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1.
Bioorg Chem ; 78: 307-311, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29625270

RESUMO

Porcelia macrocarpa (Warm.) R. E. Fries (Annonaceae) is an endemic plant in Brazil where its tasty pulp has been eaten fresh. The hexane extract from its flowers was subjected to chromatographic procedures to afford four acetylene derivatives identified as octadec-9-ynoic (stearolic acid - 1), (11E)-octadec-11-en-9-ynoic (santalbic acid - 2), 8-hydroxyoctadec-9,11-diynoic (3) and 8-hydroxyoctadec-17-en-9,11-diynoic (isanolic acid - 4) acids by NMR and HRESIMS. Among tested compounds against trypomastigote forms of T. cruzi, octadec-9-ynoic acid (1) displayed higher potential with IC50 = 27.6 µM and a selectivity index (SI) higher than 7. Compounds 2 and 3 showed IC50 of approximately 60 µM while compound 4 was inactive. The lethal action of the compound 1 was investigated using spectrofluorometric techniques to detect ROS content, plasma membrane permeability and plasma membrane potential by flow cytometry. Compound 1 showed no alteration in the production of ROS of treated trypomastigotes and no alteration of the plasma membrane permeability was observed as detected by the fluorescent probe SYTOX-green after 120 min of incubation. However, by using the potential-sensitive fluorescent probe DiSBAC2(3), compound 1 caused depolarization of the plasma membrane potential when compared to untreated parasites. Our results demonstrated the anti-T. cruzi effects of compounds 1-3 isolated from flowers of P. macrocarpa and indicated that the lethal effect of compound 1 in T. cruzi could be associated to the plasma membrane disturbance of the parasite.


Assuntos
Alcinos/farmacologia , Annonaceae/química , Membrana Celular/efeitos dos fármacos , Ácidos Graxos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Alcinos/química , Alcinos/isolamento & purificação , Animais , Membrana Celular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Flores/química , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação
2.
Fitoterapia ; 125: 55-58, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29269235

RESUMO

Baccharis retusa, a medicinal Brazilian plant from Asteraceae, has been used in Brazilian folk medicine to treatment of several illnesses, including parasitic diseases. Bioactivity-guided fractionation of the n-hexane extract from the aerial parts of B. retusa resulted in the isolation and characterization of three active related diterpenes: ent-15ß-senecioyl-oxy-kaur-16-en-19-oic acid (1), ent-kaur-16-en-19-oic (2) and ent-16-oxo-17-nor-kauran-19-oic (3) acids. The structures of isolated compounds were defined by spectroscopic analysis, including NMR and HRESIMS. Antitrypanosomal activity of 1-3 was performed against cell-derived trypomastigotes using the colorimetric resazurin assay. The obtained results demonstrated that isolated compounds displayed a reduced toxicity against NCTC cells and were effective against the trypomastigote forms of T. cruzi with IC50 values of 3.8µM (1), 75.3µM (2) and 44.2µM (3). Additionally, compound 3 displayed activity against amastigote forms of T. cruzi with IC50 of 83.2µM. Compound 1 displayed the highest selectivity index (SI) when considered the trypomastigote forms, and its effect in the plasma membrane of parasite was evaluated using the fluorescent probe SYTOX Green. A considerable permeabilization (57%) in the membrane of the parasite was observed when compared to the untreated trypomastigotes. These data demonstrate, for the first time, the antitrypanosomal activity and mechanism of action of 1 and related compounds 2 and 3, obtained from aerial parts of B. retusa.


Assuntos
Baccharis/química , Diterpenos/isolamento & purificação , Tripanossomicidas/isolamento & purificação , Animais , Brasil , Linhagem Celular , Camundongos , Componentes Aéreos da Planta/química , Plantas Medicinais/química , Trypanosoma cruzi/efeitos dos fármacos
3.
Molecules ; 22(5)2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28441357

