In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
28097740
DOI
10.1002/anie.201609737
Knihovny.cz E-zdroje
- Klíčová slova
- DprE1 inhibitors, benzothiazinones, metabolite identification, prodrugs, transient metabolites,
- MeSH
- antituberkulotika krev chemie metabolismus MeSH
- chromatografie kapalinová MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- objevování léků MeSH
- oxidace-redukce MeSH
- piperaziny krev chemie metabolismus MeSH
- spirosloučeniny krev chemie MeSH
- tandemová hmotnostní spektrometrie MeSH
- thiaziny krev chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one MeSH Prohlížeč
- antituberkulotika MeSH
- macozinone MeSH Prohlížeč
- piperaziny MeSH
- spirosloučeniny MeSH
- thiaziny MeSH
Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.
Department of Chemistry and Biochemistry University of Notre Dame Notre Dame IN 46635 USA
German Center for Infection Research partner site Munich Germany
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