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Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease
Author(s) -
Grishchenko Maria V.,
Makhaeva Galina F.,
Burgart Yanina V.,
Rudakova Elena V.,
Boltneva Natalia P.,
Kovaleva Nadezhda V.,
Serebryakova Olga G.,
Lushchekina Sofya V.,
Astakhova Tatiana Y.,
Zhilina Ekaterina F.,
Shchegolkov Evgeny V.,
Richardson Rudy J.,
Saloutin Victor I.
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200080
Subject(s) - tacrine , butyrylcholinesterase , chemistry , acetylcholinesterase , salicylamide , pharmacology , lead compound , docking (animal) , ic50 , aché , stereochemistry , biochemistry , in vitro , enzyme , organic chemistry , medicine , nursing
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 50 to 0.224 μM) and butyrylcholinesterase (BChE, IC 50 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 Cu 2+ , Fe 2+ and Zn 2+ . Thus, the new conjugates have displayed the potential to be multifunctional anti‐AD agents for further development.