Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers
Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers
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DOI：
10.1039/c9ob00503j
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发表时间：
2019-04-28
影响因子：
3.2
通讯作者：
Choi, Seok Ki
中科院分区：
文献类型：
--
作者：
Wong, Pamela T.;Bhattacharjee, Somnath;Choi, Seok Ki
尽管其结构和反应性赋予了它们独特的优点，但某些 α-亲核分子作为化学灭活剂用于反应性有机磷酸酯 (OP) 的局部去污仍未得到充分探索。在这里，我们提出了一个由三十个α-亲核体支架组成的库，每个支架都设计有吡啶醛肟（PAM）或异羟肟酸（HA）α-亲核体核心，与极性或带电支架相连，以优化物理化学性质和反应性。在动力学测定中筛选这些库化合物催化模型 OP、对氧磷 (POX) 水解的能力。这些筛选实验确定了多种先导化合物，其灭活 POX 的速度比目前用于 OP 皮肤净化的活性成分 Dekon 139 快两到四倍。我们在可变 pH 和温度条件下进行的机理研究表明，这些化合物的反应性和活化能的差异从根本上归因于核心亲核性和 pK(a)。经过筛选和机理研究，对选定的先导化合物进行了进一步评估，并证明在离体猪皮肤模型中局部净化 POX 方面比 Dekon 139 更有效。除了 OP 反应性之外，PAM 类中的几种化合物还表现出双重活性模式，因为它们保留了重新激活 POX 抑制的乙酰胆碱酯酶 (AChE) 的能力。总之，本报告描述了 α-亲核试剂的亲水支架设计的基本原理，并提供了对其化学反应性、机制和作为 OP 去污剂的实际用途的深入见解。
Despite their unique benefits imparted by their structure and reactivity, certain alpha-nucleophile molecules remain underexplored as chemical inactivators for the topical decontamination of reactive organophosphates (OPs). Here, we present a library of thirty alpha-nucleophile scaffolds, each designed with either a pyridinium aldoxime (PAM) or hydroxamic acid (HA) alpha-nucleophile core tethered to a polar or charged scaffold for optimized physicochemical properties and reactivity. These library compounds were screened for their abilities to catalyze the hydrolysis of a model OP, paraoxon (POX), in kinetic assays. These screening experiments led to the identification of multiple lead compounds with the ability to inactivate POX two-to four-times more rapidly than Dekon 139-the active ingredient currently used for skin decontamination of OPs. Our mechanistic studies, performed under variable pH and temperature conditions suggested that the differences in the reactivity and activation energy of these compounds are fundamentally attributable to the core nucleophilicity and pK(a). Following their screening and mechanistic studies, select lead compounds were further evaluated and demonstrated greater efficacy than Dekon 139 in the topical decontamination of POX in an ex vivo porcine skin model. In addition to OP reactivity, several compounds in the PAM class displayed a dual mode of activity, as they retained the ability to reactivate POX-inhibited acetylcholine esterase (AChE). In summary, this report describes a rationale for the hydrophilic scaffold design of alpha-nucleophiles, and it offers advanced insights into their chemical reactivity, mechanism, and practical utility as OP decontaminants.