Design, synthesis, biological evaluation and molecular docking study of novel pleuromutilin derivatives containing substituted benzoxazole as antibacterial agents.

A series of pleuromutilin analogs containing substituted benzoxazole were designed, synthesised, and assessed for their antibacterial activity both and . The MIC of the synthesised derivatives was initially assessed using the broth dilution method against four strains of (MRSA ATCC 43300, ATCC 29213, clinical isolation of AD3 and 144). Most of the synthesised derivatives displayed prominent activity (MIC ≤ 0.5 µg/mL). Compounds and exhibited the most effective antibacterial effect against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed that compounds and had a certain inhibitory effect against MRSA . The antibacterial activity of compound was evaluated further using a murine thigh model infected with MRSA (-1.24 logCFU/mL). Compound exhibited superior antibacterial efficacy to tiamulin. It was also found that compound did not display significant inhibitory effect on the proliferation of RAW 264.7 cells. Molecular docking study revealed that compound can effectively bind to the active site of the 50S ribosome (the binding free energy -7.50 kcal/mol).