新型3-氟-6-甲氧基喹啉衍生物作为细菌DNA促旋酶和拓扑异构酶IV的抑制剂
Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.
作者信息
Mitton-Fry Mark J, Brickner Steven J, Hamel Judith C, Barham Rose, Brennan Lori, Casavant Jeffrey M, Ding Xiaoyuan, Finegan Steven, Hardink Joel, Hoang Thuy, Huband Michael D, Maloney Meghan, Marfat Anthony, McCurdy Sandra P, McLeod Dale, Subramanyam Chakrapani, Plotkin Michael, Reilly Usa, Schafer John, Stone Gregory G, Uccello Daniel P, Wisialowski Todd, Yoon Kwansik, Zaniewski Richard, Zook Christopher
机构信息
Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
出版信息
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3353-3358. doi: 10.1016/j.bmcl.2017.06.009. Epub 2017 Jun 3.
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=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 of 85.9μM and a favorable profile in the anesthetized guinea pig model.
新型（非氟喹诺酮类）细菌II型拓扑异构酶抑制剂（NBTIs）是一类新兴的抗菌剂。我们报道了一系列经过优化的环丁基芳基取代的NBTIs。化合物14在体外（金黄色葡萄球菌MIC = 0.125μg/mL）和体内（全身和组织感染）均表现出优异的活性。对拓扑异构酶IV的抑制增强与对NBTIs耐药的金黄色葡萄球菌菌株活性提高相关。化合物14还表现出改善的hERG IC为85.9μM，并且在麻醉豚鼠模型中具有良好的特性。
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