Synthesis and Antibacterial Activity Against MRSA of Pleuromutilin Derivatives Possessing a Mercaptoethylamine Linker

Background: Methicillin resistant Staphylococcus aureus (MRSA) usually invalidate powerful antibiotics in the clinic. Pleuromutilin derivatives have been reported to possess antibacterial activity against MRSA. Objective: The antibacterial activities against MRSA of a series of thirteen synthetic pleuromutilin derivatives were investigated through in vitro models. Methods: A series of novel thioehter pleuromutilin derivatives incorporating various aromatic substituents into the C 14 side chain have been reported. The in vitro antibacterial activities of these derivatives against MRSA and Escherichia coli were tested by the broth dilution method. Results: Twelve pleuromutilin derivatives were designed, synthesized and evaluated for in vitro antibacterial activities against four Staphylococcus aureus strains. From structure-activity relationship studies, compound 11c was identified as promising compounds with the most potent in vitro antibacterial activity among the series (MIC = 0.0625-0.125 mu g/ml) against Staphylococcus aureus strains. The binding of compound 11c to the 50s ribosome was investigated by molecular modeling. Conclusion: It was found that there is a reasonable correlation between the binding free energy and the antibacterial activity.