Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity

doi:10.1021/acs.jmedchem.7b01300

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	Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity
	Li, Baoli 1; Ni, Shuaishuai 1; Mao, Fei 1; Chen, Feifei 2; Liu, Yifu 1; Wei, Hanwen 1; Chen, Wenhua 1; Zhu, Jin 1; Lan, Lefu2 ; Li, Jian 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-01-11
卷号	61 期号:1 页码:224-250
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b01300
文献子类	Article
英文摘要	CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus Newman and 13 MRSA strains (IC50 = 0.02-10.5 nM), along with lower hERG inhibition (IC50 > 30 mu M, similar to 10-fold decrease in comparison with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and heart in a mouse model with normal treatment deeper than pretreatment ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these nine multidrug-resistant MRSA strains, including excellent activity against LRSA strains and VISA strains in vivo, and all of which demonstrated that 23a has a huge potential against intractable MRSA, VISA, and LRSA issues as a therapeutic drug.
资助项目	National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[21672064] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; "Shu Guang" project - Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	RESISTANT STAPHYLOCOCCUS-AUREUS ; LINEZOLID RESISTANCE ; VANCOMYCIN-INTERMEDIATE ; VIRULENCE ; MRSA ; EPIDEMIC ; ENTEROCOCCI ; INFECTIONS ; DAPTOMYCIN ; EMERGENCE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000422810800013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272284]
专题	药理学第三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	Lan, Lefu; Li, Jian
作者单位	1.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Baoli,Ni, Shuaishuai,Mao, Fei,et al. Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(1):224-250.
APA	Li, Baoli.,Ni, Shuaishuai.,Mao, Fei.,Chen, Feifei.,Liu, Yifu.,...&Li, Jian.(2018).Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity.JOURNAL OF MEDICINAL CHEMISTRY,61(1),224-250.
MLA	Li, Baoli,et al."Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity".JOURNAL OF MEDICINAL CHEMISTRY 61.1(2018):224-250.