Abstract
A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues.
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 / pharmacokinetics
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Anti-Bacterial Agents / pharmacology
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Bacteria / drug effects
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Carboxylic Acids / chemistry*
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Fluoroquinolones / chemical synthesis
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Fluoroquinolones / chemistry*
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Fluoroquinolones / pharmacokinetics
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Fluoroquinolones / pharmacology*
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Lung / metabolism
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Molecular Structure
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Nalidixic Acid / analogs & derivatives
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Nalidixic Acid / chemical synthesis
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Nalidixic Acid / chemistry
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Nalidixic Acid / metabolism
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Nalidixic Acid / pharmacokinetics
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Nalidixic Acid / pharmacology
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Organophosphates / chemical synthesis
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Organophosphates / chemistry
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Organophosphates / pharmacokinetics
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Organophosphates / pharmacology
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Piperazines / chemistry
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Piperazines / metabolism
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Prodrugs / chemical synthesis
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Prodrugs / chemistry*
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Prodrugs / metabolism
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Prodrugs / pharmacokinetics
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Rats
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Solubility
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Structure-Activity Relationship
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Water / chemistry*
Substances
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Anti-Bacterial Agents
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Carboxylic Acids
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Fluoroquinolones
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Organophosphates
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PA 2789
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PA 2808
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Piperazines
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Prodrugs
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Water
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Nalidixic Acid