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

被引：83

作者：

Murphy, Sean T.

Case, Heather L.

Ellsworth, Edmund

Hagen, Susan

Huband, Michael

Joannides, Themis

Limberakis, Chris

Marotti, Keith R.

Ottolini, Amy M.

Rauckhorst, Mark

Starr, Jeremy

Stier, Michael

Taylor, Clarke

Zhu, Tong

Blaser, Adrian

Denny, William A.

Lu, Guo-Liang

Smaill, Jeff B.

Rivault, Freddy

机构：

[1] Pfizer Global Res & Dev, La Jolla Labs, San Diego, CA 92121 USA

[2] Pfizer Global Res & Dev, Ann Arbor Labs, Ann Arbor, MI 48105 USA

[3] Univ Auckland, Sch Med Sci, Auckland Canc Soc Res Ctr, Auckland 1020, New Zealand

[4] Ecole Super Biotechnol Strasbourg, Dept Recepteurs & Prot Membranaires, UMR7175, Inst Gilbert Laustriat, F-67400 Illkirch Graffenstaden, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 08期

关键词：

fluoroquinolones; antibacterial; resistance; nitriles; dofetilide; hERG; pK(a); PF-00951966; PF-02298732; PF-02789402;

D O I：

10.1016/j.bmcl.2007.01.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Streptococcuspneumoniae. 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. C 2007 Elsevier Ltd. All rights reserved.

引用

页码：2150 / 2155

页数：6

共 18 条

[11]

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[12] In vitro activities of novel nonfluorinated quinolones PGE 9262932 and PGE 9509924 against clinical isolates of Staphylococcus aureus and Streptococcus pneumoniae with defined mutations in DNA gyrase and topoisomerase IV [J].