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

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, Sheng Chen, Yun Chung Leung, Tak Hang Chan, Kwok Yin Wong

Research output: Journal article publicationJournal articleAcademic researchpeer-review

16 Citations (Scopus)


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 (IC50ranges 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.
Original languageEnglish
Pages (from-to)7281-7292
Number of pages12
JournalACS Omega
Issue number10
Publication statusPublished - 1 Jan 2017

ASJC Scopus subject areas

  • Chemical Engineering(all)
  • Chemistry(all)

Cite this