Xin Wang1, Daigo Inoyama1, Riccardo Russo2, Shao-Gang Li1, Ravindra Jadhav1, Thomas P Stratton1, Nisha Mittal1, Joseph A Bilotta1, Eric Singleton2, Thomas Kim2, Steve D Paget1, Richard S Pottorf1, Yong-Mo Ahn1, Alejandro Davila-Pagan1, Srinivasan Kandasamy1, Courtney Grady2, Seema Hussain3, Patricia Soteropoulos3, Matthew D Zimmerman4, Hsin Pin Ho4, Steven Park4, Véronique Dartois4, Sean Ekins5, Nancy Connell2, Pradeep Kumar2, Joel S Freundlich6. 1. Department of Pharmacology, Physiology and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA. 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. 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. 4. Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA. 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: freundjs@rutgers.edu.
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.
The nclass="Chemical">triazine antituclass="Chemical">pan class="Chemical">bercular 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.
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