Mycobacterium tuberculosis decaprenylphosphoryl-β- d-ribose oxidase inhibitors : expeditious reconstruction of suboptimal hits into a series with potent in vivo activity

Borthwick, Jennifer A. and Alemparte, Carlos and Wall, Ian and Whitehurst, Benjamin C. and Argyrou, Argyrides and Burley, Glenn and de Dios-Anton, Paco and Guijarro, Laura and Monteiro, Maria Candida and Ortega, Fatima and Suckling, Colin J and Pichel, Julia Castro and Cacho, Monica and Young, Robert J. (2020) Mycobacterium tuberculosis decaprenylphosphoryl-β- d-ribose oxidase inhibitors : expeditious reconstruction of suboptimal hits into a series with potent in vivo activity. Journal of Medicinal Chemistry, 63 (5). pp. 2557-2576. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.9b01561)

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Abstract

Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.

ORCID iDs

Borthwick, Jennifer A. ORCID logoORCID: https://orcid.org/0000-0001-6102-5648, Alemparte, Carlos, Wall, Ian, Whitehurst, Benjamin C., Argyrou, Argyrides, Burley, Glenn, de Dios-Anton, Paco, Guijarro, Laura, Monteiro, Maria Candida, Ortega, Fatima, Suckling, Colin J, Pichel, Julia Castro, Cacho, Monica and Young, Robert J.;
CORE (COnnecting REpositories)