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

• Published in: Bioorganic chemistry 2023-12, Vol.141, p.106858-106858, Article 106858
• Main Authors: Shulaeva, Marina M., Zueva, Irina V., Nikolaev, Anton E., Saifina, Liliya F., Sharafutdinova, Dilyara R., Babaev, Vasily M., Semenov, Vyacheslav E., Petrov, Konstantin A.
• Format: Article
• Language: English
• Subjects: 1,6-dimethyluracil; 3,6-dimethyluracil; Acetylcholinesterase; Adenine; Molecular modeling; Organophosphate poisoning; Paraoxon; Reactivator; Triazole-hydroxamic acids
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106858

[Display omitted] •Synthesis of conjugates of adenine and uracil derivatives with triazole-hydroxamic acids moieties as uncharged reactivators of organophosphate-inhibited cholinesterases.•Development of acetylcholinesterase reactivators with improved blood–brain barrier permeability.•Interest as a treatment for delayed organophosphate neurotoxicity. 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.