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Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria

文献类型：期刊论文

作者Shi, Chenghui2,3; Zhang, Yinyong2,4; Wang, Ting1; Lu, Wenchao2,3; Zhang, Shuhua1; Guo, Bin2,3; Chen, Qian2,3; Luo, Cheng2,3; Zhou, Xianli4; Yang, Yushe2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-03-28
卷号62期号:6页码:2950-2973
ISSN号0022-2623
DOI10.1021/acs.jmedchem.8b01750
通讯作者Zhou, Xianli(zhouxl@swjtu.edu.cn) ; Yang, Yushe(ysyang@mail.shcnc.ac.cn)
英文摘要Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX0914, we carried out systematic structural modification of this compound, and a number of compounds with increased potency were obtained. The most promising compound 33e, with incorporation of a spirocyclopropane at the oxazolidinone 5 position reduced metabolism, exhibited excellent antibacterial activity against Gram-positive pathogens and a good pharmacokinetic profile combined with high aqueous solubility. In addition, compound 33e exhibited good selectivity for Staphylococcus aureus gyrase over human Topo II alpha. In a murine model of systemic methicillin-resistant S. aureus infection, 33e exhibited superior in vivo efficacy (ED50 = 3.87 mg/kg) compared to ETX0914 (ED50 = 11.51 mg/kg).
WOS关键词TOPOISOMERASE ; DISCOVERY ; AZD0914 ; GENOTOXICITY ; METABOLISM ; MECHANISM ; COMMUNITY ; ROLES
资助项目Chinese Academy of Sciences[CASIMM0120162010] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000463116900007
源URL[http://119.78.100.183/handle/2S10ELR8/289969]  
专题新药研究国家重点实验室
通讯作者Zhou, Xianli; Yang, Yushe
作者单位1.Sichuan Primed Biotech Grp Co Ltd, Dept Microbiol, Chengdu 610041, Sichuan, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Southwest Jiaotong Univ, Sch Life Sci & Engn, Chengdu 610031, Sichuan, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Chenghui,Zhang, Yinyong,Wang, Ting,et al. Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(6):2950-2973.
APA Shi, Chenghui.,Zhang, Yinyong.,Wang, Ting.,Lu, Wenchao.,Zhang, Shuhua.,...&Yang, Yushe.(2019).Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria.JOURNAL OF MEDICINAL CHEMISTRY,62(6),2950-2973.
MLA Shi, Chenghui,et al."Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria".JOURNAL OF MEDICINAL CHEMISTRY 62.6(2019):2950-2973.

入库方式： OAI收割

来源：上海药物研究所

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