RESUMO

Leishmaniases are neglected infectious diseases caused by parasites of the 'protozoan' genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the search for new anti-leishmanial hit compounds, seven natural sesquiterpene lactones were evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum, a pathogen causing VL. The pseudoguaianolides mexicanin I and helenalin acetate demonstrated the highest selectivity and potency against intracellular amastigotes. In addition, promastigotes treated with helenalin acetate were subject to an ultrastructural and biochemical investigation. The lethal action of the compound was investigated by fluorescence-activated cell sorting and related techniques to detect alterations in reactive oxygen species (ROS) content, plasma membrane permeability, and mitochondrial membrane potential. Helenalin acetate significantly reduced the mitochondrial membrane potential and the mitochondrial structural damage was also confirmed by transmission electron microscopy, displaying an intense organelle swelling. No alteration of plasma membrane permeability or ROS content could be detected. Additionally, helenalin acetate significantly increased the production of nitric oxide in peritoneal macrophages, probably potentiating the activity against the intracellular amastigotes. Helenalin acetate could hence be a useful anti-leishmanial scaffold for further optimization studies.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacologia , Concentração Inibidora 50 , Lactonas/farmacologia , Leishmania infantum/ultraestrutura , Leishmaniose Visceral/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Sesquiterpenos/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Sesquiterpenos de Guaiano , Sesterterpenos
4.
J Nat Prod ; 80(3): 720-725, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28191951

RESUMO

Marine sponges are a rich source of terpenoids with rearranged spongian carbon skeletons. Investigation of extracts from the sponge Darwinella cf. oxeata yielded four new rearranged diterpenoids, oxeatine (2) and oxeatamides H-J (3-5), as well as the known metabolites oxeatamide A (6), oxeatamide A methyl ester (7), and membranolide (1). Oxeatine (2) has a new heterocyclic skeleton, while oxeatamide J (5) has an N-methyl urea group included in a γ-lactam moiety. UPLC-QTOF analysis of the extract obtained from the mantle of the nudibranch Felimida grahami indicated the presence of 1 and 4.


Assuntos
Diterpenos/química , Diterpenos/isolamento & purificação , Gastrópodes/química , Poríferos/química , Terpenos/química , Terpenos/isolamento & purificação , Animais , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
5.
Phytomedicine ; 24: 62-67, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28160863

RESUMO

BACKGROUND: From a previous screening of Brazilian biodiversity for antiprotozoal activity, the hexane extract from leaves of Nectandra leucantha (Nees & Mart.) (Lauraceae) demonstrated activity against Trypanosoma cruzi. Chromatographic separation of this extract afforded bioactive dehydrodieugenol (1). Furthermore, methylated derivative 2 (dehydrodieugenol dimethyl ether) was prepared and also tested against T. cruzi. PURPOSE: To examine the therapeutical potential of compounds 1 and 2 against T. cruzi as well as to elucidate the mechanism of action of bioactive compound 1 against T. cruzi. METHODS/STUDY DESIGN: Crude hexane extract from leaves was subjected to chromatographic steps to afford bioactive compound 1. In order to analyze the effect of additional methyl group in the antiparasitic activity of 1, derivative 2 was prepared (both are no pan-assay interference compounds - PAINS). These compounds were evaluated in vitro against T. cruzi (trypomastigote and amastigote forms) and analyzed for the potential effect in host cells through the production of nitric oxide and reactive oxygen species. Finally, the plasma membrane effect of the most potent compound 1 was investigated in T. cruzi trypomastigotes. RESULTS: Compounds 1 and 2 displayed activity against amastigotes of T. cruzi. Although both compounds promoted activity against intracellular amastigotes, the production of nitric oxide and reactive oxygen species of host cells were unaltered, suggesting an antiparasitic activity other than host cell activation. Considering 1 the most effective compound against T. cruzi, the interference in the plasma membrane of the trypomastigotes was investigated using the fluorescent probe SYTOX® Green. After a short-term incubation, the fluidity and integrity of the plasma membrane was completely altered, suggesting it as a primary target for compound 1 in T. cruzi. CONCLUSION: Compounds 1 and 2 selectively eliminated the intracellular parasites without host cell activation and could be important scaffolds for the search of new hit compounds.


Assuntos
Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Eugenol/uso terapêutico , Lauraceae/química , Extratos Vegetais/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Brasil , Fitoterapia , Extratos Vegetais/farmacologia , Folhas de Planta/química
6.
J Nat Prod ; 79(9): 2202-10, 2016 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-27586460

RESUMO

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.


