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Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights
Shao-Gang Li1, Catherine Vilchèze2, Sumit Chakraborty3
1Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, USA.
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.
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