Recently, a new class of reactivators of chemical warfare agent inhibited acetylcholinesterase (AChE) with promising in vitro potential was developed by the covalent linkage of an oxime nucleophile and a peripheral site ligand. However, the complexity of these molecular structures thwarts their accessibility. We report the compatibility of various oxime-based compounds with the use of the Ugi multicomponent reaction in which four readily accessible building blocks are mixed together to form a product that links a reactivating unit and a potential peripheral site ligand. A small library of imidazole and imidazolium reactivators was successfully synthesized using this method. Some of these compounds showed a promising ability to reactivate AChE inhibited by various types of CWA in vitro. Molecular modeling was used to understand differences in reactivation potential between these compounds. Four compounds were evaluated in vivo using sarin-exposed rats. One of the reactivators showed improved in vivo efficacy compared to the current antidote pralidoxime (2-PAM).

中文翻译：

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Ugi多组分反应在神经药抑制乙酰胆碱酯酶活化剂合成中的应用

最近，通过肟亲核试剂与外围位点配体的共价键连接，开发了一种新型的化学战剂活化剂抑制乙酰胆碱酯酶（AChE），具有令人鼓舞的体外潜力。但是，这些分子结构的复杂性阻碍了它们的可及性。我们报告了各种基于肟的化合物与Ugi多组分反应的相容性，在该反应中，四个易于使用的结构单元混合在一起，形成了连接再活化单元和潜在的外围位点配体的产物。使用此方法成功合成了一个小的咪唑和咪唑活化剂库。这些化合物中的一些显示出在体外激活被各种类型的CWA抑制的AChE的有希望的能力。使用分子建模来了解这些化合物之间重新活化潜能的差异。使用暴露于沙林的大鼠体内评估了四种化合物。与目前的解毒剂普拉利肟（2-PAM）相比，其中一种活化剂显示出更高的体内功效。