An in-depth evaluation was undertaken of a new antibacterial natural product (1) recently isolated and characterised from the plant Hypericum olympicum L. cf. uniflorum. Minimum inhibitory concentrations (MICs) were determined for a panel of bacteria, including: meticillin-resistant and -susceptible strains of Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus; vancomycin-resistant and -susceptible Enterococcus faecalis and Enterococcus faecium; penicillin-resistant and -susceptible Streptococcus pneumoniae; group A streptococci (Streptococcus pyogenes); and Clostridium difficile. MICs were 2-8mg/L for most staphylococci and all enterococci, but were ?16mg/L for S. haemolyticus and were >32mg/L for all species in the presence of blood. Compound 1 was also tested against Gram-negative bacteria, including Escherichia coli, Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium but was inactive. The MIC for Mycobacterium bovis BCG was 60mg/L, and compound 1 inhibited the ATP-dependent Mycobacterium tuberculosis MurE ligase [50% inhibitory concentration (IC50)=75?M]. In a radiometric accumulation assay with a strain of S. aureus overexpressing the NorA multidrug efflux pump, the presence of compound 1 increased accumulation of (14)C-enoxacin in a concentration-dependent manner, implying inhibition of efflux. Only moderate cytotoxicity was observed, with IC50 values of 12.5, 10.5 and 8.9?M against human breast, lung and fibroblast cell lines, respectively, highlighting the potential value of this chemotype as a new antibacterial agent and efflux pump inhibitor.
New antibacterial acylphloroglucinols (1-5) were isolated and characterized from the aerial parts of the plant Hypericum olympicum L. cf. uniflorum. The structures of these compounds were confirmed by extensive 1D- and 2D-NMR experiments to be 4,6-dihydroxy-2-O-(3?,7?-dimethyl-2?,6?-octadienyl)-1-(2-methylbutanoyl)benzene (1), 4,6-dihydroxy-2-O-(7?-hydroxy-3?,7?-dimethyl-2?,5?-octadienyl)-1-(2-methylbutanoyl)benzene (2), 4,6-dihydroxy-2-O-(6?-hydroxy-3?,7?-dimethyl-2?,7?-octadienyl)-1-(2-methylbutanoyl)benzene (3), 4,6-dihydroxy-2-O-(6?-hydroperoxy-3?,7?-dimethyl-2?,7?-octadienyl)-1-(2-methylbutanoyl)benzene (4), and 4,6-dihydroxy-2-O-(6?,7?-epoxy-3?,7?-dimethyloct-2?-enyl)-1-(2-methylbutanoyl)benzene (5). These new natural products have been given the trivial names olympicins A-E (1-5). All compounds were evaluated against a panel of methicillin-resistant Staph. aureus and multidrug-resistant strains of Staph. aureus. Compound 1 exhibited minimum inhibitory concentrations (MICs) of 0.5-1 mg/L against the tested Staph. aureus strains. Compounds 2 to 5 were also shown to be active, with MICs ranging from 64 to 128 mg/L. Compound 1 was synthesized using a simple four-step method that can be readily utilized to give a number of structural analogues of 1.
Two new prenylated benzophenone peroxide derivatives, peroxysampsones A and B (1 and 2, resp.), together with a known compound, plukenetione C (3), were isolated from the roots of the Chinese medicinal plant Hypericum sampsonii, and their structures were elucidated by detailed spectral analysis. These compounds are the unusual peroxides of polyprenylated benzophenone derivatives, containing the unique caged moiety of 4,5-dioxatetracyclo[18.104.22.168(9,13).0(1,7)]hexadecane-12,14,15-trione. In the biological test, peroxysampsone A (1) showed comparable activity with norfloxacin against a NorA over-expressing multidrug-resistant (MDR) strain of Staphylococcus aureus SA-1199B.
In a project to isolate and characterise anti-staphylococcal compounds from members of the genus Hypericum, a dibenzofuran and a pyranone were isolated from the dichloromethane and hexane extracts of Hypericum revolutum ssp. revolutum Vahl (Guttiferae) and Hypericum choisianum Wall. ex. N. Robson (Guttiferae), respectively. The structures of these compounds were elucidated by 1- and 2D-NMR spectroscopy and mass spectrometry as 3-hydroxy-1,4,7-trimethoxydibenzofuran (1) and 4-(3-O-3)-3-methylbutenyl-6-phenyl-pyran-2-one (2). The metabolites were evaluated against a panel of multidrug-resistant strains of Staphylococcus aureus. Compound 1 exhibited a minimum inhibitory concentration (MIC) of 256 microg/ml, whereas compound 2 was inactive at a concentration of 512 microg/ml.
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