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Tetrahedron Lett. 2015 Jun 3;56(23):3246-3250.

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

Author information

1
Department 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.
2
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
4
Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA. ; Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010, USA.
5
Department 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. ; Department of Pharmacology & Physiology, 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.

KEYWORDS:

metabolomics; prodrug; thienopyrimidine; tuberculosis

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