Novel pyrimidines as antitubercular agents

Daigo Inoyama, Steven D. Paget, Riccardo Russo, Srinivasan Kandasamy, Pradeep Kumar, Eric Singleton, James Occi, Margareta Tuckman, Matthew D. Zimmerman, Hsin Pin Ho, Alexander L. Perryman, Véronique Dartois, Nancy Connell, Joel S. Freundlicha

Research output: Contribution to journalArticle

Abstract

Mycobacterium tuberculosis 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 in vitro activity, in vitro 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.

Original languageEnglish (US)
Article numbere02063-1
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

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Keywords

  • Antitubercular
  • Mycobacterium tuberculosis
  • Pharmacokinetics
  • Pyrimidine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Inoyama, D., Paget, S. D., Russo, R., Kandasamy, S., Kumar, P., Singleton, E., Occi, J., Tuckman, M., Zimmerman, M. D., Ho, H. P., Perryman, A. L., Dartois, V., Connell, N., & Freundlicha, J. S. (2018). Novel pyrimidines as antitubercular agents. Antimicrobial agents and chemotherapy, 62(3), [e02063-1]. https://doi.org/10.1128/AAC.02063-17