RESUMO
Bioactivity-guided fractionation of the EtOH extract of the branches of Kielmeyera variabilis led to the isolation of a new acylphoroglucinol (1), which was active against all the MRSA strains tested herein, with pronounced activity against strain EMRSA-16. Compound 1 displayed an MIC of 0.5 mg/L as compared with an MIC of 128 mg/L for the control antibiotic norfloxacin. The structure of the new compound was elucidated by 1D and 2D NMR spectroscopic analysis and mass spectrometry, and experimental and calculated ECD were used to determine the absolute configurations. The compounds ß-sitosterol (2), stigmasterol (3), ergost-5-en-3-ol (4), and osajaxanthone (5) also occurred in the n-hexane fraction. The EtOAc fraction contained nine known xanthones: 3,6-dihydroxy-1,4,8-trimethoxyxanthone (6), 3,5-dihydroxy-4-methoxyxanthone (7), 3,4-dihydroxy-6,8-dimethoxyxanthone (8), 3,4-dihydroxy-2-methoxyxanthone (9), 5-hydroxy-1,3-dimethoxyxanthone (10), 4-hydroxy-2,3-dimethoxyxanthone (11), kielcorin (12), 3-hydroxy-2-methoxyxanthone (13), and 2-hydroxy-1-methoxyxanthone (14), which showed moderate to low activity against the tested MRSA strains.
Assuntos
Antibacterianos , Clusiaceae/química , Floroglucinol , Staphylococcus aureus/efeitos dos fármacos , Xantonas , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Brasil , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Componentes Aéreos da Planta/química , Estereoisomerismo , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/farmacologiaRESUMO
Human African trypanosomiasis is a neglected tropical disease in sub Saharan Africa that is fatal if left untreated. In a search for new natural products with antitrypanosomal activity, we recently identified abruquinones B and I from Abrus precatorius as potent in vitro trypanocidal compounds with high selectivity indices. To obtain sufficient compound for in vivo efficacy tests in mice, a second batch of plant material was re-collected and extracted. However, the chemical profiles of the two batches differed, and additional abruquinones were isolated and identified by HR-ESI-MS, and 1D and 2D NMR ((1)H, (13)C, COSY, HMBC, HSQC, and NOESY) spectroscopy. Abruquinones J (1), K (2), and L (3) were new, while abruquinones A (4) and D (5) were known from the first batch of plant material. The absolute configuration of compounds 1 to 3 was determined by comparison of electronic circular dichroism (ECD) spectra with calculated ECD data. Compounds 2 to 5 showed high in vitro activity against T. b. rhodesiense (IC50 of 0.01, 0.02, 0.02 and 0.01 µM, respectively), and remarkable SIs of 508, 374, 1379, and 668, respectively.
Assuntos
Abrus/química , Tripanossomicidas/isolamento & purificação , Animais , Benzopiranos/isolamento & purificação , Benzopiranos/toxicidade , Benzoquinonas/isolamento & purificação , Benzoquinonas/toxicidade , Testes de Sensibilidade Microbiana , RatosRESUMO
In vitro and in vivo activities against Trypanosoma cruzi were evaluated for two sesquiterpene lactones: psilostachyin A and cynaropicrin. Cynaropicrin had previously been shown to potently inhibit African trypanosomes in vivo, and psilostachyin A had been reported to show in vivo effects against T. cruzi, albeit in another test design. In vitro data showed that cynaropicrin was more effective than psilostachyin A. Ultrastructural alterations induced by cynaropicrin included shedding events, detachment of large portions of the plasma membrane, and vesicular bodies and large vacuoles containing membranous structures, suggestive of parasite autophagy. Acute toxicity studies showed that one of two mice died at a cynaropicrin dose of 400 mg/kg of body weight given intraperitoneally (i.p.). Although no major plasma biochemical alterations could be detected, histopathology demonstrated that the liver was the most affected organ in cynaropicrin-treated animals. Although cynaropicrin was as effective as benznidazole against trypomastigotes in vitro, the treatment (once or twice a day) of T. cruzi-infected mice (up to 50 mg/kg/day cynaropicrin) did not suppress parasitemia or protect against mortality induced by the Y and Colombiana strains. Psilostachyin A (0.5 to 50 mg/kg/day given once a day) was not effective in the acute model of T. cruzi infection (Y strain), reaching 100% animal mortality. Our data demonstrate that although it is very promising against African trypanosomes, cynaropicrin does not show efficacy compared to benznidazole in acute mouse models of T. cruzi infection.