Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

14 Scopus Citations
View graph of relations

Author(s)

  • Kin-Fai Chan
  • Ning Sun
  • Siu-Cheong Yan
  • Iris L. K. Wong
  • Hok-Kiu Lui
  • Kwan-Choi Cheung
  • Jian Yuan
  • Fung-Yi Chan
  • Zhiwei Zheng
  • Edward W. C. Chan
  • Yun-Chung Leung
  • Tak Hang Chan
  • Kwok-Yin Wong

Detail(s)

Original languageEnglish
Pages (from-to)7281-7292
Journal / PublicationACS Omega
Volume2
Issue number10
Online published27 Oct 2017
Publication statusPublished - 31 Oct 2017
Externally publishedYes

Abstract

We have recently identified a new class of filamenting temperature-sensitive mutant Z (FtsZ)-interacting compounds that possess a 2,4,6-trisubstituted pyrimidine-quinuclidine scaffold with moderate antibacterial activity. Employing this scaffold as a molecular template, a compound library of amine-linked 2,4,6-trisubstituted pyrimidines with 99 candidates was successfully established by employing an efficient convergent synthesis designed to explore their structure-activity relationship. The results of minimum inhibitory concentration (MIC) assay against Staphylococcus aureus strains and cytotoxicity assay against the mouse L929 cell line identified those compounds with potent antistaphylococcal properties (MIC ranges from 3 to 8 μg/mL) and some extent of cytotoxicity against normal cells (IC50 ranges from 6 to 27 μM). Importantly, three compounds also exhibited potent antibacterial activities against nine clinically isolated methicillin-resistant S. aureus (MRSA) strains. One of the compounds, 14av-amine16, exhibited low spontaneous frequency of resistance, low toxicity against Galleria mellonella larvae, and the ability to rescue G. mellonella larvae (20% survival rate at a dosage of 100 mg/kg) infected with a lethal dose of MRSA ATCC 43300 strain. Biological characterization of compound 14av-amine16 by saturation transfer difference NMR, light scattering assay, and guanosine triphosphatase hydrolysis assay with purified S. aureus FtsZ protein verified that it interacted with the FtsZ protein. Such a property of FtsZ inhibitors was further confirmed by observing iconic filamentous cell phenotype and mislocalization of the Z-ring formation of Bacillus subtilis. Taken together, these 2,4,6-trisubstituted pyrimidine derivatives represent a novel scaffold of S. aureus FtsZ inhibitors.

Citation Format(s)

Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors. / Chan, Kin-Fai; Sun, Ning; Yan, Siu-Cheong; Wong, Iris L. K.; Lui, Hok-Kiu; Cheung, Kwan-Choi; Yuan, Jian; Chan, Fung-Yi; Zheng, Zhiwei; Chan, Edward W. C.; Chen, Sheng; Leung, Yun-Chung; Chan, Tak Hang; Wong, Kwok-Yin.

In: ACS Omega, Vol. 2, No. 10, 31.10.2017, p. 7281-7292.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review