Abstract
We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then screened in vitro against panel of susceptible and resistant Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis (Mtb). Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against the tested bacteria. Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis. Selected compound 10b showed good human microsomal stability and CYP-profile, and showed low activity against hERG channel.
© 2012 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / chemical synthesis
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Acetamides / chemistry
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Acetamides / metabolism
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Acetamides / pharmacology
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology*
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Bacteria / drug effects*
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Bacterial Infections / drug therapy
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Cytochrome P-450 Enzyme System / metabolism
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Drug Design
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Microbial Sensitivity Tests
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Microsomes, Liver / metabolism
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Mycobacterium tuberculosis / drug effects
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Oxazolidinones / chemical synthesis
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Oxazolidinones / chemistry*
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Oxazolidinones / metabolism
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Oxazolidinones / pharmacology*
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / chemistry
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Triazoles / metabolism
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Triazoles / pharmacology
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Tuberculosis / drug therapy
Substances
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Acetamides
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Anti-Bacterial Agents
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Ether-A-Go-Go Potassium Channels
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Oxazolidinones
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Triazoles
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acetamide
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Cytochrome P-450 Enzyme System