A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The
in vitro
antibacterial activity of these semisynthetic derivatives against four strains of
Staphylococcus aureus
(MRSA ATCC 43300,
S.aureus
ATCC 29213,
S.aureus
AD3, and
S.aureus
144) were evaluated by the broth dilution method. Compound
13
was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 μg/mL). Furthermore, compound
13
was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound
13
exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound
13
showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 μg/mL. Molecular docking study revealed that compound
13
can effectively bind to the active site of the 50S ribosome (the binding free energy = −9.66 kcal/mol).
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 9 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 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10−8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10−8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).
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