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

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.

SUBMITTER: Li SG

PROVIDER: S-EPMC4527344 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Li Shao-Gang SG Vilchèze Catherine C Chakraborty Sumit S Wang Xin X Kim Hiyun H Anisetti Monica M Ekins Sean S Rhee Kyu Y KY Jacobs William R WR Freundlich Joel S JS

Tetrahedron letters 20150601 23

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 ...[more]

PMID: 26257441

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