TY - JOUR

T1 - Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

AU - Makhaeva, Galina F.

AU - Kovaleva, Nadezhda V.

AU - Rudakova, Elena V.

AU - Boltneva, Natalia P.

AU - Grishchenko, Maria V.

AU - Lushchekina, Sofya V.

AU - Astakhova, Tatiana Y.

AU - Serebryakova, Olga G.

AU - Timokhina, Elena N.

AU - Zhilina, Ekaterina F.

AU - Shchegolkov, Evgeny V.

AU - Ulitko, Mariya V.

AU - Radchenko, Eugene V.

AU - Palyulin, Vladimir A.

AU - Burgart, Yanina V.

AU - Saloutin, Victor I.

AU - Bachurin, Sergey O.

AU - Richardson, Rudy J.

N1 - 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.

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

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UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=tsmetrics&SrcApp=tsm_test&DestApp=WOS_CPL&DestLinkType=FullRecord&KeyUT=000935706300001

U2 - 10.3390/ijms24032285

DO - 10.3390/ijms24032285

M3 - Article

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 3

M1 - 2285

ER -