The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents

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• 作者：Sean T. Murphy ; Heather L. Case ; Edmund Ellsworth ; Susan Hagen ; Michael Hub ; Themis Joannides ; Chris Limberakis ; Keith R. Marotti ; Amy M. Ottolini ; Mark Rauckhorst ; et al.
• 关键词：Fluoroquinolones ; Antibacterial ; Resistance ; Nitriles ; Dofetilide ; hERG ; pK_a ; PF-00951966 ; PF- 02298732 ; PF-02789402
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：15 April 2007
• 年：2007
• 卷：17
• 期：8
• 页码：2150-2155
• 全文大小：162 K

文摘

Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats.