Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents

doi:10.1021/jm200614t

	Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents
	Xin, Qisheng 1; Fan, Houxing 1; Guo, Bin1 ; He, Huili 1; Gao, Suo 1; Wang, Hui 2; Huang, Yanqin 3; Yang, Yushe1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2011-11-10
卷号	54 期号:21 页码:7493-7502
ISSN号	0022-2623
DOI	10.1021/jm200614t
文献子类	Article
英文摘要	A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound 45 exhibited excellent in vitro activity, with a MIC value of 0.25-0.5 mu g/mL against MASA and an activity against linezolid-resistant strains of 8-16-fold higher potency than linezolid. In a MRSA systemic infection model, compound 45 displayed an ED50 < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats.
资助项目	National Natural Science Foundation of China[20672125] ; National Science and Technology Major Project of China[2009ZX09301-001]
WOS关键词	TRICYCLIC FUSED OXAZOLIDINONE ; STAPHYLOCOCCUS-AUREUS ; RESISTANCE ; RING
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000296408100007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278336]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yang, Yushe
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.China Pharmaceut Univ, Dept Microbiol, Nanjing 210009, Jiangsu Provinc, Peoples R China; 3.MicuRx Pharmaceut Inc, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xin, Qisheng,Fan, Houxing,Guo, Bin,et al. Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents[J]. JOURNAL OF MEDICINAL CHEMISTRY,2011,54(21):7493-7502.
APA	Xin, Qisheng.,Fan, Houxing.,Guo, Bin.,He, Huili.,Gao, Suo.,...&Yang, Yushe.(2011).Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents.JOURNAL OF MEDICINAL CHEMISTRY,54(21),7493-7502.
MLA	Xin, Qisheng,et al."Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents".JOURNAL OF MEDICINAL CHEMISTRY 54.21(2011):7493-7502.