Synthesis and biological evaluation of novel N, N'-diarylurea derivatives as potent antibacterial agents against MRSA

Xiaonan Du; Minghua Wang; Xinxin Hu; Tongying Nie; Mei Zhu; Guoning Zhang; Xuefu You; Yucheng Wang

doi:10.1016/j.bmcl.2022.128975

Synthesis and biological evaluation of novel N, N'-diarylurea derivatives as potent antibacterial agents against MRSA

Bioorg Med Chem Lett. 2022 Nov 1:75:128975. doi: 10.1016/j.bmcl.2022.128975. Epub 2022 Sep 5.

Authors

Xiaonan Du¹, Minghua Wang¹, Xinxin Hu¹, Tongying Nie¹, Mei Zhu¹, Guoning Zhang², Xuefu You³, Yucheng Wang⁴

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
² Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: zhangguoning@imb.pumc.edu.cn.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: xuefuyou@imb.pumc.edu.cn.
⁴ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: wangyucheng@imb.pumc.edu.cn.

PMID: 36067930
DOI: 10.1016/j.bmcl.2022.128975

Abstract

A series of new N, N'-diarylurea derivatives were designed and synthesized, some of which exhibited potent antibacterial activity against the drug-susceptible and drug-resistant Gram-positive strains. Especially, compounds 2c, 2g-2l showed broader antibacterial spectrum and more potent antibacterial activity (MIC = 0.30-2.72 μM) against MRSA and MRSE than the control levofloxacin (MIC = 0.69-22.14 μM). In addition, compounds 2c, 2g, 2h and 2l exhibited much better antibacterial activity (MIC = 1.29-2.86 μM) against VRE (E. faecium) than sorafenib (MIC = 275.37 μM), PK150 (MIC = 5.07-10.13 μM) and SC78 (MIC = 2.40-4.79 μM). More importantly, the low cytotoxicity of compounds on cell lines HeLa and HepG2 implied a relatively wide therapeutic window, which was of high importance for further study.

Keywords: Antibacterial; MRSA; N, N’-diarylurea; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents* / pharmacology
Levofloxacin / pharmacology
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests
Sorafenib
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Levofloxacin
Sorafenib