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

doi:10.1016/j.tetlet.2015.02.129

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

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

25 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 language	English (US)
Pages (from-to)	3246-3250
Number of pages	5
Journal	Tetrahedron Letters
Volume	56
Issue number	23
DOIs	https://doi.org/10.1016/j.tetlet.2015.02.129
State	Published - May 25 2015

Keywords

Metabolomics
Prodrug
Thienopyrimidine
Tuberculosis

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.tetlet.2015.02.129

Cite this

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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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AU - Li, Shao Gang

AU - Vilchèze, Catherine

AU - Chakraborty, Sumit

AU - Wang, Xin

AU - Kim, Hiyun

AU - Anisetti, Monica

AU - Ekins, Sean

AU - Rhee, Kyu Y.

AU - Jacobs, William R.

AU - Freundlich, Joel S.

PY - 2015/5/25

Y1 - 2015/5/25

N2 - 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.

AB - 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.

KW - Metabolomics

KW - Prodrug

KW - Thienopyrimidine

KW - Tuberculosis

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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