Total synthesis of acylphloroglucinols and their antibacterial activities against clinical isolates of multi-drug resistant (MDR) and methicillin-resistant strains of Staphylococcus aureus

Abstract Bioassay-directed drug discovery efforts focusing on various species of the genus Hypericum led to the discovery of a number of new acylphloroglucinols including ( S , E )-1-(2-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,6-dihydroxyphenyl)-2-methylbutan-1-one ( 6 , olympicin A) from H . olympicum , with MICs ranging from 0.5 to 1 mg/L against a series of clinical isolates of multi-drug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) strains. The promising activity and interesting chemistry of olympicin A prompted us to carry out the total synthesis of 6 and a series of analogues in order to assess their structure-activity profile as a new group of antibacterial agents. Following the synthesis of 6 and structurally-related acylphloroglucinols 7 – 15 and 18 – 24 , their antibacterial activities against a panel of S. aureus strains were evaluated. The presence of an alkyloxy group consisting of 8–10 carbon atoms ortho to a five-carbon acyl substituent on the phloroglucinol core are important structural features for promising anti-staphylococcal activity.