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

Jennifer A. Borthwick, Carlos Alemparte, Ian Wall, Benjamin C. Whitehurst, Argyrides Argyrou, Glenn Burley, Paco de Dios-Anton, Laura Guijarro, Maria Candida Monteiro, Fatima Ortega, Colin J Suckling, Julia Castro Pichel, Monica Cacho, Robert J. Young

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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.
Original languageEnglish
Pages (from-to)2557-2576
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number5
Early online date10 Jan 2020
Publication statusPublished - 12 Mar 2020


  • mycobacterium tuberculosis
  • cellular potency
  • infection model

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