Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights. Issue 23 (3rd June 2015)

• Record Type: Journal Article
• Authors: Li, Shao-Gang; Vilchèze, Catherine; Chakraborty, Sumit; Wang, Xin; Kim, Hiyun; Anisetti, Monica; Ekins, Sean; Rhee, Kyu Y.; Jacobs, William R.; Freundlich, Joel S.
• Is Part Of: Tetrahedron letters. Volume 56:Issue 23(2015)
• Page Start: 3246
• Page End: 3250
• Publication Date: 2015-06-03
• Subjects: Tuberculosis -- Thienopyrimidine -- Metabolomics -- Prodrug; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2015.02.129
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: 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. Isoxazole4e and thiazole4m 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.