROGEN BOND IC50 INTESTINE ABSORPTION LIPOPHILICITY LIVER CELL MALE MOLECULAR DOCKING MOLECULAR DYNAMICS MOLECULAR MODEL MOUSE MTT ASSAY NONHUMAN PHYSICAL CHEMISTRY PROTEIN AGGREGATION QUANTITATIVE STRUCTURE ACTIVITY RELATION QUANTUM CHEMISTRY STEADY STATE STRUCTURE ACTIVITY RELATION WATER SOLUBILITY |
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| Описание |
A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a–c, intermediate for salicylimines 10a–c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure–activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD. © 2023 by the authors.
-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, РФФИ: 19-53-26016a; Ministry of Education and Science of the Russian Federation, Minobrnauka: #AAAA-A19-119011790134-1, 22041400110-4 This research was supported by the Russian Foundation for Basic Research (Project #19-53-26016a) and IPAC RAS State Targets Project #FFSN-2021-0005 as part of biochemical research and molecular modeling. Synthesis and analysis of compounds were performed in the frame of work for the Ministry of Science and Higher Education of the Russian Federation (Project #AAAA-A19-119011790134-1). Quantum chemical analysis of AO activity was supported by the Ministry of Science and Higher Education of the Russian Federation, contract #22041400110-4. Support for RJR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research & Development Foundation (ARDF) and an Mcubed grant from the University of Michigan. The funding sources had no role in the study design; collection, analysis, and interpretation of data; writing of the manuscript; or the decision to submit the article for publication. |
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| Дата |
2024-04-05T16:15:34Z
2024-04-05T16:15:34Z 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, GF, Kovaleva, NV, Rudakova, EV, Boltneva, NP, Grishchenko, MV, Lushchekina, SV, Astakhova, TY, Serebryakova, OG, Timokhina, EN, Zhilina, EF, Shchegolkov, EV, Ulitko, MV, Radchenko, EV, Palyulin, VA, Burgart, YV, Saloutin, VI, Bachurin, SO & Richardson, RJ 2023, 'Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease', International Journal of Molecular Sciences, Том. 24, № 3, 2285. https://doi.org/10.3390/ijms24032285
Makhaeva, G. F., Kovaleva, N. V., Rudakova, E. V., Boltneva, N. P., Grishchenko, M. V., Lushchekina, S. V., Astakhova, T. Y., Serebryakova, O. G., Timokhina, E. N., Zhilina, E. F., Shchegolkov, E. V., Ulitko, M. V., Radchenko, E. V., Palyulin, V. A., Burgart, Y. V., Saloutin, V. I., Bachurin, S. O., & Richardson, R. J. (2023). Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease. International Journal of Molecular Sciences, 24(3), [2285]. https://doi.org/10.3390/ijms24032285 1661-6596 Final All Open Access, Gold, Green https://www.scopus.com/inward/record.uri?eid=2-s2.0-85148003235&doi=10.3390%2fijms24032285&partnerID=40&md5=fe6438dda642e3160d82a1abfe2c8c8b https://www.mdpi.com/1422-0067/24/3/2285/pdf?version=1675907905 http://elar.urfu.ru/handle/10995/130201 10.3390/ijms24032285 85148003235 000935706300001 |
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| Язык |
en
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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 |
MDPI
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| Источник |
International Journal of Molecular Sciences
International Journal of Molecular Sciences |
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