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Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease.

ABSTRACT: New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC₅₀ to 0.224 μM) and butyrylcholinesterase (BChE, IC₅₀ to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugates were mixed-type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE-induced β-amyloid aggregation. The new conjugates exhibited high ABTS^.+ -scavenging activity. N-(6-(1,2,3,4-Tetrahydroacridin-9-ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu²⁺ , Fe²⁺ and Zn²⁺ . Thus, the new conjugates have displayed the potential to be multifunctional anti-AD agents for further development.

SUBMITTER: Grishchenko MV

PROVIDER: S-EPMC9314152 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease.

Grishchenko Maria V MV Makhaeva Galina F GF Burgart Yanina V YV Rudakova Elena V EV Boltneva Natalia P NP Kovaleva Nadezhda V NV Serebryakova Olga G OG Lushchekina Sofya V SV Astakhova Tatiana Y TY Zhilina Ekaterina F EF Shchegolkov Evgeny V EV Richardson Rudy J RJ Saloutin Victor I VI

ChemMedChem 20220323 10

New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC<sub>50</sub> to 0.224 μM) and butyrylcholinesterase (BChE, IC<sub>50</sub> to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugate ...[more]

PMID: 35322571

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Project description: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.

Dataset Information

Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease.

Publications

Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease.

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