文献类型：期刊文献

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

作者：Wang, Youxin[1];Chen, Feifei[2];Di, Hongxia[2];Xu, Yong[3];Xiao, Qiang[3];Wang, Xuehai[4];Wei, Hanwen[1];Lu, Yanli[1];Zhang, Lingling[1];Zhu, Jin[1];Sheng, Chunquan[5];Lan, Lefu[2];Li, Jian[1]

机构：[1]E 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;[3]Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Peoples R China;[4]Humanwell Healthcare Grp Co Ltd, 666 Gaoxin Rd, Wuhan 430075, Peoples R China;[5]Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China

年份：2016

卷号：59

期号：7

起止页码：3215

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000374430800025)】；

基金：Financial support for this research provided by the National Natural Science Foundation of China (Grants 21222211, 21372001 and 21472207), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (Grant 14SG28), the Program for New Century Excellent Talents in University (Grant NCET-12-0853), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.

语种：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.