Abstract
The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / therapeutic use
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Barbiturates / chemical synthesis*
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Barbiturates / pharmacokinetics
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Barbiturates / therapeutic use
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Female
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Fluoroquinolones / pharmacology
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
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Heterocyclic Compounds, 4 or More Rings / therapeutic use
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Humans
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Inhibitory Concentration 50
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Isoxazoles / chemical synthesis*
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Isoxazoles / pharmacokinetics
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Isoxazoles / therapeutic use
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Male
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Mice
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Pyridones / chemical synthesis
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Pyridones / pharmacokinetics
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Pyridones / therapeutic use
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Rats, Wistar
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Spiro Compounds / chemical synthesis
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Spiro Compounds / pharmacokinetics
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Staphylococcal Infections / drug therapy
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Staphylococcus aureus / drug effects
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Stereoisomerism
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemical synthesis*
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Topoisomerase II Inhibitors / pharmacokinetics
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Topoisomerase II Inhibitors / therapeutic use
Substances
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11-fluoro-2,4,8-trimethyl-2,4,4a,6-tetrahydro-1H,1'H-spiro(isoxazolo(4,5-g)(1,4)oxazino(4,3-a)quinoline-5,5'-pyrimidine)-2',4',6'(3'H)-trione
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Anti-Bacterial Agents
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Barbiturates
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Fluoroquinolones
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Heterocyclic Compounds, 4 or More Rings
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Isoxazoles
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Pyridones
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Spiro Compounds
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Topoisomerase II Inhibitors