Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Autor: Mitton-Fry MJ; Pfizer Worldwide Research and Development, Groton, CT 06340, USA. Electronic address: mitton-fry.1@osu.edu., Brickner SJ; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Hamel JC; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Barham R; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Brennan L; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Casavant JM; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Ding X; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Finegan S; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Hardink J; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Hoang T; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Huband MD; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Maloney M; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Marfat A; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., McCurdy SP; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., McLeod D; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Subramanyam C; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Plotkin M; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Reilly U; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Schafer J; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Stone GG; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Uccello DP; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Wisialowski T; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Yoon K; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Zaniewski R; Pfizer Worldwide Research and Development, Groton, CT 06340, USA., Zook C; Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 01; Vol. 27 (15), pp. 3353-3358. Date of Electronic Publication: 2017 Jun 03.
DOI: 10.1016/j.bmcl.2017.06.009
Abstrakt: Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC 90 =0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC 50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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