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.
Angew Chem Int Ed Engl. 2017 Feb 13;56(8):2187-2191. doi: 10.1002/anie.201609737. Epub 2017 Jan 18.
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.
硝噻嗪酮类化合物是最有效的抗结核药物之一。本文首次报道了一个体内还原过程，可得到临床候选药物 BTZ043 和 PBTZ169 的 Meisenheimer 配合物。该还原是可逆的，在所有研究的哺乳动物物种中均发生，对体内 ADME 特征有深远影响，并对临床研究的设计和实施具有重要意义。通过化学研究证实了这种还原，这些化学研究使 Meisenheimer 配合物及其后续化学的完全表征成为可能。将体内和化学研究与 LC-MS 表征和测定方法的开发相结合，也为这一非常有前途的抗结核药物类别的合理先导优化提供了基础。
