| Samenvatting: | A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound <b>9</b> was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound <b>9</b> had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound <b>9</b> (K<sub>D</sub> = 1.77 × 10<sup>−8</sup> M) showed stronger affinity to the 50S ribosome than tiamulin (K<sub>D</sub> = 2.50 × 10<sup>−8</sup> M). The antibacterial activity of compound <b>9</b> was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log<sub>10</sub> CFU/mL), and compound <b>9</b> performed a treatment effect (~1.3 log<sub>10</sub> CFU/mL). In addition, compound <b>9</b> was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC<sub>50</sub> = 2.92 μg/mL).
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