First synthesis of racemic saphenamycin and its enantiomers. investigation of biological activity.
The natural antibiotic saphenamycin, 6-[1-(2-hydroxy-6-methyl-benzoyloxy)-ethyl]-phenazine-1-carboxylic acid, was synthesized from saphenic acid using temporary allyl protection of carboxy and phenoxy functionalities. Resolution of racemic saphenic acid was performed by crystallization of the corresponding (-)-brucine diastereomeric salts and the absolute configuration of (-)-brucinium (-)-saphenate was determined by X-ray crystallography to have R-configuration. This also proved to be the configuration of natural saphenic acid. Enantiomers of saphenamycin were obtained from resolved saphenic acid and screened against a range of skin flora and resistant Staphylococcus aureus strains. Biological activities of saphenamycin enantiomers were compared with that of the synthetic racemate as well as earlier reported activities of saphenamycin isolated from natural sources. No significant difference was observed in activity of the enantiomers of saphenamycin, which revealed that the chirality of saphenamycin has no consequences for the antibiotic activity. Saphenamycin proved to be a potent antibiotic against fusidic acid and rifampicin resistant S. aureus strains showing MIC of 0.1-0.2 microg/mL.
Laursen
Jane B
JB
Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs., Lyngby, Denmark
Jørgensen
Charlotte G
CG
Nielsen
John
J
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010619:Phenazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012459:Salicylates; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D010619:Phenazines; D012459:Salicylates; C036716:saphenamycin; C005236:6-methylsalicylic acid