Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights

Shao Gang Li, Catherine Vilchèze, Sumit Chakraborty, Xin Wang, Hiyun Kim, Monica Anisetti, Sean Ekins, Kyu Y. Rhee, William R. Jacobs, Joel S. Freundlich

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The metabolic instability of an antitubercular small molecule CD117 was addressed through iterative alteration of a key sulfide substituent and interrogation of the effect on growth inhibition of cultured Mycobacterium tuberculosis. This process was informed by studies of the intramycobacterial metabolism of CD117 and its inactive carboxylic acid derivative. Isoxazole 4e and thiazole 4m demonstrated significant gains in mouse liver microsomal stability with slight losses in whole-cell activity. This work illustrates the challenges of antitubercular hit evolution, requiring a balance of chemical and biological insights.

Original languageEnglish (US)
Pages (from-to)3246-3250
Number of pages5
JournalTetrahedron Letters
Volume56
Issue number23
DOIs
StatePublished - May 25 2015

Keywords

  • Metabolomics
  • Prodrug
  • Thienopyrimidine
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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