Conjugates of nucleobases with triazole-hydroxamic acids for the reactivation of acetylcholinesterase and treatment of delayed neurodegeneration induced by organophosphate poisoning.

Autor: Shulaeva MM; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Zueva IV; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Nikolaev AE; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Saifina LF; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Sharafutdinova DR; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Babaev VM; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation., Semenov VE; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation. Electronic address: sve@iopc.ru., Petrov KA; Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center 'Kazan Scientific Center of the Russian Academy of Sciences', Arbuzov str., 8, Kazan 420088, Russian Federation; Kazan Federal University, Kremlyovskaya str., 18, Kazan 420008, Russian Federation.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Dec; Vol. 141, pp. 106858. Date of Electronic Publication: 2023 Sep 15.
DOI: 10.1016/j.bioorg.2023.106858
Abstrakt: A series of new uncharged conjugates of adenine, 3,6-dimetyl-, 1,6-dimethyl- and 6-methyluracil with 1,2,4-triazole-3-hydroxamic and 1,2,3-triazole-4-hydroxamic acid moieties were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. It is shown that triazole-hydroxamic acids can reactivate acetylcholinesterase (AChE) inhibited by paraoxon (POX) in vitro, offering reactivation constants comparable to those of pralidoxime (2-PAM). However, in contrast to 2-PAM, triazole-hydroxamic acids demonstrated the ability to reactivate AChE in the brain of rats poisoned with POX. At a dose of 200 mg/kg (i.v.), the lead compound 3e reactivated 22.6 ± 7.3% of brain AChE in rats poisoned with POX. In a rat model of POX-induced delayed neurodegeneration, compound 3e reduced the neuronal injury labeled with FJB upon double administration 1 and 3 h after poisoning. Compound 3e was also shown to prevent memory impairment of POX-poisoned rats as tested in a Morris water maze.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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