<i>Mycobacterium tuberculosis</i> Decaprenylphosphoryl-β-<scp>d</scp>-ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity
Alan D. Borthwick, Carlos Alemparte, Ian D. Wall, Benjamin C. Whitehurst, Argyrides Argyrou, Glenn A. Burley, Paco de Dios-Antón, Laura Guijarro, Maria Cândida Monteiro, Fátima Ortega, Colin J. Suckling, Julia Castro Pichel, Mónica Cacho, Robert J. Young
Abstract
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.