利用结构导向设计发现吡唑并吡啶酮类作为新型的DNA回旋酶B抑制剂
Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design.
作者信息
Cross Jason B, Zhang Jing, Yang Qingyi, Mesleh Michael F, Romero Jan Antoinette C, Wang Bin, Bevan Doug, Poutsiaka Katherine M, Epie Felix, Moy Terence, Daniel Anu, Shotwell Joseph, Chamberlain Brian, Carter Nicole, Andersen Ole, Barker John, Ryan M Dominic, Metcalf Chester A, Silverman Jared, Nguyen Kien, Lippa Blaise, Dolle Roland E
机构信息
Cubist Pharmaceuticals, Inc. , 65 Hayden Avenue, Lexington, Massachusetts 02421, United States.
Evotec U.K., Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
出版信息
ACS Med Chem Lett. 2016 Feb 16;7(4):374-8. doi: 10.1021/acsmedchemlett.5b00368. eCollection 2016 Apr 14.
Abstract
The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.
摘要
DNA促旋酶B的ATP酶亚基是一个颇具吸引力的抗菌靶点，因为它在细菌中高度保守且在DNA复制中发挥着关键作用。通过利用结构导向设计优化一个片段筛选命中支架，发现了一类新型的吡唑并吡啶酮抑制剂。这些抑制剂对革兰氏阳性菌显示出强效抗菌活性，并且对临床上重要的病原体耐药发生率低。
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