Highlights d Optimization of an antitubercular agent afforded gains in solubility and plasma PK d The triazines release intrabacterial NO , as the predominant mechanism of action d The triazines/their intrabacterial metabolites also inhibit InhA and FAS-II pathway

infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their activity, cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.

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Serine/threonine protein kinases play a major role in peptidoglycan biosynthesis in Mycobacterium tuberculosis. To explore the mechanism in detail, in the present study, we have constructed a double knockout (DKO) strain lacking pknI and dacB2 in M. tuberculosis. Initially, we analyzed the colony morphology and found that the DKO strain showed smoother colony morphology on solid agar and irregular shape in transmission electron microscopy. In addition, the DKO strain exhibits defective biofilm and cord formation. The DKO strain was found to be hypersensitive to cell wall damaging agents such as lysozyme, malachite green, ethidium bromide and to isoniazid, a first line anti-TB drug. In conclusion, our data suggest that both pknI and dacB2 play an important role in the maintenance of colony morphology, cell wall permeability and integrity of M. tuberculosis.