Design, synthesis, biological evaluation and molecular docking studies of novel pleuromutilin derivatives containing nitrogen heterocycle and alkylamine groups

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2078-2091. doi: 10.1080/14756366.2022.2104267.

Abstract

A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The in vitro antibacterial activity of these semisynthetic derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus AD3, and S.aureus 144) were evaluated by the broth dilution method. Compound 13 was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 μg/mL). Furthermore, compound 13 was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound 13 exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound 13 showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 μg/mL. Molecular docking study revealed that compound 13 can effectively bind to the active site of the 50S ribosome (the binding free energy = -9.66 kcal/mol).

Keywords: MRSA; Pleuromutilin; alkylamine; antibacterial activity; molecular docking; nitrogen heterocycles.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Diterpenes* / chemistry
  • Diterpenes* / pharmacology
  • Methicillin-Resistant Staphylococcus aureus*
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Nitrogen / pharmacology
  • Pleuromutilins
  • Polycyclic Compounds* / pharmacology
  • Staphylococcus aureus

Substances

  • Anti-Bacterial Agents
  • Diterpenes
  • Polycyclic Compounds
  • Nitrogen

Grants and funding

This work was supported by the National Key Research and Development Program of China [No. 2021YFD1800600], the Guangdong Special Support Program innovation team [No. 2019BT02N054] and the Guangdong Natural Science Funds for Distinguished Young Scholar [No. 2019B151502002].