Conjugates of nucleobases with triazole-hydroxamic acids for the reactivation of acetylcholinesterase and treatment of delayed neurodegeneration induced by organophosphate poisoning.
Bioorg Chem
; 141: 106858, 2023 12.
Article
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| MEDLINE
| ID: mdl-37774432
ABSTRACT
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.
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Banco de datos:
MEDLINE
Asunto principal:
Reactivadores de la Colinesterasa
/
Intoxicación por Organofosfatos
Límite:
Animals
Idioma:
En
Año:
2023
Tipo del documento:
Article