Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Molecules. 2018 Sep 7;23(9):2291. doi: 10.3390/molecules23092291.
The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (AChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial AChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate AChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited AChE. The SAR features concerning the heteroarenium part of the reactivator's molecule are described.
乙酰胆碱酯酶（AChE）重激活剂（如，肟碘解磷定、苯甲羟肟酸）已成为有机磷（OP）中毒治疗的重要组成部分，与阿托品和地西泮一起使用。它们被称为 OP 中毒的因果治疗，因为它们能够将 OP 部分从 AChE 活性位点中分离出来，从而恢复其功能。在这种方法中，确定了十五种新型 AChE 重激活剂。它们的分子设计源自以前的 K-肟化合物 K048 和 K074，保留了分子的肟部分和带有杂芳族部分的修饰部分。合成了新型化合物，并在体外评估了对沙林、对氧磷、甲基对氧磷或敌敌畏抑制的人 AChE（AChE）的作用，并与商业 AChE 重激活剂（氯解磷定、羟肟酸、托品烷三醇肟、碘解磷定、苯甲羟肟酸）或以前制备的化合物（K048、K074、K075、K203）进行了比较。一些呈现出的肟重激活剂显示出具有与使用的标准相当或更高的重新激活 AChE 的能力。进行了分子建模研究，其中一个化合物具有重新激活 GA 抑制的 AChE 的能力。描述了与重激活剂分子的杂芳族部分相关的 SAR 特征。
