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.