RESUMO
Leishmaniasis, a complex of diseases caused by protozoa of the genus Leishmania, is endemic in 98 countries, affecting approximately 12 million people worldwide. Current treatments for leishmaniasis have many disadvantages, such as toxicity, high costs, and prolonged treatment, making the development of new treatment alternatives highly relevant. Several studies have verified the antileishmanial activity of ß-carboline compounds. In the present study, we investigated the in vitro antileishmanial activity of N-butyl-[1-(4-methoxy)phenyl-9H-ß-carboline]-3-carboxamide (ß-CB) against Leishmania amazonensis. The compound was active against promastigote, axenic amastigote, and intracellular amastigote forms of L. amazonensis, exhibiting high selectivity for the parasite. Moreover, ß-CB did not exhibit hemolytic or mutagenic potential. Promastigotes treated with the alkaloid presented rounding of the body cell, cell membrane projections, an increase in the number of promastigotes presenting two flagella, and parasites of abnormal phenotype, with three or more flagella and/or nuclei. Furthermore, we observed an increase in the subpopulation of cells in the G2/M stage of the cell cycle. Altogether, these results suggest that ß-CB likely prevents cytokinesis, although it does not interfere with the duplication of cell structures. We also verified an increase in O2(·-) production and the accumulation of lipid storage bodies. Cell membrane integrity was maintained, in addition to the absence of phosphatidylserine externalization, DNA fragmentation, and autophagosomes. Although the possibility of an apoptotic process cannot be discarded, ß-CB likely exerts its antileishmanial activity through a cytostatic effect, thus preventing cellular proliferation.
Assuntos
Antiprotozoários/farmacologia , Carbolinas/farmacologia , Citocinese/efeitos dos fármacos , Citostáticos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Estágios do Ciclo de Vida/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Cultura Axênica , Carbolinas/síntese química , Linhagem Celular , Citostáticos/síntese química , Eritrócitos/efeitos dos fármacos , Feminino , Flagelos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leishmania mexicana/crescimento & desenvolvimento , Leishmaniose Cutânea/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Leishmaniasis has an overwhelming impact on global public health especially in tropical and subtropical countries and the currently available antileishmanial drugs have serious side effects and low efficacy. Natural and synthetic compounds have been tested in the past few years against Leishmania and the beta-carboline class of compounds have shown great results in antiparasitic chemotherapy. In the present study, three 1-substituted beta-carboline-3-carboxamides (3-5) and 1-substituted beta-carboline-3-carboxylic acid (2) were synthesized and screened for in vitro activity against L. amazonensis. Compound 5 (N-benzyl 1-(4-methoxy)phenyl-9H-beta-carboline-3-carboxamide) had the best activity against promastigote and axenic amastigote forms with IC(50) of 2·6 and 1·0 µM, respectively. Its CC(50) on macrophages cell line was higher than 2457·0 µM with an SI ratio of 930·2. Against intracellular amastigote forms, it had a dose-dependent relationship with a 50% growth inhibitory concentration of 1·0 µM. Through morphological and ultrastructure analysis of promastigote forms treated with compound 5, alterations on cell shape and number of flagella and nuclear membrane damage were observed. For this, compound 5 supports the idea for more in vitro and in vivo studies.
Assuntos
Antiprotozoários/farmacologia , Carbolinas/farmacologia , Leishmania/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Carbolinas/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Leishmania/crescimento & desenvolvimento , Leishmania/ultraestrutura , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Microscopia Eletrônica de Varredura , Testes de Sensibilidade Parasitária/métodosRESUMO
Leishmaniasis, Chagas' disease and schistosomiasis (bilharzia) are parasitic diseases with wide distribution on the American continent, affecting millions of people. In the present study, biological assays for antiprotozoal and molluscicidal activities were carried out with ethanolic extracts of plant species from the Brazilian part of the Upper Paraná River. Crude extracts were obtained by percolation with absolute ethanol from the leaves of Cayaponia podantha Cogn., Nectandra falcifolia (Nees) Castiglioni and Paullinia elegans Cambess., as well as from the aerial parts of Helicteres gardneriana St. Hil. & Naud. and Melochia arenosa Benth., all belonging to genera used in folk medicine. Trypanocidal activity of plants was assayed on epimastigote cultures in liver infusion tryptose. Anti-leishmanial activity was determined over cultures of promastigote forms of the parasite in Schneider's Drosophila medium. Microscopic countings of parasites, after their incubation in the presence of different concentrations of the crude extracts, were made in order to determine the percentage of growth inhibition. C. podantha and M. arenosa, at a concentration of 10 æg/mL, showed 90.4 ± 11.52 and 88.9 ± 2.20 percent growth inhibition, respectively, of epimastigote forms of Trypanosoma cruzi, whereas N. falcifolia demonstrated an LD50 of 138.5 æg/mL against promastigote forms of Leishmania (Viannia) braziliensis. Regarding molluscicidal activity, the acute toxicity of the extracts on Biomphalaria glabrata was evaluated by a rapid screening procedure. M. arenosa was 100 percent lethal to snails at 200 æg/mL and showed an LD50 of 143 æg/mL. Screening of plant extracts represents a continuous effort to find new antiparasitic drugs.
