title: Synthesis and pharmacological evaluations of 4-hydroxycoumarin derivatives as a new class of anti-Staphylococcus aureus agents.
abstract: OBJECTIVE
  Due to the increasing prevalence of drug-resistant Staphylococcus 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Zhou-peng
authors.initials: ZP
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Qu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Yang
authors.forename: Zi-dan
authors.initials: ZD
authors.lastname: Zhang
authors.forename: Yu-kun
authors.initials: YK
authors.lastname: Wang
authors.forename: Xiao-xing
authors.initials: XX
authors.lastname: Luo
authors.forename: Ming-kai
authors.initials: MK
authors.lastname: Li
mesh_terms: D015110:4-Hydroxycoumarins / Q000096:biosynthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D008168:Lung / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus
chemical_list: D015110:4-Hydroxycoumarins; D000900:Anti-Bacterial Agents; C068805:4-hydroxycoumarin
keywords: Staphylococcus aureus; coumarin; dihydropyran; single crystal