Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl
| Autor: | Eduardo H.S. Sousa, Luiz Gonzaga de França Lopes, Vania Bernardes-Génisson, Remi Chauvin, Tércio de F. Paulo, Carine Duhayon |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Models Molecular Stereochemistry Antitubercular Agents General Medicine Hydrogen Peroxide Prodrug Sulfinic acid Toxicology Phenylthiourea Tautomer chemistry.chemical_compound chemistry Nucleophile Electrophile Reactivity (chemistry) Sulfenic acid Prodrugs Ethionamide Oxidation-Reduction Thioacetazone Carbodiimide |
| Zdroj: | Chemical research in toxicology. 34(8) |
| ISSN: | 1520-5010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|