A series of pleuromutilin derivatives containing an oxazolidinone skeleton were synthesized and evaluated in vitro and in vivo as antibacterial agents. Most of the synthesized derivatives exhibited potent antibacterial activities against three strains of Staphylococcus aureus (including MRSA ATCC 33591, MRSA ATCC 43300, and MSSA ATCC 29213) and two strains of Staphylococcus epidermidis (including MRSE ATCC 51625 and MSSE ATCC 12228). Compound 28 was the most active antibacterial agent in vitro (MIC = 0.008-0.125 μg·mL-1) and exhibited a significant bactericidal effect, low cytotoxicity, and weak inhibition (IC50 = 20.66 μmol·L-1) for CYP3A4, as well as exhibited less possibility to cause bacterial resistance. Furthermore, in vivo activities indicated that the compound was effective in reducing MRSA load in a murine thigh infection model. Moreover, it clearly facilitated the healing of MRSA skin infection and inhibited the secretion of the TNF-α, IL-6, and MCP-1 inflammatory factors in serum. These results suggest that oxazolidinone pleuromutilin is a promising therapeutic candidate for drug-resistant bacterial infections.
Keywords: MRSA; antibacterial activities; oxazolidinone; pleuromutilin; synthesis.