Synthesis and Characterization of Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Antibacterial Activity against Gram-Negative Bacteria
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:60 |
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| Enthalten in: |
Journal of medicinal chemistry - 60(2017), 9 vom: 11. Mai, Seite 3776-3794 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Surivet, Jean-Philippe [VerfasserIn] |
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| Links: |
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| Themen: |
Anti-Bacterial Agents |
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| Anmerkungen: |
Date Completed 11.07.2017 Date Revised 22.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.6b01831 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM270935649 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Zumbrunn, Cornelia |e verfasserin |4 aut | |
| 700 | 1 | |a Bruyère, Thierry |e verfasserin |4 aut | |
| 700 | 1 | |a Bur, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Kohl, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Locher, Hans H |e verfasserin |4 aut | |
| 700 | 1 | |a Seiler, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Ertel, Eric A |e verfasserin |4 aut | |
| 700 | 1 | |a Hess, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Enderlin-Paput, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Enderlin-Paput, Stéphanie |e verfasserin |4 aut | |
| 700 | 1 | |a Gauvin, Jean-Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Mirre, Azely |e verfasserin |4 aut | |
| 700 | 1 | |a Hubschwerlen, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Ritz, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Rueedi, Georg |e verfasserin |4 aut | |
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