title: In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation.
abstract: 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.
authors.affiliation: Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany.|InfectControl 2020, Beutenbergstrasse 11a, 07745, Jena, Germany.
authors.forename: Florian
authors.identifier: 0000-0003-2283-1457
authors.initials: F
authors.lastname: Kloss
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46635, USA.|Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46, Olomouc, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Krchnak
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46635, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Krchnakova
authors.affiliation: Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany.|Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany.|InfectControl 2020, Beutenbergstrasse 11a, 07745, Jena, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schieferdecker
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Leopoldstrasse 5, 80802, Munich, Germany.|German Center for Infection Research (DZIF) partner site Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dreisbach
authors.affiliation: German Center for Infection Research (DZIF) partner site Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Krone
authors.affiliation: Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Leopoldstrasse 5, 80802, Munich, Germany.|German Center for Infection Research (DZIF) partner site Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46635, USA.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D002853:Chromatography, Liquid; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010879:Piperazines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D013141:Spiro Compounds / Q000097:blood / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D013843:Thiazines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D000995:Antitubercular Agents; D010879:Piperazines; D013141:Spiro Compounds; D013843:Thiazines; C000592783:macozinone
keywords: DprE1 inhibitors; benzothiazinones; metabolite identification; prodrugs; transient metabolites