A chemical activation study of the thiocarbonyl-type antitubercular prodrugs, ethionamide (ETH), thioacetazone (TAZ), and isoxyl (ISO), was performed. Biomimetic oxidation of ethionamide using H₂O₂ (1 equiv) led to ETH–SO as the only stable S-oxide compound, which was found to occur in solution in the preferential form of a sulfine (ETH═S═O vs the sulfenic acid tautomer ETH–S–OH), as previously observed in the crystal state. It was also demonstrated that ETH–SO is capable of reacting with amines, as the putative sulfinic derivative (ETH–SO₂H) was supposed to do. Unlike ETH, oxidation of TAZ did not allow observation of the mono-oxygenated species (TAZ–SO), leading directly to the more stable sulfinic acid derivative (TAZ–SO₂H), which can then lose a SO_xH group after further oxidation or when placed in a basic medium. It was also noticed that the unstable TAZ–SO intermediate can lead to the carbodiimide derivative as another electrophilic species. It is suggested that TAZ–SOH, TAZ–SO₂H, and the carbodiimide compound can also react with NH₂-containing nucleophilic species, and therefore be involved in toxic effects. Finally, ISO showed a very complex reactivity, here assigned to the coexistence of two mono-oxygenated structures, the sulfine and sulfenic acid tautomers. The mono- and dioxygenated derivatives of ISO are also highly unstable, leading to a panel of multiple metabolites, which are still reactive and likely contribute to the toxicity of this prodrug.

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进一步深入了解硫羰基型抗结核前药的氧化途径：乙硫异烟胺、硫乙酰酮和异氧基

对硫代羰基型抗结核前药乙硫异烟胺 (ETH)、硫代乙酰腙 (TAZ) 和异氧基 (ISO) 进行了化学活化研究。使用 H ₂ O ₂ (1 equiv)仿生氧化乙硫异烟胺导致 ETH-SO 作为唯一稳定的S-氧化物化合物，发现它以亚磺酸的优先形式出现在溶液中（ETH=S=O vs酸互变异构体 ETH-S-OH)，如先前在晶体状态中观察到的。还证明 ETH-SO 能够与胺反应，正如假定的亚磺酸衍生物 (ETH-SO ₂ H) 应该做的那样。与 ETH 不同，TAZ 的氧化不允许观察单氧化物质 (TAZ-SO)，直接导致更稳定的亚磺酸衍生物 (TAZ-SO)₂ H)，在进一步氧化后或置于碱性介质中时，会失去 SO _x H 基团。还注意到不稳定的 TAZ-SO 中间体会导致碳二亚胺衍生物作为另一种亲电物质。表明 TAZ-SOH、TAZ-SO ₂ H 和碳二亚胺化合物也可以与含NH ₂的亲核物质反应，因此参与毒性作用。最后，ISO 表现出非常复杂的反应性，这里归因于两种单氧化结构的共存，即亚磺酸和亚磺酸互变异构体。ISO 的单加氧和双加氧衍生物也非常不稳定，导致产生一组多种代谢物，这些代谢物仍然具有反应性并可能导致该前药的毒性。