Design, synthesis, antibacterial activity evaluation and molecular docking study of pleuromutilin derivatives bearing amide side chains

Chem Biol Drug Des. 2022 Oct;100(4):564-579. doi: 10.1111/cbdd.14106. Epub 2022 Jul 1.

Abstract

A seize of pleuromutilin derivatives containing amide side chains were designed and synthesized as potential antibiotics against Methicillin-resistant Staphylococcus aureus (MRSA). Among all target compounds (compounds 11-30), compound 25 was found to have the strongest antibacterial activity against MRSA (minimum inhibitory concentration = 0.5 μg/ml). The result of the time-kill curves indicated that compound 25 could repress the growth of MRSA in vitro obviously (-3.72 log10 CFU/ml reduction). Furthermore, molecular docking studies demonstrated that compound 25 was localized in the binding pocket of 50S ribosomal subunit (ΔGb = -8.99 kcal/mol). Besides, compound 25 displayed low cytotoxicity to RAW 264.7 cells. The results suggested that compound 25 might be further developed into a novel antimicrobial agent against MRSA.

Keywords: MRSA; amide side chain; antibacterial activity; molecular docking; pleuromutilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology
  • Anti-Bacterial Agents / chemistry
  • Diterpenes* / chemistry
  • Methicillin-Resistant Staphylococcus aureus* / metabolism
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Pleuromutilins
  • Polycyclic Compounds
  • Structure-Activity Relationship

Substances

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