Synthesis and evaluation of novel pleuromutilin derivatives with a substituted pyrimidine moiety

Eur J Med Chem. 2015 Aug 28:101:179-84. doi: 10.1016/j.ejmech.2015.06.034. Epub 2015 Jun 22.

Abstract

A series of novel pleuromutilin derivatives possessing 6-hydroxy pyrimidine moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), Bacillus subtilis (B. subtilis), and Escherichia coli (E. coli) were tested by the agar dilution method. The majority of the screened compounds displayed potent activities. Compounds 3 and 6a were found to be the most active antibacterial agents against MRSA and MRSE. Moreover, in the vivo experiment, compound 6a showed comparable antibacterial activity to that of tiamulin, with ED50 of 5.47 mg/kg body weight against MRSA.

Keywords: Antibacterial activity; MRSA; Pleuromutilin derivatives; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacillus subtilis / drug effects*
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Diterpenes / pharmacology
  • Dose-Response Relationship, Drug
  • Escherichia coli / drug effects*
  • Methicillin Resistance / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Pleuromutilins
  • Polycyclic Compounds
  • Pyrimidines / chemistry*
  • Staphylococcus aureus / drug effects*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Diterpenes
  • Polycyclic Compounds
  • Pyrimidines
  • pyrimidine