Halogenation is an indispensable method in the structural modification of lead compounds. It is known to increase lipophilicity and is hence used to improve membrane permeability and thus bioavailability. In this study, we compare the water solubility (logS) of organohalogen compounds and their non-halogenated parent compounds using the molecular matched pair (MMP) analysis method. Unexpectedly, 19.9% of the compounds increased their water solubility upon halogenation. Iodination was observed to have the greatest effect on solubility, followed by chlorination, bromination, and fluorination. Introducing amino, hydroxyl and carboxyl groups into organohalogens improves their aqueous solubilities, whereas introducing a trifluoromethyl group has the opposite effect. According to our quantum chemical calculations, the increased water solubility upon halogenation is, at least partially, attributed to an increased polarity and polarizability. These results improve our understanding of the influence of halogenation on bioactivity.

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卤化对小有机化合物水溶性的意外影响

卤化是先导化合物结构修饰中不可缺少的方法。已知它可以增加亲脂性，因此用于改善膜渗透性，从而提高生物利用度。在本研究中，我们使用分子匹配对（MMP）分析方法比较了有机卤素化合物及其非卤化母体化合物的水溶性（logS）。出乎意料的是，19.9% 的化合物在卤化后水溶性增加。据观察，碘化对溶解度影响最大，其次是氯化、溴化和氟化。在有机卤素中引入氨基、羟基和羧基可以提高其水溶性，而引入三氟甲基则具有相反的效果。根据我们的量子化学计算，卤化后水溶性的增加至少部分归因于极性和极化率的增加。这些结果提高了我们对卤化对生物活性影响的理解。