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

Journal: ACS omega
Published Date: Oct 27, 2017

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 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 (IC ranges from 6 to 27 μM). Importantly, three compounds also exhibited potent antibacterial activities against nine clinically isolated methicillin-resistant (MRSA) strains. One of the compounds, , exhibited low spontaneous frequency of resistance, low toxicity against larvae, and the ability to rescue 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 by saturation transfer difference NMR, light scattering assay, and guanosine triphosphatase hydrolysis assay with purified 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 . Taken together, these 2,4,6-trisubstituted pyrimidine derivatives represent a novel scaffold of FtsZ inhibitors.

Authors

  • Kin-Fai Chan
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Ning Sun
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Siu-Cheong Yan
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Iris L K Wong
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Hok-Kiu Lui
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Kwan-Choi Cheung
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Jian Yuan
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Fung-Yi Chan
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Zhiwei Zheng
    Shenzhen Key Laboratory for Food Biological Safety Control, Food Safety and Technology Research Centre, The Hong Kong PolyU Shenzhen Research Institute, Shenzhen 518057, China.
  • Edward W C Chan
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Sheng Chen
    Department of Thoracic Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
  • Yun-Chung Leung
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Tak Hang Chan
    State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • Kwok-Yin Wong
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.

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