Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections
文献类型：期刊论文
| 作者 | Wang, Youxin4; Chen, Feifei5; Di, Hongxia5; Xu, Yong1; Xiao, Qiang1; Wang, Xuehai3; Wei, Hanwen4; Lu, Yanli4; Zhang, Lingling4; Zhu, Jin4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 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. |
| WOS关键词 | VIRULENCE ; BIOSYNTHESIS ; STAPHYLOXANTHIN ; NEUTROPHILS ; STRATEGIES ; BACTERIA |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000374430800025 |
| 出版者 | AMER CHEMICAL SOC |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。