Cytochrome P450-Mediated Metabolism of Antimycobacterial N α-Aroyl- N-aryl-phenylalanine Amides

  • ACS Infect Dis. 2026 Jun 12;12(6):1992-2003. doi: 10.1021/acsinfecdis.6c00100.
Johannes Doering  1 ,  Erik Meerz  1 ,  Rüdiger W Seidel  1 ,  Markus Lang  1 ,  Andreas M Kany  2  3 ,  Seppo Auriola  4 ,  Risto Olavi Juvonen  4 ,  Hannu Raunio  4 ,  Richard Goddard  5 ,  Matthew D Zimmerman  6 ,  Véronique Dartois  6  7 ,  Anna K H Hirsch  2  3  8 ,  Thomas Dick  6  7  9 ,  Adrian Richter  1
Affiliations
  • 1. Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
  • 2. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123 Saarbrücken, Germany.
  • 3. PharmaScienceHub, Campus Building A2.3, 66123 Saarbrücken, Germany.
  • 4. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Box 1627, Kuopio FI-70211, Finland.
  • 5. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
  • 6. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110,United States.
  • 7. Hackensack Meridian School of Medicine, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
  • 8. Department of Pharmacy, Saarland University, Campus Building E8.1, 66123 Saarbrücken, Germany.
  • 9. Department of Microbiology and Immunology, Georgetown University, Washington D.C. 20057,United States.
PMID: 42227659 DOI: 10.1021/acsinfecdis.6c00100
Abstract

Nα-Aroyl-N-aryl-phenylalanine amides (AAPs) are a class of antimycobacterial substances that inhibit the RNA polymerase and are effective against various pathogenic and opportunistic mycobacteria, including Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium. Further development of these promising compounds, however, has been hindered by their low microsomal stability, leading to insufficient bioavailability. The present study investigates the mechanism by which microsomal Enzymes metabolically degrade AAPs and identifies the resulting metabolites using LC-MS/MS. Rapid oxidation of the ortho-phenylenediamine structure, present in various substances in this class, plays a key role in this process. Additionally, we demonstrated in vitro and in vivo that Cytochrome P450 enzyme inhibitors significantly slow the degradation of AAPs. Identification of metabolites will inform further chemical modification of AAPs to achieve metabolic stability.

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