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Antitubercular Triazines: Optimization and Intrabacterial Metabolism.
- Source :
-
Cell Chemical Biology . Feb2020, Vol. 27 Issue 2, p172-172. 1p. - Publication Year :
- 2020
-
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 F 420 H 2 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. • Optimization of an antitubercular agent afforded gains in solubility and plasma PK • The triazines release intrabacterial NO⋅ as the predominant mechanism of action • The triazines/their intrabacterial metabolites also inhibit InhA and FAS-II pathway Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO⋅ release and inhibition of the cell wall biosynthesis enzyme InhA. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 24519456
- Volume :
- 27
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cell Chemical Biology
- Publication Type :
- Academic Journal
- Accession number :
- 141755122
- Full Text :
- https://doi.org/10.1016/j.chembiol.2019.10.010