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In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation
Author(s) -
Kloss Florian,
Krchnak Viktor,
Krchnakova Anna,
Schieferdecker Sebastian,
Dreisbach Julia,
Krone Volker,
Möllmann Ute,
Hoelscher Michael,
Miller Marvin J.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201609737
Subject(s) - in vivo , adme , chemistry , combinatorial chemistry , pharmacology , in vitro , computational biology , biochemistry , biology , microbiology and biotechnology
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.