Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation,RSC Medicinal Chemistry

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Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-04 , DOI: 10.1039/d1md00194a
Jayme Cannon _{1,

2} , Shengzhuang Tang _{1,

2} , Kelly Yang ₁ , Racquel Harrison ₁ , Seok Ki Choi _{1,

2}

Affiliation

A conventional approach in the therapeutic decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of α-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each composed of an OP-reactive oxime core linked to an amine-terminated scaffold, which varied through an N-alkyl functionalization. This library was screened by enzyme assays performed with human and electric eel subtypes of OP-inactivated AChE, which led to identifying three oxime leads that displayed significant enhancements in reactivation activity comparable to 2-PAM. They were able to reactivate both enzymes inactivated by three OP types including paraoxon, chlorpyrifos and malaoxon, suggesting their broad spectrum of OP susceptibility. All compounds in the library were able to retain catalytic reactivity in paraoxon inactivation by rates increased up to 5 or 8-fold relative to diacetylmonoxime (DAM) under controlled conditions at pH (8.0, 10.5) and temperature (17, 37 °C). Finally, selected lead compounds displayed superb efficacy in paraoxon decontamination on porcine skin in vitro. In summary, we addressed an unmet need in therapeutic OP decontamination by designing and validating a series of congeneric oximes that display dual modes of action.

中文翻译：

双效肟设计用于通过催化失活和乙酰胆碱酯酶再激活对反应性有机磷酸盐进行治疗性去污

活性有机磷酸盐 (OP) 的治疗性去污的常规方法依赖于肟化合物对 OP 的化学降解。然而，由于它们在乙酰胆碱酯酶 (AChE)（OP 的主要靶标）的再激活中缺乏活性，因此它们的功效受到限制。在这里，我们描述了一组新发现的具有这种双重作用模式的 α-亲核试剂肟衍生物。因此，我们准备了一个 9 成员肟库，每个都由一个 OP 反应性肟核心组成，该核心连接到一个胺端支架，其通过N-烷基官能化。该文库通过对人类和电鳗 OP 灭活的 AChE 亚型进行的酶测定进行筛选，这导致鉴定出与 2-PAM 相当的再激活活性显着增强的三种肟先导。他们能够重新激活被三种 OP 类型（包括对氧磷、毒死蜱和 malaoxon）灭活的两种酶，这表明它们具有广谱的 OP 敏感性。文库中的所有化合物都能够在对氧磷失活中保持催化反应性，在受控条件下，在 pH 值（8.0、10.5）和温度（17、37°C）下，相对于二乙酰单肟 (DAM) 的速率增加了 5 或 8 倍。最后，选定的先导化合物在体外对猪皮肤的对氧磷净化中表现出极好的功效. 总之，我们通过设计和验证一系列显示双重作用模式的同源肟，解决了治疗性 OP 净化中未满足的需求。

更新日期：2021-08-16

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