title: 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 culturedMycobacterium tuberculosis. This process was informed by studies of the intramycobacterial metabolism of CD117 and its inactive carboxylic acid derivative. Isoxazole4eand thiazole4mdemonstrated 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.
authors.affiliation: 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.
authors.forename: Shao-Gang
authors.initials: SG
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.affiliation: Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hiyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Monica
authors.initials: M
authors.lastname: Anisetti
authors.affiliation: Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA. ; Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Rhee
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: 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.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
keywords: metabolomics; prodrug; thienopyrimidine; tuberculosis