Design, synthesis and antibacterial evaluation of 2,4-disubstituted-6-thiophenyl-pyrimidines

Zhiyuan Fang, Sichao Zheng, Kin Fai Chan, Wenchang Yuan, Qi Guo, Wenyu Wu, Hoi Kui Lui, Yujing Lu, Yun Chung Leung, Tak Hang Chan, Kwok Yin Wong, Ning Sun

Research output: Journal article publicationJournal articleAcademic researchpeer-review

22 Citations (Scopus)

Abstract

The increasing incidences of multidrug resistant bacterial infections urge the development of novel antibacterial having a new mechanism of action. The small molecule-based inhibitors targeting at the cell division protein FtsZ has been recognized as a promising approach to search for new antibacterial with high potency. In the present study, a series of novel 2,4-disubstituted-6-thiophenyl-pyrimidine derivatives were synthesized and their antibacterial activities against clinically related pathogens were investigated. The compounds show strong antibacterial activities against MRSA and VREs. The antibacterial activity of compound Bb2 against MRSA and VREs (MIC values: 2 μg/mL) is stronger than that of methicillin and vancomycin. From the in vitro and in vivo results, Bb2 was found to inhibit GTPase activity and FtsZ polymerization. The compound is able to inhibit bacterial cell division through interacting with GTP binding site of FtsZ and thus causing cell death. In addition, S. aureus was found to develop resistance to methicillin but not for Bb2, which was proved in our resistance generation experiments.

Original languageEnglish
Pages (from-to)141-153
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume161
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • 2,4-Disubstituted-6-thiophenyl-pyrimidines
  • Antibacterial activity
  • Bacterial resistance
  • FtsZ inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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