lignans and Chagas-Disease

In the present study, the phytochemical study of the

Topics: Animals; Biological Products; Chagas Disease; Computer Simulation; Drug Discovery; Fibroblasts; Kidney; Lauraceae; Lignans; Macaca mulatta; Mice; Mice, Inbred BALB C; Phytochemicals; Reactive Oxygen Species; Trypanocidal Agents; Trypanosoma cruzi

This paper reports the synthesis of (±)-licarin A 1, a dihydrobenzofuran neolignan, resultant of an oxidative coupling reaction of isoeugenol and horseradish peroxidase (HRP) enzyme. Following, three semi-synthetic derivatives from this compound were obtained: benzylated (±)-licarin A 2, methylated (±)-licarin A 3 and acetylated (±)-licarin A 4. After structural elucidation and assignment by Nuclear Magnetic Resonance of

Topics: Animals; Chagas Disease; Computer Simulation; Lignans; Schistosoma mansoni; Schistosomiasis; Schistosomicides; Trypanocidal Agents; Trypanosoma cruzi

Topics: AMP-Activated Protein Kinases; Biphenyl Compounds; Chagas Disease; Humans; Lignans; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Sirtuin 3

Piperaceae species are abundant in the tropics and are important components of secondary vegetation. Many of these plants have received considerable attention due to their wide range of biological activities. Here, the trypanocidal activity of extracts and fractions with different polarities obtained from Colombian Piper jericoense plant was evaluated. A furofuran lignan, (1S,3aS,4S,6aS)-1-(3',4'-dimethoxyphenyl)-4-(3″,4″-methylendioxyphenyl)hexahydrofuro[3,4-c]furan, (1), was isolated from Colombian Piper jericoense leaves ethyl acetate extract. Its relative configuration at the stereogenic centers was established on the basis of various spectroscopic analyses, including 1D- (1H, 13C, and DEPT) and 2D-NMR (COSY, NOESY, HMQC and HMBC) and a 2D INADEQUATE NMR experiment as well as by comparison of their spectral data with those of related compounds such as (+)-Kobusin (2). The activity against Trypanosoma cruzi indicated that compound 1 was active against all parasite forms (epimastigote, amastigote and trypomastigote) and presented lower toxicity than the reference drug, benznidazole (Bz), evidenced by a selective index of 18.4 compared to that of Bz, which was 6.7. Moreover, this compound inhibited the infectious process, and it was active in infected mice in the acute phase. This compound significantly inhibited the T. cruzi Fe-SOD enzyme, whereas Cu/Zn-SOD from human cells was not affected. Ultrastructural analyses, together with metabolism-excretion studies in the parasite, were also performed to identify the possible mechanism of action of the tested compound. Interestingly, the lignan affected the parasite structure, but it did not alter the energetic metabolism.

Topics: Animals; Benzodioxoles; Chagas Disease; Chlorocebus aethiops; Erythrocytes; Female; Humans; Inhibitory Concentration 50; Lignans; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Piper; Plant Extracts; Plant Leaves; Trypanosoma cruzi; Vero Cells

Topics: Animals; Antiparasitic Agents; Cell Line; Cell Membrane; Chagas Disease; Humans; Lauraceae; Lignans; Macaca mulatta; Membrane Potential, Mitochondrial; Plant Leaves; Trypanosoma cruzi

Nifurtimox and benznidazole, medications currently used for the treatment of the Chagas disease, are not always successful. We determine whether (-)-cubebin and (-)-hinokinin could be used as alternative drugs for the treatment of parasitic infections by Trypanosoma cruzi. To this end, male BALB/c mice were treated with both drugs, and the nuclear parameters (largest diameter, smallest diameter, and perimeter) were determined from slides prepared from the spleen, liver, and heart. The cytotoxicity of the substances was determined after 24-h treatment. Results revealed increased cell nuclei in untreated infected animals as compared to uninfected mice. The values obtained for infected animals treated with (-)-cubebin and (-)-hinokinin were close to those observed for uninfected mice. For the spleen, perimeter values of 10.85 μm (p < 0.01) and 10.90 μm (p < 0.05) were obtained for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas untreated infected animals furnished a perimeter of 11.76 μm. As for the liver, perimeter values of 19.06 μm (p < 0.01) and 18.61 μm (p < 0.001) were achieved for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas a perimeter of 18.54 μm was obtained for untreated infected animals. The cytotoxicity assays demonstrated that (-)-cubebin and (-)-hinokinin does not display toxicity. Therefore, (-)-cubebin and (-)-hinokinin are promising therapeutic agents and could be used in future clinical studies concerning treatment of the Chagas disease. Even if the karyometry is not used frequently, it can complement other methods, such as PCR, and furthermore, it is a simple method which is easily possible to analyze the activity of substances in the tissues of treated infected animals compared to uninfected animals.

