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

التفاصيل البيبلوغرافية
العنوان: Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl.
المؤلفون: de Freitas Paulo T; CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205 Route de Narbonne, BP 44099, F-31077 Toulouse, Cedex 4, France.; Université de Toulouse, Université Paul Sabatier, UPS, 118 Route de Narbonne, F-31062 Toulouse, Cedex 9, France.; Laboratory of Bioinorganic, Department of Organic and Inorganic Chemistry Federal University of Ceará, Fortaleza, Ceará 60455-760, Brazil., Duhayon C; CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205 Route de Narbonne, BP 44099, F-31077 Toulouse, Cedex 4, France.; Université de Toulouse, Université Paul Sabatier, UPS, 118 Route de Narbonne, F-31062 Toulouse, Cedex 9, France., de França Lopes LG; Laboratory of Bioinorganic, Department of Organic and Inorganic Chemistry Federal University of Ceará, Fortaleza, Ceará 60455-760, Brazil., Silva Sousa EH; Laboratory of Bioinorganic, Department of Organic and Inorganic Chemistry Federal University of Ceará, Fortaleza, Ceará 60455-760, Brazil., Chauvin R; CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205 Route de Narbonne, BP 44099, F-31077 Toulouse, Cedex 4, France.; Université de Toulouse, Université Paul Sabatier, UPS, 118 Route de Narbonne, F-31062 Toulouse, Cedex 9, France., Bernardes-Génisson V; CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205 Route de Narbonne, BP 44099, F-31077 Toulouse, Cedex 4, France.; Université de Toulouse, Université Paul Sabatier, UPS, 118 Route de Narbonne, F-31062 Toulouse, Cedex 9, France.
المصدر: Chemical research in toxicology [Chem Res Toxicol] 2021 Aug 16; Vol. 34 (8), pp. 1879-1889. Date of Electronic Publication: 2021 Jul 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: Washington, DC : American Chemical Society, c1988-
مواضيع طبية MeSH: Antitubercular Agents/*metabolism , Ethionamide/*metabolism , Phenylthiourea/*analogs & derivatives , Prodrugs/*metabolism , Thioacetazone/*metabolism, Antitubercular Agents/chemistry ; Ethionamide/chemistry ; Hydrogen Peroxide/metabolism ; Models, Molecular ; Oxidation-Reduction ; Phenylthiourea/chemistry ; Phenylthiourea/metabolism ; Prodrugs/chemistry ; Thioacetazone/chemistry
مستخلص: A chemical activation study of the thiocarbonyl-type antitubercular prodrugs, ethionamide (ETH), thioacetazone (TAZ), and isoxyl (ISO), was performed. Biomimetic oxidation of ethionamide using H 2 O 2 (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-SO 2 H) 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-SO 2 H), which can then lose a SO x H 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-SO 2 H, and the carbodiimide compound can also react with NH 2 -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.
المشرفين على المادة: 0 (Antitubercular Agents)
0 (Prodrugs)
43M23X81Y2 (thiocarlide)
6F82C6Q54C (Phenylthiourea)
BBX060AN9V (Hydrogen Peroxide)
MMG78X7SSR (Thioacetazone)
OAY8ORS3CQ (Ethionamide)
تواريخ الأحداث: Date Created: 20210728 Date Completed: 20211223 Latest Revision: 20211223
رمز التحديث: 20231215
DOI: 10.1021/acs.chemrestox.1c00164
PMID: 34319702
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-5010
DOI:10.1021/acs.chemrestox.1c00164