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Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity

2013; American Chemical Society; Volume: 56; Issue: 18 Linguagem: Inglês

10.1021/jm400963y

1520-4804

Jean‐Philippe Surivet, Cornelia Zumbrunn, Georg Rueedi, Christian Hubschwerlen, Daniel Bur, Thierry Bruyère, Hans H. Locher, Daniel Ritz, Wolfgang Keck, Peter Seiler, Christopher Kohl, Jean-Christophe Gauvin, Azely Mirre, Verena Kaegi, Marina dos Santos, Mika Gaertner, Jonathan Delers, Michel Enderlin-Paput, M. BOEHME,

Antibiotics Pharmacokinetics and Efficacy

There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K(+) channel block. On the other hand, analog 49e displayed lower hERG K(+) channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.