Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl - Archive ouverte HAL Access content directly
Journal Articles Chemical Research in Toxicology Year : 2021

Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl

Abstract

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 SOxH 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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hal-03669331 , version 1 (16-05-2022)

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Tércio de Freitas Paulo, Carine Duhayon, Luiz Gonzaga de França Lopes, Eduardo Henrique Silva Sousa, Remi Chauvin, et al.. Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl. Chemical Research in Toxicology, 2021, 34 (8), pp.1879-1889. ⟨10.1021/acs.chemrestox.1c00164⟩. ⟨hal-03669331⟩
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