Assuntos
Guanidinas/síntese química , Leishmania infantum/efeitos dos fármacos , Poríferos/química , Trypanosoma cruzi/efeitos dos fármacos , Alcaloides/farmacologia , Animais , Guanidinas/química , Guanidinas/farmacologia , Biologia Marinha , Estrutura Molecular , Óxido Nítrico/metabolismo
7.
Parasitol Res ; 114(12): 4625-35, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26346453

RESUMO

The present study aimed to investigate the in vitro antileishmanial activity of strychnobiflavone flavonoid against Leishmania infantum, as well as its mechanism of action, and evaluate the ex vivo biodistribution profile of the flavonoid in naive BALB/c mice. The antileishmanial activity (IC50 value) of strychnobiflavone against stationary promastigote and amastigote-like stages of the parasites was of 5.4 and 18.9 µM, respectively; with a 50% cytotoxic concentration (CC50) value of 125.0 µM on murine macrophages, resulting in selectivity index (SI) of 23.2 and 6.6, respectively. Amphotericin B, used as a positive control, presented SI values of 7.6 and 3.3 for promastigote and amastigote-like stages of L. infantum, respectively. The strychnobiflavone was also effective in reducing in significant levels the percentage of infected macrophages, as well as the number of amastigotes per macrophage, after the treatment of infected macrophages using the flavonoid. By using different fluorescent probes, we investigated the bioenergetics metabolism of L. infantum promastigotes and demonstrated that the flavonoid caused the depolarization of the mitochondrial membrane potential, without affecting the production of reactive oxygen species. In addition, using SYTOX(®) green as a fluorescent probe, the strychnobiflavone demonstrated no interference in plasma membrane permeability. For the ex vivo biodistribution assays, the flavonoid was labeled with technetium-(99m) and studied in a mouse model by intraperitoneal route. After a single dose administration, the scintigraphic images demonstrated a highest uptake by the liver and spleen of the animals within 60 min, resulting in low concentrations after 24 h. The present study therefore demonstrated, for the first time, the antileishmanial activity of the strychnobiflavone against L. infantum, and suggests that the mitochondria of the parasites may be the possible target organelle. The preferential distribution of this compound into the liver and spleen of the animals could warrant its employ in the treatment of visceral leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Flavonoides/administração & dosagem , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Strychnos/química , Animais , Antiprotozoários/isolamento & purificação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Flavonoides/isolamento & purificação , Humanos , Leishmania infantum/fisiologia , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual
8.
J Nat Prod ; 78(5): 1101-12, 2015 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-25924111

RESUMO

HPLC-UV-ELSD-MS-guided fractionation of the anti-parasitic extract obtained from the marine sponge Monanchora arbuscula, collected off the southeastern coast of Brazil, led to the isolation of a series of guanidine and pyrimidine alkaloids. The pyrimidines monalidine A (1) and arbusculidine A (7), as well as the guanidine alkaloids batzellamide A (8) and hemibatzelladines 9-11, represent new minor constituents that were identified by analysis of spectroscopic data. The total synthesis of monalidine A confirmed its structure. Arbusculidine A (7), related to the ptilocaulin/mirabilin/netamine family of tricyclic guanidine alkaloids, is the first in this family to possess a benzene ring. Batzellamide A (8) and hemibatzelladines 9-11 represent new carbon skeletons that are related to the batzelladines. Evaluation of the anti-parasitic activity of the major known metabolites, batzelladines D (12), F (13), L (14), and nor-L (15), as well as of synthetic monalidine A (1), against Trypanosoma cruzi and Leishmania infantum is also reported, along with a detailed investigation of parasite cell-death pathways promoted by batzelladine L (14) and norbatzelladine L (15).


