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1.
Eur J Med Chem ; 176: 162-174, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103897

RESUMO

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 µM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 µM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 µM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.


Assuntos
Anisóis/farmacologia , Lignanas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anisóis/síntese química , Anisóis/química , Anisóis/toxicidade , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Humanos , Lignanas/síntese química , Lignanas/química , Lignanas/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo
2.
Bioorg Chem ; 89: 103001, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31129501

RESUMO

This work describes the isolation of six metabolites from leaves and branches of Piper cernuum (Piperaceae): (-)-cubebin (1), (-)-hinokinin (2), (-)-kusunokinin (3), trans-dehydroagarofuran (4), 11-hydroxi-4,5-secoeudesmane-4,5-dione (5), and (-)-bornyl p-coumarate (6). Antitrypanosomal activity and toxicity of purified compounds were performed in vitro against trypomastigote forms of Trypanosoma cruzi and NCTC cells, respectively. Compounds 2, 3 and 5 showed moderate activities with IC50 values of 33.1, 31.8 and 45.9 µM, respectively, while compounds 1 and 4 were inactive (IC50 > 100 µM). On the other hand, compound 6 displayed an IC50 value of 2.1 µM, a selectivity index (SI) of 18 and induced a considerable interference in the plasma membrane permeability (87%) in trypomastigotes of T. cruzi. Additionally, the lethal effect of compound 6 in T. cruzi could be associated to the plasma membrane permeability. Finally, experiments using scanning electron microscopy (SEM) confirmed the obtained results in which was possible to observe total alteration parasites topography after treatment with compound 6 in comparison to untreated parasites. These data indicated that the lethal action of compound 6 is directly related to structural disruption of the membrane.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Piperaceae/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células Cultivadas , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação
3.
Artigo em Português | Sec. Est. Saúde SP, LILACS, Sec. Est. Saúde SP, SESSP-IALPROD, Sec. Est. Saúde SP, SESSP-IALACERVO | ID: biblio-1007421

RESUMO

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neo- lignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 mM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 mM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 mM. The phenolic ac- etate derivative of natural dehydrodieugenol


Assuntos
Trypanosoma cruzi , Doença , Doença de Chagas
4.
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
5.
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
6.
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
7.
Bioorg Med Chem Lett ; 26(4): 1180-3, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26821820

RESUMO

The essential oils from leaves of Piper malacophyllum (Piperaceae) showed to be mainly composed by two alkenylphenol derivatives: gibbilimbols A and B. After isolation and structural characterization by NMR and MS data analysis, both compounds were evaluated against promastigote/amastigote forms of Leishmania (L.) infantum as well as trypomastigote/amastigote forms of Trypanosoma cruzi. The obtained results indicated that gibbilimbol B displayed potential against the tested parasites and low toxicity to mammalian cells, stimulating the preparation of several quite simple synthetic analogues in order to improve its activity and to explore the preliminary structure-activity relationships (SAR) data. Among the prepared derivatives, compound LINS03003 (n-octyl-4-hydroxybenzylamine) displayed the most potent IC50 values of 5.5 and 1.8 µM against amastigotes of T. cruzi and L. (L.) infantum, respectively, indicating higher activity than the natural prototype. In addition, this compound showed remarkable selectivity index (SI) towards the intracellular forms of Leishmania (SI=13.1) and T. cruzi (SI=4.3). Therefore, this work indicated that preparation of synthetic compounds structurally based in the bioactive natural products could be an interesting source of novel and selective compounds against these protozoan parasites.


Assuntos
Antiprotozoários/síntese química , Fenóis/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Óleos Voláteis/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Piperaceae/química , Piperaceae/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
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