Topics: 4-Butyrolactone; Animals; Antiprotozoal Agents; Benzodioxoles; Biometry; Cell Line; Chagas Disease; Dioxoles; Disease Models, Animal; Fibroblasts; Karyotyping; Lignans; Liver; Macaca mulatta; Male; Mice; Mice, Inbred BALB C; Spleen; Trypanosoma cruzi

Even though the Chagas' disease, caused by the protozoan Trypanosoma cruzi, was described 100years ago by Carlos Chagas, it still represents a major public health concern and is found in 18 developing countries in South and Central America. In Brazil, Benznidazole (Rochagan) is the only drug with trypanocidal activity available in the market, despite its several side effects and limited efficacy in the chronic phase of the infection. In view of the need for new substances displaying biological activity against T. cruzi, there has been growing interest in research toward the attainment of compounds capable of acting on the parasite while being devoid of serious side effects. In this context, this study aims to evaluate the in vivo therapeutic activity of dibenzylbutyrolactone lignans (-)-cubebin and (-)-hinokinin during the acute phase of infection by T. cruzi. As a study criterion, animals with acute parasitemia were investigated by tissue morphometric analysis. There was significant parasitemia reduction in the groups of animals treated with (-)-cubebin or (-)-hinokin oral administration, compared to the negative control. Values close to those of the uninfected control were found in the groups treated with (-)-cubebin and (-)-hinokinin via kariometry, showing that there was positive cellular response compared to the infected control.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; Chagas Disease; Dioxoles; Lignans; Male; Mice; Mice, Inbred BALB C; Nitroimidazoles; Piper; Trypanocidal Agents; Trypanosoma cruzi

The dibenzylbutyrolactone lignan (-)-hinokinin (HK) was derived by partial synthesis from (-)-cubebin, isolated from the dry seeds of the pepper, Piper cubeba. Considering the good trypanosomicidal activity of HK and recalling that natural products are promising starting points for the discovery of novel potentially therapeutic agents, the aim of the present study was to investigate the (anti) mutagenic∕ genotoxic activities of HK.. The mutagenic∕ genotoxic activities were evaluated by the Ames test on Salmonella typhimurium strains TA98, TA97a, TA100 and TA102, and the comet assay, so as to assess the safe use of HK in the treatment of Chagas' disease. The antimutagenic ∕antigenotoxic potential of HK were also tested against the mutagenicity of a variety of direct and indirect acting mutagens, such as 4- nitro-o-phenylenediamine (NOPD), sodium azide (SA), mitomycin C (MMC), benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 2-aminoanthracene (2-AA) and 2-aminofluorene (2-AF), by the Ames test, and doxorubicin (DXR) by the comet assay.. The mutagenicity∕genotoxicity tests showed that HK did not induce any increase in the number of revertants or extent of DNA damage, demonstrating the absence of mutagenic and genotoxic activities. On the other hand, the results on the antimutagenic potential of HK showed a strong inhibitory effect against some direct and indirect-acting mutagens.. Regarding the use of HK as an antichagasic drug, the absence of mutagenic effects in animal cell and bacterial systems is encouraging. In addition, HK may be a new potential antigenotoxic ∕ antimutagenic agent from natural sources. However, the protective activity of HK is not general and varies with the type of DNA damage-inducing agent used.

Topics: 4-Butyrolactone; Animals; Antimutagenic Agents; Benzodioxoles; Cell Line; Chagas Disease; Comet Assay; Cricetinae; Dioxoles; DNA Damage; Humans; Lignans; Mutagens; Piper; Plant Extracts; Salmonella; Seeds; Trypanocidal Agents

Tetrahydrofuran lignans represent a well-known group of phenolic compounds capable of acting as antiparasitic agents. In the search for new medicines for the treatment of Chagas disease, one promising compound is grandisin which has shown significant activity on trypomastigote forms of Trypanosoma cruzi. In this work, the in vitro metabolism of grandisin was studied in the pig cecum model and by biomimetic phase I reactions, aiming at an ensuing a preclinical pharmacokinetic investigation. Although grandisin exhibited no metabolization by the pig microbiota, one putative metabolite was formed in a biomimetic model using Jacobsen catalyst. The putative metabolite was tested against T. cruzi revealing loss of activity in comparison to grandisin.

