Skin sensitization occurs when an exogenous chemical substance forms a covalent adduct with a dermal protein electrophile or nucleophile. This instigates an immune response which leads to inflammation. The local lymph node assay is an in vivo model used in the assessment of relative skin sensitizing potency of chemicals. The method is time consuming and expensive, as well as poses ethical questions given that a number of mice must be sacrificed for each compound assessed. In this work, we investigate the use of an inexpensive, rapid, and ethical method to predict the skin sensitization potential of Schiff base chemicals. We employ quantum chemical methods to rationalize the sensitization potential of 22 compounds with a diverse range of activities. To this end, we have evaluated the mechanistic profile associated with this type of reaction using gas‐phase models. We subsequently use the predicted rate determining barriers and key physico‐chemical parameters (such as logP) to establish stucture activity relationship (SAR) guidelines to predict the skin sensitization potential for new chemicals. We find that the predicted rate determining barriers for aldehydes, ketone, and 1,2 and 1,3 diones generally decrease in the given order, which concurs with the overall trends in sensitization. We find that lipophilicity also plays a role, with those chemicals displaying both low barriers to reaction, and lower lipophilicity (ie, diones), being more likely to display undesirable skin sensitization effects. These findings are in line with experiment‐based observations in the literature and point to the value 3D quantum chemical calculations could have if combined with other orthogonal approaches to estimate skin sensitization potential of chemicals.

中文翻译：

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理论研究估计席夫碱域化学物质的皮肤致敏潜力

当外源性化学物质与皮肤蛋白亲电试剂或亲核试剂形成共价加合物时，就会发生皮肤过敏。这激发了导致炎症的免疫反应。局部淋巴结测定法是一种体内模型，用于评估化学物质对皮肤的相对致敏能力。该方法既耗时又昂贵，并且由于必须为每种评估的化合物牺牲许多小鼠而提出了伦理问题。在这项工作中，我们调查了使用便宜，快速且符合道德的方法来预测席夫碱化学品的皮肤致敏性的可能性。我们采用量子化学方法来合理化具有多种活性的22种化合物的敏化潜能。为此，我们已经使用气相模型评估了与此类反应相关的机理。随后，我们使用预测的速率决定性障碍和关键的理化参数（例如logP）来建立结构活性关系（SAR）准则，以预测对新化学物质的皮肤增敏潜力。我们发现，醛，酮以及1,2和1,3二酮的预测速率决定性障碍通常会以给定顺序降低，这与致敏作用的总体趋势一致。我们发现亲脂性也起着作用，这些化学物质既显示出较低的反应障碍，又显示出较低的亲脂性（即二酮），更有可能表现出不良的皮肤致敏作用。