RESUMO
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-(3â³,7â³-dimethyl-2â³,6â³-octadienyl)-1-(2'-methylbutanoyl)benzene (1), 4,6-dihydroxy-2-O-(7â³-hydroxy-3â³,7â³-dimethyl-2â³,5â³-octadienyl)-1-(2'-methylbutanoyl)benzene (2), 4,6-dihydroxy-2-O-(6â³-hydroxy-3â³,7â³-dimethyl-2â³,7â³-octadienyl)-1-(2'-methylbutanoyl)benzene (3), 4,6-dihydroxy-2-O-(6â³-hydroperoxy-3â³,7â³-dimethyl-2â³,7â³-octadienyl)-1-(2'-methylbutanoyl)benzene (4), and 4,6-dihydroxy-2-O-(6â³,7â³-epoxy-3â³,7â³-dimethyloct-2â³-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.
Assuntos
Antibacterianos , Hypericum/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Floroglucinol , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
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 1â¯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.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Floroglucinol/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Floroglucinol/síntese química , Floroglucinol/química , Relação Estrutura-AtividadeRESUMO
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 2-8 mg/L for most staphylococci and all enterococci, but were ≥16 mg/L for S. haemolyticus and were >32 mg/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 60 mg/L, and compound 1 inhibited the ATP-dependent Mycobacterium tuberculosis MurE ligase [50% inhibitory concentration (IC(50)) = 75 µM]. 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 µM 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.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hypericum/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Extratos Vegetais/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/toxicidade , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Extratos Vegetais/isolamento & purificaçãoRESUMO
The leaves of Boenninghausenia albiflora afforded an insecticidal coumarin which was identified as murraxocin (7-methoxy-8-[1'-ethoxy-2'-hydroxy-3'-methyl-but-3'enyl]-coumarin) (1), on the basis of extensive 1- and 2-dimensional NMR experiments. This compound has previously been isolated from Murraya exotica but this is the first report of the full (1)H and (13)C data for this compound. This natural product was evaluated against important forest insect pests and was active against Plecoptera reflexa, Clostera cupreata and Crypsiptya coclesalis at different concentrations varying from 1.0% to 5% w/v. In the crude extract 70% mortality was observed, and for compound 1 80% mortality was observed at a concentration of 1.0% w/v. The percentage of insect mortality increased in a dose-dependent manner. Coumarins are poorly studied insecticides and there is potential to exploit this chemically simple group of natural products.