Evolution ofSmall Molecule Inhibitors of <i>Mycobacterium tuberculosis</i> Menaquinone Biosynthesis

A dire need exists for novel drugs to treat <i>Mycobacterium tuberculosis</i> infection. In an effort to build on our early efforts targeting the MenG enzyme within the menaquinone biosynthetic pathway, we have pursued the optimization of diaryl amide JSF-2911 to address its poor metabolic stability and modest <i>in vitro</i> potency. A hit evolution campaign focused on modification of the amine substructure within this hit compound, resulting in a range of analogues that have been profiled extensively. Among these derivatives, JSF-4536 and JSF-4898 demonstrated significantly improved biological profiles, notably offering submicromolar MIC values versus <i>M. tuberculosis</i> and promising values characterizing the mouse liver microsome stability, aqueous solubility, and mouse pharmacokinetic profile. JSF-4898 enhanced the efficacy of rifampicin in a subacute model of <i>M. tuberculosis</i> infection in mice. The findings suggest a rationale for the further optimization of MenG inhibitors to provide a novel therapeutic strategy to address <i>M. tuberculosis</i> infection.