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Synthesis and Characterization of Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Antibacterial Activity against Gram-Negative Bacteria.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 May 11; Vol. 60 (9), pp. 3776-3794. Date of Electronic Publication: 2017 Apr 24. - Publication Year :
- 2017
-
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.
- Subjects :
- Animals
Anti-Bacterial Agents adverse effects
Anti-Bacterial Agents chemical synthesis
Guinea Pigs
Humans
Microbial Sensitivity Tests
Myocytes, Cardiac drug effects
Pyrans adverse effects
Pyrans chemical synthesis
Topoisomerase Inhibitors adverse effects
Anti-Bacterial Agents pharmacology
Gram-Negative Bacteria drug effects
Pyrans pharmacology
Topoisomerase Inhibitors chemical synthesis
Topoisomerase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28406300
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01831