Design, Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug-Resistant Bacteria

Authors

  • Dr. Jun Chang,

    1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    Search for more papers by this author
  • Si-Ji Zhang,

    1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    Search for more papers by this author
  • Yong-Wei Jiang,

    1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    Search for more papers by this author
  • Dr. Liang Xu,

    1. Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041 (China)
    Search for more papers by this author
  • Dr. Jian-Ming Yu,

    1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    Search for more papers by this author
  • Prof. Wen-Jiang Zhou,

    Corresponding author
    1. Animal Center, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    • Wen-Jiang Zhou, Animal Center, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)

      Xun Sun, Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)

    Search for more papers by this author
  • Prof. Dr. Xun Sun

    Corresponding author
    1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
    • Wen-Jiang Zhou, Animal Center, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)

      Xun Sun, Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)

    Search for more papers by this author

Abstract

Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), gentamicin-resistant Enterococcus faecalis (GRE), methicillin-resistant Streptococcus pneumoniae (MRS), and vancomycin-resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N-(6-phenylheptyl)demethylvancomycin (12 a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ∼18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half-life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation.

Ancillary