Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections

doi:10.1021/acs.jmedchem.5b01984

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	Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections
	Wang, Youxin 4; Chen, Feifei 5; Di, Hongxia 5; Xu, Yong 1; Xiao, Qiang 1; Wang, Xuehai 3; Wei, Hanwen 4; Lu, Yanli 4; Zhang, Lingling 4; Zhu, Jin 4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2016-04-14
卷号	59 期号:7 页码:3215-3230
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.5b01984
文献子类	Article
英文摘要	Blocking the staphyloxanthin biosynthesis process has emerged as a new promising antivirulence strategy. Previously, we first revealed that CrtN is a druggable target against infections caused by pigmented Staphylococcus aureus (S. aureus) and that naftifine was an effective CrtN inhibitor. Here, we identify a new type of benzofuran-derived CrtN inhibitor with submicromolar IC50 values that is based on the naftifine scaffold. The most potent analog, 5m, inhibits the pigment production of S. aureus Newman and three MRSA strains, with IC50 values of 0.38-5.45 nM, without any impact on the survival of four strains (up to 200 mu M). Notably, compound 5m (1 mu M) could significantly sensitize four strains to immune clearance and could effectively attenuate the virulence of three strains in vivo. Moreover, 5m was determined to be a weak antifungal reagent (MIC > 16 mu g/mL). Combined with good oral bioavailability (F = 42.2%) and excellent safety profiles, these data demonstrate that 5m may be a good candidate for the treatment of MRSA infections.
资助项目	National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[21472207] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; Shanghai Education Development Foundation[14SG28] ; Program for New Century Excellent Talents in University[NCET-12-0853] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	VIRULENCE ; BIOSYNTHESIS ; STAPHYLOXANTHIN ; NEUTROPHILS ; STRATEGIES ; BACTERIA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000374430800025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276075]
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.Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Peoples R China; 2.Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China 3.Humanwell Healthcare Grp Co Ltd, 666 Gaoxin Rd, Wuhan 430075, Peoples R China; 4.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 5.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	Wang, Youxin,Chen, Feifei,Di, Hongxia,et al. Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(7):3215-3230.
APA	Wang, Youxin.,Chen, Feifei.,Di, Hongxia.,Xu, Yong.,Xiao, Qiang.,...&Li, Jian.(2016).Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections.JOURNAL OF MEDICINAL CHEMISTRY,59(7),3215-3230.
MLA	Wang, Youxin,et al."Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections".JOURNAL OF MEDICINAL CHEMISTRY 59.7(2016):3215-3230.