Abstract
We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Aryl Hydrocarbon Hydroxylases / metabolism
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Cytochrome P-450 CYP1A2 / metabolism
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Cytochrome P-450 CYP1A2 Inhibitors
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 CYP2D6 / metabolism
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Cytochrome P-450 CYP2D6 Inhibitors
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Gram-Negative Bacteria / drug effects
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Gram-Positive Bacteria / drug effects
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Humans
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Male
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Methicillin-Resistant Staphylococcus aureus / drug effects*
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Mice
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Mice, Inbred ICR
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Microbial Sensitivity Tests
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Models, Chemical
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Molecular Structure
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Monoamine Oxidase / metabolism
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Oxazolidinones / chemical synthesis
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Oxazolidinones / chemistry
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Oxazolidinones / pharmacology*
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Prosencephalon / drug effects
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Prosencephalon / enzymology
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Rats
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Staphylococcal Infections / microbiology
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Staphylococcal Infections / prevention & control*
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Cytochrome P-450 CYP1A2 Inhibitors
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Cytochrome P-450 CYP2D6 Inhibitors
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Oxazolidinones
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2D6
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Monoamine Oxidase