Assuntos
Animais , Antiprotozoários/farmacologia , Biomphalaria/efeitos dos fármacos , Leishmania braziliensis/efeitos dos fármacos , Moluscocidas/farmacologia , Plantas Medicinais/química , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/isolamento & purificação , Brasil , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Moluscocidas/isolamento & purificação , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologiaRESUMO
Leishmaniasis, Chagas' disease and schistosomiasis (bilharzia) are parasitic diseases with wide distribution on the American continent, affecting millions of people. In the present study, biological assays for antiprotozoal and molluscicidal activities were carried out with ethanolic extracts of plant species from the Brazilian part of the Upper Paraná River. Crude extracts were obtained by percolation with absolute ethanol from the leaves of Cayaponia podantha Cogn., Nectandra falcifolia (Nees) Castiglioni and Paullinia elegans Cambess., as well as from the aerial parts of Helicteres gardneriana St. Hil. & Naud. and Melochia arenosa Benth., all belonging to genera used in folk medicine. Trypanocidal activity of plants was assayed on epimastigote cultures in liver infusion tryptose. Anti-leishmanial activity was determined over cultures of promastigote forms of the parasite in Schneider's Drosophila medium. Microscopic countings of parasites, after their incubation in the presence of different concentrations of the crude extracts, were made in order to determine the percentage of growth inhibition. C. podantha and M. arenosa, at a concentration of 10 microg/mL, showed 90.4 +/- 11.52 and 88.9 +/- 2.20% growth inhibition, respectively, of epimastigote forms of Trypanosoma cruzi, whereas N. falcifolia demonstrated an LD50 of 138.5 microg/mL against promastigote forms of Leishmania (Viannia) braziliensis. Regarding molluscicidal activity, the acute toxicity of the extracts on Biomphalaria glabrata was evaluated by a rapid screening procedure. M. arenosa was 100% lethal to snails at 200 microg/mL and showed an LD50 of 143 microg/mL. Screening of plant extracts represents a continuous effort to find new antiparasitic drugs.
Assuntos
Antiprotozoários/farmacologia , Biomphalaria/efeitos dos fármacos , Leishmania braziliensis/efeitos dos fármacos , Moluscocidas/farmacologia , Plantas Medicinais/química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/isolamento & purificação , Brasil , Moluscocidas/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologiaRESUMO
The crude methanolic extract of the aerial parts of Tillandsiastreptocarpa was investigated for their acute toxicity and antioedematogenic, antioxidant and antimicrobial activities. Also, the antioedematogenic activity of the hexane fraction resulting from the partition of the crude methanolic extract was evaluated. The methanolic extract and the hexane fraction showed significant (P < 0.05) inhibition of ear oedema, observed at 2 mg/ear in the croton oil-induced mice ear oedema test. In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging test, a high reactivity and potent antioxidant effect (IC(50) = 0.0056%, w/v) were observed for the methanolic extract. The antimicrobial activity assay showed that the crude methanolic extract was inactive toward Escherichiacoli, Staphylococcusaureus, Pseudomonasaeruginosa, Bacillussubtilis, Candidaalbicans, C. parapsilosis, C. krusei and C. tropicalis (MIC > 500 microg/ml). The methanolic extract showed no toxic effect on mice at a single dose of 2000 mg/kg (p.o). Common side effects including mild diarrhoea, loss of weight and depression were not recorded. The compounds cycloartenol, 4',5-dihydroxy-3',7-dimethoxyflavanone and a mixture of the steroids stigmasterol, beta-sitosterol and campesterol, were isolated from the hexane fraction and identified by spectroscopic methods.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Sequestradores de Radicais Livres/farmacologia , Tillandsia , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/tratamento farmacológico , Feminino , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/uso terapêutico , Masculino , Camundongos , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Componentes Aéreos da Planta , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
Aerial parts of Solanum orbignianum afforded a new steroidal alkaloid glycoside, leptinidine 3-O-beta-D-glucopyranoside, together with the known alkaloids leptinidine, leptinine I and leptinine II. Their structures were established by spectroscopic methods.