Abstract：
:There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Surivet JP,Zumbrunn C,Bruyère T,Bur D,Kohl C,Locher HH,Seiler P,Ertel EA,Hess P,Enderlin-Paput M,Enderlin-Paput S,Gauvin JC,Mirre A,Hubschwerlen C,Ritz D,Rueedi Gdoi
10.1021/acs.jmedchem.6b01831subject
Has Abstractpub_date
2017-05-11 00:00:00pages
3776-3794issue
9eissn
0022-2623issn
1520-4804journal_volume
60pub_type
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