Despite its efficacy as a skin decontaminant of reactive organophosphates (OP), Dekon 139—a potassium salt of 2,3-butanedione monooxime (DAM)—is associated with adverse events related to percutaneous absorption largely due to its small size and lipophilicity. In order to address this physicochemical issue, we synthesized and evaluated the activity of a focused library of 14 hydrophilic oxime compounds, each designed with either a DAM or monoisonitrosoacetone (MINA) oxime tethered to a polar or charged scaffold in order to optimize the size, hydrophilicity, and oxime acidity. High-throughput colorimetric assays were performed with paraoxon (POX) as a model OP to determine the kinetics of POX inactivation by these compounds under various pH and temperature conditions. This primary screening led to the identification of 6 lead compounds, predominantly in the MINA series, which displayed superb catalytic activity by reducing the POX half-life (t_1/2) by 2–3 fold relative to Dekon 139. Our mechanistic studies show that POX inactivation by the oxime compounds occurred faster at a higher temperature and in a pH-dependent manner in which the negatively charged oximate species is ≥ 10–fold more effective than the neutral oxime species. Lastly, using one of the lead compounds, we demonstrated its promising efficacy for POX decontamination in porcine skin ex vivo, and showed its potent ability to protect acetylcholine esterase (AChE) through POX inactivation. In summary, we report the rational design and chemical biological validation of novel hydrophilic oximes which address an unmet need in therapeutic OP decontamination.

尽管Dekon 139（2,3-丁二酮一肟（DAM）的钾盐）可作为皮肤活性有机磷酸盐（OP）的去污剂，但由于其体积小和亲脂性，与经皮吸收相关的不良事件相关。为了解决这个物理化学问题，我们合成并评估了14种亲水性肟化合物的聚焦文库的活性，每种化合物都设计了DAM或单异亚硝基丙酮（MINA）肟，束缚在极性或带电的支架上，以优化尺寸，亲水性和肟酸度。使用对氧磷（POX）作为模型OP进行高通量比色测定，以确定这些化合物在各种pH和温度条件下POX失活的动力学。初步筛选确定了6种先导化合物，相对于Dekon 139，t _1/2）降低了2-3倍。我们的机理研究表明，肟化合物对POX的灭活在较高的温度下以及pH依赖的方式下发生的速度更快，其中带负电荷的肟酸种类≥10–倍数比中性肟更有效。最后，使用一种先导化合物，我们证明了其对猪皮肤离体POX净化的有前途的功效，并显示了通过POX灭活保护乙酰胆碱酯酶（AChE）的强大能力。总而言之，我们报告了新型亲水性肟的合理设计和化学生物学验证，这些亲水性肟解决了OP净化性治疗中未满足的需求。