Design, synthesis, and structure-activity relationship studies of novel pleuromutilin derivatives having a piperazine ring

A series of novel pleuromutilin derivatives possessing piperazine moieties were synthesized under mild conditions. The in vitro antibacterial activities of these derivatives against Staphylococcus aureus and Escherichia coli were tested by the agar dilution method. Structure-activity relationship studies resulted in compounds 11b, 13b, and 14a with the most potent in vitro antibacterial activity among the series (minimal inhibitory concentration=0.0625-0.125g/mL). The binding of compounds 11b, 13b, and 14a to the E.coli ribosome was investigated by molecular modeling, and it was found that there is a reasonable correlation between the binding free energy and the antibacterial activity.