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

Abstract

A series of pleuromutilin analogs containing substituted benzoxazole were designed, synthesised, and assessed for their antibacterial activity both in vivo and in vitro. The MIC of the synthesised derivatives was initially assessed using the broth dilution method against four strains of Staphylococcus aureus (MRSA ATCC 43300, S. aureus ATCC 29213, clinical isolation of S. aureus AD3 and S. aureus 144). Most of the synthesised derivatives displayed prominent in vitro activity (MIC ≤ 0.5 µg/mL). Compounds 50 and 57 exhibited the most effective antibacterial effect against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed that compounds 50 and 57 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 50 was evaluated further using a murine thigh model infected with MRSA (–1.24 log₁₀CFU/mL). Compound 50 exhibited superior antibacterial efficacy to tiamulin. It was also found that compound 50 did not display significant inhibitory effect on the proliferation of RAW 264.7 cells. Molecular docking study revealed that compound 50 can effectively bind to the active site of the 50S ribosome (the binding free energy −7.50 kcal/mol).

GRAPHICAL ABSTRACT

Keywords:

• Pleuromutilin
• Antibiotic
• MRSA
• Benzoxazole
• molecular docking

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was supported by the National Key Research and Development Program of China [No. 2022YFD1802100], the Guangdong Special Support Program innovation team [No. 2019BT02N054] and the Guangdong Natural Science Funds for Distinguished Young Scholar [No. 2019B151502002].