Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

摘要: The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, pharmacokinetic properties nitrofuranyl isoxazolines were improved by incorporation outer ring elements OPC-67683. This successfully increased stability resulting pentacyclic lead compound Lee1106 (referred to herein 9a). current study, we report synthesis antimicrobial 9a panel analogs, developed increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors Mycobacterium tuberculosis with favorable selectivity indices (>150) a narrow spectrum activity. vivo, compounds showed long half-lives high volumes distribution. Based on testing lack toxicity in series lead. exerted lengthy post antibiotic effect was highly active nonreplicating M. grown under hypoxia. low cross resistance mechanism activation distinct from pre-clinical candidates PA-824 Together these studies show that is nanomolar inhibitor actively growing well tuberculosis.