biostudies-literatureUnknown68(5)Sharma PA 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 pharmacokineJournal of medicinal chemistry5774-5803https://www.ebi.ac.uk/biostudies/studies/S-EPMC12333353biostudies-literatureEvolution of Small Molecule Inhibitors of <i>Mycobacterium tuberculosis</i> Menaquinone Biosynthesis.PMC12333353Sukheja PCangialosi JJohnson KSharma POcke EJiang QLi SGZimmerman MDTsotetsi KKumar PPark SRusso RNelson AMPenalva-Lopez SSuryavanshi SMorrison ESingh PSharma VAlland DThadkapally SSarathy JPFreundlich JSfalseEvolution of Small 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 pharmacokine2025-01-01T00:00:00Z2025 Mar2026-05-01T08:39:20.141Z2026-04-19T03:07:59.362ZS-EPMC123333534003549910.1021/acs.jmedchem.4c03156