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

doi:10.1021/acs.jmedchem.8b01750

	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
	Shi, Chenghui 2,3; Zhang, Yinyong 2,4; Wang, Ting 1; Lu, Wenchao 2,3; Zhang, Shuhua 1; Guo, Bin 2,3; Chen, Qian 2,3; Luo, Cheng 2,3; Zhou, Xianli 4; Yang, Yushe 2,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2019-03-28
卷号	62 期号:6 页码:2950-2973
ISSN号	0022-2623
DOI	10.1021/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).
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关键词	TOPOISOMERASE ; DISCOVERY ; AZD0914 ; GENOTOXICITY ; METABOLISM ; MECHANISM ; COMMUNITY ; ROLES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000463116900007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289969]
专题	中国科学院上海药物研究所
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.