Antitubercular Triazines: Optimization and Intrabacterial Metabolism

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. 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.