There is an urgent medical need for novel antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for thousands of deaths every year in the US. Bacterial type II topoisomerases (DNA gyrase and topoIV) are essential enzymes intervening during the bacterial replication process. While fluoroquinolones block DNA topoisomerases by interacting with structurally closely related GyrA and ParC subunits of DNA gyrase and topoIV respectively, the emergence of resistant mutants has limited their clinical utility. Exploiting a novel binding site present in GyrA and ParC, allows to overcome resistance to fluoroquinolones. In continuation of our antibacterial program dedicated to novel bacterial topoisomerase inhibitors (NBTIs), we present a novel series of tetrahydropyran-based topoisomerase inhibitors that display potent enzyme-inhibitory activity and potent anti-staphylococcal antibacterial activity. In vitro and in vivo parameters illustrating the potential utility for human use of this series will be presented.

Synthesis and characterization of novel tetrahydropyran-based bacterial topoisomerase inhibitors

248th National Meeting (2014)

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