| Literature DB >> 28610977 |
Mark J Mitton-Fry1, Steven J Brickner2, Judith C Hamel2, Rose Barham2, Lori Brennan2, Jeffrey M Casavant2, Xiaoyuan Ding2, Steven Finegan2, Joel Hardink2, Thuy Hoang2, Michael D Huband2, Meghan Maloney2, Anthony Marfat2, Sandra P McCurdy2, Dale McLeod2, Chakrapani Subramanyam2, Michael Plotkin2, Usa Reilly2, John Schafer2, Gregory G Stone2, Daniel P Uccello2, Todd Wisialowski2, Kwansik Yoon2, Richard Zaniewski2, Christopher Zook2.
Abstract
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 MIC90=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 IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.Entities:
Keywords: Antibacterial; Fluoroquinoline; Gyrase; MRSA; NBTI; Topoisomerase
Mesh：
Substances：
Year: 2017 PMID： 28610977 DOI： 10.1016/j.bmcl.2017.06.009
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823