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.
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.
Bioorg Chem. 2023 Dec;141:106858. doi: 10.1016/j.bioorg.2023.106858. Epub 2023 Sep 15.
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.
一系列新型的腺嘌呤、3,6-二甲基-、1,6-二甲基尿嘧啶与 1,2,4-三唑-3-羟肟酸和 1,2,3-三唑-4-羟肟酸的无电荷缀合物被合成并研究为有机磷抑制的胆碱酯酶的重活化剂。结果表明，三唑-羟肟酸能够体外重激活被对氧磷（POX）抑制的乙酰胆碱酯酶（AChE），提供与氯解磷定（2-PAM）相当的重激活常数。然而，与 2-PAM 相反，三唑-羟肟酸表现出在被 POX 中毒的大鼠脑中重激活 AChE 的能力。在 200mg/kg（iv.）的剂量下，先导化合物 3e 在被 POX 中毒的大鼠中重激活了 22.6±7.3%的脑 AChE。在 POX 诱导的迟发性神经退行性变的大鼠模型中，化合物 3e 在双重给药后 1 和 3 小时后，用 FJB 标记神经元损伤减少。研究还表明，化合物 3e 能够预防 POX 中毒大鼠的记忆障碍，如在 Morris 水迷宫中测试所示。
