Synthesis and pharmacological evaluations of 4-hydroxycoumarin derivatives as a new class of anti- S taphylococcus aureus agents.

Objectives Due to the increasing prevalence of drug-resistant S taphylococcus aureus infection, we develop novel 4-hydroxycoumarin derivatives as antimicrobials. Methods The antibacterial activity of 4-hydroxycoumarin derivatives against drug-susceptive S . aureus ( ATCC 29213) and methicillin-resistant S . aureus ( MRSA) were evaluated using minimal inhibitory concentration ( MIC) assay; the activity of favourable compound was further observed using bacterial growth curves assay and in the MRSA infection mice. Key findings Compared with dihydropyran derivatives, compound 1 as one of biscoumarins showed most potent activity with MIC values of 4-8 μg/ml and apparently inhibited the growth rate of S . aureus ATCC 29213 and USA300 strain in concentrations of both 16 and 32 mg/ml. In the mice infected with MRSA USA300, administration of 5 mg/kg compound 1 improved the animal survival rate to 66.7%, and improved the pathological change in lung tissue compared with the infection model animals. No significant cytotoxicity of compound 1 was observed on the umbilical vein endothelial cells ( HUVECs) under the concentration of 800 μg/ml. Conclusion Compared with the dihydropyran derivatives, biscoumarins exhibited more promising activity against both drug-sensitive and drug-resistant S . aureus, and it is efficacious in treating MRSA infections in mouse models with a favourable safety in human cells. [ABSTRACT FROM AUTHOR]