The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents.
Murphy ST, Case HL, Ellsworth E, Hagen S, Huband M, Joannides T, Limberakis C, Marotti KR, Ottolini AM, Rauckhorst M, Starr J, Stier M, Taylor C, Zhu T, Blaser A, Denny WA, Lu GL, Smaill JB, Rivault F.
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.