Kinetic study and structural elucidation of the main ketoconazole metabolite
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2020
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Ketoconazole (KTZ) is a commonly used drug worldwide for both skin and systemic treatment of mycotic infections. A major concern regarding the oral use of this drug is the possibility of severe hepatotoxicity caused mainly by its major metabolite, namely, N-deacetyl-KTZ (DAK), which is also found as a KTZ impurity. Based on the toxicological relevance of DAK, here we assessed the time-dependent KTZ concentration in pH 2 and 37 °C by quantitative 1H nuclear magnetic resonance (NMR) with high specificity and sensitivity, and obtained for the first time a crystal form of DAK, as a dihydrochloride salt. The overall conformation of DAK resembles that found in the crystal structure of racemic KTZ and of its pure 2S,4R-enantiomer. The molecules are line-shaped, with the imidazole ring laid back on itself due to an intramolecular CH … π interaction between one methylene group and the imidazole ring. Centrossymetric dimers made up of two DAKH2Cl2 units held together by four classical NH⋯Cl-hydrogen bonds build the three-dimensional network. Besides such structural knowledge, its crystal structure provides an analytical pattern in the solid state for this relevant toxic metabolite and impurity from KTZ.
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Antifungal, Nuclear magnetic resonance, Crystal structure, Conformation, Crystal packing, Kinetics
Citação
SOUZA, Patricia da Cruz; WILHEMS, Renan Ziemann; QUEIROZ JÚNIOR, Luiz Henrique Keng; MARTINS, Felipe Terra. Kinetic study and structural elucidation of the main ketoconazole metabolite. Journal of Molecular Structure, Amsterdam, v. 1220, e128737, 2020. DOI: 10.1016/j.molstruc.2020.128737. Disponível em: https://www.sciencedirect.com/science/article/abs/pii/S0022286020310620?via%3Dihub. Acesso em: 20 nov. 2023.