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Guanidinas/isolamento & purificação , Guanidinas/farmacologia , Poríferos/química , Pirimidinas/isolamento & purificação , Pirimidinas/farmacologia , Alcaloides/química , Animais , Brasil , Guanidinas/química , Leishmania infantum/efeitos dos fármacos , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Testes de Sensibilidade Parasitária , Pirimidinas/química , Trypanosoma cruzi/efeitos dos fármacos
9.
Acta Trop ; 130: 112-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24239532

RESUMO

Leishmaniasis is a neglected disease that affects poorest population mainly in developing countries, representing one of the major causes of mortality and morbidity. Therefore, efforts to find new chemotherapeutics for leishmaniasis remain a priority. Previous reports demonstrated the in vitro and in vivo antileishmanial activity of nitazoxanide, an antiprotozoan agent used in the treatment of infectious diarrhea. The present work was carried out to determine the effect of nitazoxanide in combination with current antileishmanial drugs. Mouse peritoneal macrophages were infected with Leishmania (Leishmania) infantum amastigotes in order to calculate the 50% and 90% inhibitory concentration values. Drug interactions were assessed with fixed ratio isobologram method and fractional inhibitory concentrations (FIC50 and FIC90); sum of FIC (ΣFIC50 and ΣFIC90) and overall mean ΣFIC (xΣFIC50 and xΣFIC90) were calculated for each combination. The nature of interactions was classified according to the xΣFIC50 and xΣFIC90. The combination between nitazoxanide and amphotericin B, Glucantime(®), miltefosine and sitamaquine showed xΣFIC50 values of 1.13, 0.83, 1.06 and 0.94, respectively, indicating additive interaction. Considering the in vitro activity of nitazoxanide and the obtained results, further in vivo studies may be considered to evaluate possible drug interactions in visceral leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Aminoquinolinas/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/administração & dosagem , Combinação de Medicamentos , Macrófagos Peritoneais/parasitologia , Meglumina/farmacologia , Antimoniato de Meglumina , Camundongos , Nitrocompostos , Compostos Organometálicos/farmacologia , Testes de Sensibilidade Parasitária , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tiazóis/farmacologia
10.
PLoS Negl Trop Dis ; 7(12): e2556, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24340110

RESUMO

Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. The development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two-dimensional (1)H- and (13)C NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3-hydroxy-2-methyl-1-oxobutyl)-6″,6″-dimethylpyrane-[2″,3″:8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (cmax. = 1,300 µM). The lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2-yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-i'j']diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17-octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.


Assuntos
Antiprotozoários/farmacologia , Calophyllum/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/análise , Antiprotozoários/isolamento & purificação , Antiprotozoários/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/análise , Cumarínicos/isolamento & purificação , Cumarínicos/toxicidade , Eritrócitos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/fisiologia , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Espectrometria de Massas por Ionização por Electrospray , Trypanosoma cruzi/fisiologia
11.
Exp Parasitol ; 132(3): 383-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22981719

RESUMO

Leishmaniasis and Chagas disease are parasitic protozoan infections that affect the poorest population in the world, causing high mortality and morbidity. As a result of highly toxic and long-duration treatments, novel, safe and more efficacious drugs are essential. In this work, the methanol (MeOH) extract from the leaves of Piper malacophyllum (Piperaceae) was fractioned to afford one alkenylphenol, which was characterized as 4-[(3'E)-decenyl]phenol (gibbilimbol B) by spectroscopic methods. Anti-protozoan in vitro assays demonstrated for the first time that Leishmania (L.) infantum chagasi was susceptible to gibbilimbol B, with an in vitro EC(50) of 23 µg/mL against axenic promastigotes and an EC(50) of 22 µg/mL against intracellular amastigotes. Gibbilimbol B was also tested for anti-trypanosomal activity (Trypanosoma cruzi) and showed an EC(50) value of 17 µg/mL against trypomastigotes. To evaluate the cytotoxic parameters, this alkenylphenol was tested in vitro against NCTC cells, showing a CC(50) of 59 µg/mL and absent hemolytic activity at the highest concentration of 75 µg/mL. Using the fluorescent probe SYTOX Green suggested that the alkenylphenol disrupted the Leishmania plasma membrane upon initial incubation. Further drug design studies aiming at derivatives could be a promising tool for the development of new therapeutic agents for leishmaniasis and Chagas disease.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Fenóis/farmacologia , Piper/química , Animais , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/toxicidade , Bioensaio , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Células Clonais , Cricetinae , Eritrócitos/efeitos dos fármacos , Feminino , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Macrófagos Peritoneais/parasitologia , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/toxicidade , Trypanosoma cruzi/efeitos dos fármacos
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