Topics: Animals; Antiprotozoal Agents; Cecum; Chagas Disease; Furans; Lignans; Molecular Structure; Piper; Plant Extracts; Swine; Trypanosoma cruzi

Because of its severe side effects and variable efficacy, the current treatment for Chagas disease is unsatisfactory. Natural compounds are good alternative chemotherapeutic agents for the treatment of this infection. Recently, our group reported the antiproliferative activity and morphological alterations in epimastigotes and intracellular amastigotes of Trypanosoma cruzi treated with eupomatenoid-5, a neolignan isolated from leaves of Piper regnellii var. pallescens. Here, we demonstrate that eupomatenoid-5 exhibited activity against trypomastigotes, the infective form of T. cruzi (EC₅₀ 40.5 μM), leading to ultrastructural alteration and lipoperoxidation in the cell membrane. Additionally, eupomatenoid-5 induced depolarization of the mitochondrial membrane, lipoperoxidation and increased G6PD activity in epimastigotes of T. cruzi. These findings support the possibility that different mechanisms may be targeted, according to the form of the parasite, and that the plasma membrane and mitochondria are the structures that are most affected in trypomastigotes and epimastigotes, respectively. Thus, the trypanocidal action of eupomatenoid-5 may be associated with mitochondrial dysfunction and oxidative damage, which can trigger destructive effects on biological molecules of T. cruzi, leading to parasite death.

Topics: Benzofurans; Chagas Disease; Glucose-6-Phosphate; Humans; Hydrogen Peroxide; Lignans; Lipid Peroxidation; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membranes; Oxidative Stress; Phenols; Phosphogluconate Dehydrogenase; Piper; Plant Extracts; Plant Leaves; Trypanocidal Agents; Trypanosoma cruzi

Trypanosoma cruzi is the ethiological agent for Chagas disease in Latin America. This study aimed to test the trypanocidal effect of licarin A and burchellin isolated from plants in northeastern Brazil. These neolignans were tested on T. cruzi and on peritoneal macrophages, to evaluate drug toxicity. Epimastigote growth was inhibited in 45% with licarin A and 20% with burchellin with an IC(50)/96 h of 462.7 microM and 756 microM, respectively. Epimastigotes treated with licarin A presented swollen mitochondria and disorganized mitochondrial cristae, kDNA and Golgi complex. When treated with burchellin, they presented enormous autophagosomes and chromatin disorganization. Licarin A and burchellin were able to induce trypomastigote death with IC(50)/24 h of 960 microM and 520 microM, respectively. Although licarin A presented an IC(50) for trypomastigotes higher than for epimastigotes, both substances acted as therapeutic trypanocidal agents, because they were able to kill parasites without affecting macrophages. Due to our results, burchellin and licarin A need to be further analysed to observe if they may be used as alternative blood additive prophylaxis against Chagas disease, since it has been established that blood transfusion is an important mechanism in the transmission process.

Topics: Animals; Benzofurans; Blood Transfusion; Brazil; Cell Survival; Chagas Disease; Humans; Inhibitory Concentration 50; Lignans; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Plant Extracts; Trypanocidal Agents; Trypanosoma cruzi

The (-)-hinokinin display high activity against Trypanosoma cruzi in vitro and in vivo. (-)-Hinokinin-loaded poly(D,L-lactide-co-glycolide) microparticles were prepared and characterized in order to protect (-)-hinokinin of biological interactions and promote its sustained release for treatment of Chagas disease. The microparticles contain (-)-hinokinin were prepared by the classical method of the emulsion/solvent evaporation. The scanning electron microscopy, light-scattering analyzer were used to study the morphology and particle size, respectively. The encapsulation efficiency was determined, drug release studies were kinetically evaluated, and the trypanocidal effect was evaluated in vivo. (-)-Hinokinin-loaded microparticles obtained showed a mean diameter of 0.862 microm with smooth surface and spherical shape. The encapsulation efficiency was 72.46 +/- 2.92% and developed system maintained drug release with Higuchi kinetics. The preparation method showed to be suitable, since the morphological characteristics, encapsulation efficiency, and in vitro release profile were satisfactory. In vivo assays showed significant reduction of mice parasitaemia after administration of (-)-hinokinin-loaded microparticles. Thus, the developed microparticles seem to be a promising system for sustained release of (-)-hinokinin for treatment of Chagas disease.

