Open Access
International Journal of Molecular Sciences, volume 24, issue 3, pages 2285
Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease
G. F. Makhaeva
1
,
N. V. Kovaleva
1
,
Elena V Rudakova
1
,
N. P. Boltneva
1
,
Maria V Grishchenko
2
,
S. Lushchekina
1, 3
,
Tatiana Y. Astakhova
3
,
Olga G Serebryakova
1
,
Elena N Timokhina
3
,
Ekaterina F. Zhilina
2
,
E.V. Shchegol’kov
2
,
Mariya V Ulitko
4
,
Eugene V. Radchenko
1, 5
,
V. A. Palyulin
1, 5
,
Yanina V. Burgart
2
,
Victor Saloutin
2
,
S. O. Bachurin
1
,
Rudy J. Richardson
6, 7, 8, 9
Publication type: Journal Article
Publication date: 2023-01-24
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.6
ISSN: 16616596, 14220067
Catalysis
Organic Chemistry
Inorganic Chemistry
Physical and Theoretical Chemistry
Computer Science Applications
Spectroscopy
Molecular Biology
General Medicine
Abstract
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.
Top-30
Citations by journals
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1
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Frontiers in Pharmacology
1 publication, 9.09%
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Archiv der Pharmazie
1 publication, 9.09%
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Molecules
1 publication, 9.09%
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Russian Journal of General Chemistry
1 publication, 9.09%
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Bioorganic Chemistry
1 publication, 9.09%
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Royal Society Open Science
1 publication, 9.09%
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Russian Chemical Bulletin
1 publication, 9.09%
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European Journal of Medicinal Chemistry
1 publication, 9.09%
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Medical Principles and Practice
1 publication, 9.09%
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Current Neuropharmacology
1 publication, 9.09%
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Russian Chemical Reviews
1 publication, 9.09%
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1
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Citations by publishers
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1
2
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Elsevier
2 publications, 18.18%
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Frontiers Media S.A.
1 publication, 9.09%
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Wiley
1 publication, 9.09%
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Multidisciplinary Digital Publishing Institute (MDPI)
1 publication, 9.09%
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Pleiades Publishing
1 publication, 9.09%
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The Royal Society
1 publication, 9.09%
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Springer Nature
1 publication, 9.09%
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S. Karger AG
1 publication, 9.09%
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Bentham Science
1 publication, 9.09%
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Autonomous Non-profit Organization Editorial Board of the journal Uspekhi Khimii
1 publication, 9.09%
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1
2
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Makhaeva G. F. et al. Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease // International Journal of Molecular Sciences. 2023. Vol. 24. No. 3. p. 2285.
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Makhaeva G. F., Kovaleva N. V., Rudakova E. V., Boltneva N. P., Grishchenko M. V., Lushchekina S., Astakhova T. Y., Serebryakova O. G., Timokhina E. N., Zhilina E. F., Shchegol’kov E., Ulitko M. V., Radchenko E. V., Palyulin V. A., Burgart Y. V., Saloutin V., Bachurin S. O., Richardson R. J. Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease // International Journal of Molecular Sciences. 2023. Vol. 24. No. 3. p. 2285.
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TY - JOUR
DO - 10.3390/ijms24032285
UR - https://doi.org/10.3390/ijms24032285
TI - Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease
T2 - International Journal of Molecular Sciences
AU - Makhaeva, G. F.
AU - Kovaleva, N. V.
AU - Rudakova, Elena V
AU - Boltneva, N. P.
AU - Grishchenko, Maria V
AU - Lushchekina, S.
AU - Astakhova, Tatiana Y.
AU - Serebryakova, Olga G
AU - Timokhina, Elena N
AU - Zhilina, Ekaterina F.
AU - Shchegol’kov, E.V.
AU - Ulitko, Mariya V
AU - Radchenko, Eugene V.
AU - Palyulin, V. A.
AU - Burgart, Yanina V.
AU - Saloutin, Victor
AU - Bachurin, S. O.
AU - Richardson, Rudy J.
PY - 2023
DA - 2023/01/24 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 2285
IS - 3
VL - 24
SN - 1661-6596
SN - 1422-0067
ER -
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@article{2023_Makhaeva,
author = {G. F. Makhaeva and N. V. Kovaleva and Elena V Rudakova and N. P. Boltneva and Maria V Grishchenko and S. Lushchekina and Tatiana Y. Astakhova and Olga G Serebryakova and Elena N Timokhina and Ekaterina F. Zhilina and E.V. Shchegol’kov and Mariya V Ulitko and Eugene V. Radchenko and V. A. Palyulin and Yanina V. Burgart and Victor Saloutin and S. O. Bachurin and Rudy J. Richardson},
title = {Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease},
journal = {International Journal of Molecular Sciences},
year = {2023},
volume = {24},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {jan},
url = {https://doi.org/10.3390/ijms24032285},
number = {3},
pages = {2285},
doi = {10.3390/ijms24032285}
}
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Makhaeva, G. F., et al. “Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease.” International Journal of Molecular Sciences, vol. 24, no. 3, Jan. 2023, p. 2285. https://doi.org/10.3390/ijms24032285.