Novel Pyrimidines as Antitubercular Agents.

Antimicrobial agents and chemotherapy, Volume: 62, Issue: 3
March 23, 2018
Daigo Inoyama D, Steven D Paget SD, Riccardo Russo R, Srinivasan Kandasamy S, Pradeep Kumar P, Eric Singleton E, James Occi J, Margareta Tuckman M, Matthew D Zimmerman MD, Hsin Pin Ho HP, Alexander L Perryman AL, VĂ©ronique Dartois V, Nancy Connell N, Joel S Freundlich JS

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.