Affordable Access

deepdyve-link
Publisher Website

Antitubercular Triazines: Optimization and Intrabacterial Metabolism.

Authors
  • Wang, Xin1
  • Inoyama, Daigo1
  • Russo, Riccardo2
  • Li, Shao-Gang1
  • Jadhav, Ravindra1
  • Stratton, Thomas P1
  • Mittal, Nisha1
  • Bilotta, Joseph A1
  • Singleton, Eric2
  • Kim, Thomas2
  • Paget, Steve D1
  • Pottorf, Richard S1
  • Ahn, Yong-Mo1
  • Davila-Pagan, Alejandro1
  • Kandasamy, Srinivasan1
  • Grady, Courtney2
  • Hussain, Seema3
  • Soteropoulos, Patricia3
  • Zimmerman, Matthew D4
  • Ho, Hsin Pin4
  • And 6 more
  • 1 Department of Pharmacology, Physiology and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA. , (Jersey)
  • 2 Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA. , (Jersey)
  • 3 Genomics Center, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA; Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA. , (Jersey)
  • 4 Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA. , (Jersey)
  • 5 Collaborations in Chemistry Inc., Raleigh, NC 27606, USA.
  • 6 Department of Pharmacology, Physiology and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA; Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: [email protected] , (Jersey)
Type
Published Article
Journal
Cell chemical biology
Publication Date
Feb 20, 2020
Volume
27
Issue
2
Identifiers
DOI: 10.1016/j.chembiol.2019.10.010
PMID: 31711854
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO⋅ release and InhA inhibition. Copyright © 2019 Elsevier Ltd. All rights reserved.

Report this publication

Statistics

Seen <100 times