Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are essential enzymes for DNA replication and well-established antibacterial targets. Fluoroquinolones are known as these inhibitors. However fluoroquinolone-resistant bacteria are increasing recently and cause serious clinical problems. Therefore, there is a clinical need to develop a novel chemical class of antibacterial agent. We identified 8-(methylamino)-2-oxo-1,2-dihydroquinoline scaffold as a potent and novel series of GyrB/ParE inhibitor. A representative compound showed antimicrobial activity against both Gram-positive and Gram-negative pathogens, especially Neisseria gonorrhoeae including antibiotic-resistant strains. It also showed in vivo efficacy in a mouse model of N. gonorrhoeae infection. Details of design, synthesis, structure activity relationship and biological activity of these compounds will be disclosed.

Design, synthesis and evaluation of 8-(methylamino)-2-oxo-1,2-dihydroquinoline derivatives as novel DNA gyrase and topoisomerase IV inhibitors

254th National Meeting (2017)

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