文献类型：期刊文献

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

作者：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, Lefu[2];Li, Jian[1]

机构：[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

年份：2018

卷号：61

期号：1

起止页码：224

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000422810800013)】；

基金：The financial support for this research was provided by the National Key R&D Program of China (Grant no. 2017YFB0202600), the National Natural Science Foundation of China (Grant no. 21672064), and the "Shu Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (Grant no. 14SG28). The Fundamental Research Funds for the Central Universities are gratefully acknowledged.

语种：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.