Topics: 4-Butyrolactone; Animals; Antiprotozoal Agents; Benzodioxoles; Chagas Disease; Delayed-Action Preparations; Dioxanes; Dioxoles; Disease Models, Animal; Humans; Lactic Acid; Lignans; Mice; Microspheres; Parasitemia; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Treatment Outcome; Trypanosoma cruzi

Bioguided fractionation of extract from the leaves of Aristolochia cymbifera led to the isolation of the furofuran lignans fargesin, epieudesmin, and sesamin; the dibenzylbutyrolactone lignans hinokinin and kusunokinin; and an ENT-labdane diterpene named copalic acid. Our data demonstrated that copalic acid and kusunokinin were the most active compounds against trypomastigotes of Trypanosoma cruzi. Additionally, copalic acid demonstrated the highest parasite selectivity as a result of low toxicity to mammalian cells, despite a considerable hemolytic activity at higher concentrations. Among the isolated compounds, kusunokinin could be considered the most promising candidate, as it displayed significant activity against intracellular amastigotes (IC(50) = 17 µM) and trypomastigotes (IC(50) = 51 µM) without hemolytic activity. Fargesin, hinokinin, epieudesmin, and sesamin were also effective against trypomastigotes, but these compounds were highly toxic to mammalian cells and no parasite selectivity could be identified. The need for novel drugs for American trypanosomiasis is evident, and these secondary metabolites from A. cymbifera represent a useful tool for drug design.

Topics: Animals; Aristolochia; Chagas Disease; Diterpenes; Hemolytic Agents; Inhibitory Concentration 50; Lignans; Macrophages; Mice; Mice, Inbred BALB C; Phytotherapy; Plant Extracts; Plant Leaves; Trypanocidal Agents; Trypanosoma cruzi

The reduction of parasitism tissue upon treatment with two lignano lactones, namely (-)- cubebin (CUB) and (-)-hinokinin (HNK), was evaluated in the chronic phase of Chagas' disease by quantifying the enzyme beta-galactosidase expressed by the CL B5 clone strain of Trypanosoma cruzi. Tissue karyometry was also performed. Treatment with the assessed lignans led to a larger reduction in parasitism tissue in all evaluated organs, compared with benznidazole (BZN). Oral treatment with CUB or HNK was more effective. Karyometry results demonstrated that the infected control animals had increased nuclear area compared with uninfected controls, indicating cellular hypertrophy. Results also revealed that use of CUB or HNK was able to significantly prevent this increase, and a slight decrease in the nuclear area was observed, compared with mice treated with BZN. Taken together, these data demonstrate that CUB and HNK could be considered as potential compounds for the development of new drugs for treatment of Chagas' disease.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; beta-Galactosidase; Chagas Disease; Chronic Disease; Dioxoles; Heart; Karyometry; Lactones; Lignans; Liver; Mice; Mice, Inbred BALB C; Spleen; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Five (-)-cubebin derivative compounds, (-)-O-acetyl cubebin (3), (-)-O-benzyl cubebin (4), (-)-O-(N,N-dimethylaminoethyl)-cubebin (5), (-)-hinokinin (6) and (-)-6,6'-dinitrohinokinin (7), previously synthesised by our research group, were evaluated on in vitro assay against free amastigote forms of Trypanosoma cruzi, the asogic agent of Chagas' disease. It was observed that 6 was the most active compound (IC(50)=0.7 microM), and that 4 and 5 displayed moderate activity against the parasite, giving IC(50) values of 5.7 and 4.7 microM, respectively. In contrast, it was observed that compound 3 was inactive and that 7 displayed low activity with IC(50) values of congruent with 1.5 x 10(4) and 95.3 microM, respectively.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; Chagas Disease; Inhibitory Concentration 50; Lignans; Membrane Glycoproteins; Parasitic Sensitivity Tests; Protozoan Proteins; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Seven lignans isolated from the hexane extract of the leaves of Zanthoxyllum naranjillo (Rutaceae) were tested in both in vitro and in vivo assays against two strains of Trypanosoma cruzi (Bolivia and Y). Of the seven assayed lignans, three were inactive [(+)-sesamin, (+)-piperitol-4'-O-gamma, gamma-dimethylallyl ether and (-)-3,4-dimethoxy-3',4'-demethylenedioxycubebin] and three were partially active in the in vitro assays [(-)-hibalactone, (-)-kaerophylin and (-)-cubebin]. Healthy animals developed the disease after injection of the tested infected blood samples containing these three compounds. One compound [(-)-methylpluviatolide] was highly effective in the in vitro assay and healthy animals injected with the tested samples did not develop the disease. Moreover, only (-)-methylpluviatolide was highly active against the bloodstream forms of both strains of T. cruzi for the in vivo assay. However, it was not active against the tissue forms of the parasite.

Topics: Animals; Bolivia; Brazil; Chagas Disease; Lignans; Medicine, Traditional; Mice; Plant Extracts; Plant Leaves; Plants, Medicinal; Trypanocidal Agents; Trypanosoma cruzi