2. Academic Validation
  3. Whole cell hydride Meisenheimer complex biotransformation guided optimization of antimycobacterial benzothiazinones

Whole cell hydride Meisenheimer complex biotransformation guided optimization of antimycobacterial benzothiazinones

  • Eur J Med Chem. 2024 Jan 15:264:116023. doi: 10.1016/j.ejmech.2023.116023.
Melanie Joch 1,  K Philip Wojtas 1,  Héctor Torres-Gómez 1,  Yan Li 1,  Florian Meyer 1,  Maria Straßburger 1,  Valerie Kerndl 1,  Hans-Martin Dahse 2,  Christian Hertweck 3,  Harald Hoffmann 4,  Helmar Görls 5,  Kerstin Walter 6,  Christoph Hölscher 6,  Florian Kloss 7
Affiliations

Affiliations

  • 1 Transfer Group Anti-infectives, Leibniz Institute for Natural Products Research and Infection Biology, Leibniz-HKI, Beutenbergstr. 11a., 07745, Jena, Germany.
  • 2 Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Leibniz-HKI, Beutenbergstr. 11a, 07745, Jena, Germany.
  • 3 Biomolecular Chemistry, Leibniz Institute for Natural Products Research and Infection Biology, Leibniz-HKI, Beutenbergstr. 11a, 07745, Jena, Germany; Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University Jena, 07743, Jena, Germany.
  • 4 Institute of Microbiology and Laboratory Medicine, IMLred GmbH, Robert-Koch-Allee 2, 82131, Gauting, Germany; SYNLAB Gauting, SYNLAB MVZ Dachau GmbH, Robert-Koch-Allee 2, 82131, Gauting, Germany.
  • 5 Institute of Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 8, 07743, Jena, Germany.
  • 6 Infection Immunology, Leibniz Lung Center, Research Center Borstel, Parkallee 1-40, 23845, Borstel, Germany; German Center for Infection Research (DZIF), Innenhofstrasse 7, 38124, Braunschweig, Germany.
  • 7 Transfer Group Anti-infectives, Leibniz Institute for Natural Products Research and Infection Biology, Leibniz-HKI, Beutenbergstr. 11a., 07745, Jena, Germany. Electronic address: [email protected].
PMID: 38071794 DOI: 10.1016/j.ejmech.2023.116023
Abstract

Nitrobenzothiazinones (BTZs) are potent active substances against Mycobacterium tuberculosis with currently two investigational drugs in clinical development for the treatment of tuberculosis. BTZs are the first examples for which a metabolic pathway towards transient hydride Meisenheimer complexes (HMC) has been shown in mammals, including humans. In this study, lead optimization efforts on BTZs are guided by the systematic evaluation of the HMC formation propensity combined with multiparameter assessment. For this purpose, a novel cell-based assay was specifically developed and fully implemented, and a library of 5- and 7-substituted BTZs was prepared to study substituent effects on the HMC formation. The multiparameter optimization revealed 5-methylated BTZs as the most preferred scaffolds, demonstrating a reduced HMC formation propensity combined with potent activity and good microsomal stability in vitro. In vivo experiments showed good systemic exposure upon oral administration and efficacy in a murine M. tuberculosis Infection model. This study reports a qualified in vitro HMC assay, which not only enabled the selection of next-generation BTZs with improved pharmacokinetic properties but also allowed forecasting their in vivo metabolism.

Figures
Products