Natural Compounds: Natural Sesquiterpene Esters. Part 1 and Part 2

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Results were expressed as the ratio between the weight on each day and the weight registered the day of the infection multiplied by GraphPad Prism 5. To calculate the IC 50 values, the percentages of inhibition were plotted against the drug concentration and fitted with a straight line determined by a linear regression Sigma Plot 10 software. Results presented are representative of three to four independent experiments. Parasitemia and weight loss were analyzed using a non parametric test: Mann-Whitney test.

The survival curves were analyzed with a log rank test. Comparisons were referred to the control group. The Mikania variifolia dichloromethane extract was evaluated for its trypanocidal activity on T. Two active fractions were obtained by bioassay-guided fractionation which caused inhibitions of Three compounds 1—3 were isolated from these fractions. From the active fractions MM3 and MM4 of the organic extract of Mikania micrantha , four compounds 1—4 were isolated. Compounds 1—4 were identified by spectroscopic methods and by comparison with literature data [ 18 ]. Compound 1 was identified as mikanolide; compound 2 as dihydromikanolide, compound 3 as deoxymikanolide and compound 4 as scandenolide Fig 1.

The content of these sesquiterpene lactones is shown in Table 1.

Biosynthesis of thiocarboxylic acid-containing natural products | Nature Communications

The trypanocidal activity of the isolated compounds was analyzed on T. For benznidazole, an IC 50 of 1. Epimastigotes were adjusted at 1. Growth inhibition of parasites was evaluated by a [ 3 H] thymidine uptake assay. The trypanocidal activity against bloodstream trypomastigotes was then analyzed for each drug. The reference drug benznidazole showed an IC 50 of Finally, the inhibition of amastigotes replication was tested on transgenic T.

Mikanolide, deoxymikanolide and dihydromikanolide were active against this replicative form of the parasite with IC 50 values of 4. The IC 50 value for benznidazole was 1. Plates were incubated for 6 h and quantified at nm. Scandenolide showed IC 50 values of A moderate activity against L. The reference drug, amphotericin B, presented an IC 50 value of 0. Growth inhibition of parasites was evaluated by a MTT assay. The in vitro cytotoxic effect of each compound was evaluated on a human cell line by the trypan blue exclusion method.

Viable human cells were incubated in the absence and presence of increasing concentrations of the compounds. Deoxymikanolide presented a CC 50 value of These SI values were higher than those obtained for mammalian cells. CC 50 values for dihydromikanolide and mikanolide were Selectivity indexes for these STLs were 50 and 1. Selectivity indexes of the compounds for L. Since deoxymikanolide presented good selectivity on differents T.

As shown in Fig 6A , infected mice that received deoxymikanolide presented a lower blood parasitemia, as compared to controls. Moreover, in terms of area under the parasitemia curve, a 1.

More importantly, in deoxymikanolide-treated mice, a significant decrease in the mortality caused by T. These results highlight the in vivo efficacy of deoxymikanolide to induce the killing of circulating trypomastigotes during the acute infection.

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Parasitemia A , body weight loss B , and Survival C , during the acute phase of the parasite infection were analyzed. Results presented are representative of three independent experiments. Four sesquiterpene lactones of the germacranolide type have been isolated and identified from M. Mikanolide, dihydromikanolide and deoxymikanolide were identified in M. All the compounds, with the exception of scandenolide, showed high activity on T.

Mikanolide, deoxymikanolide and dihydromikanolide were also active against trypomastigote and amastigote forms. Due to the existence of coinfections with both T.


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Mikanolide and deoxymikanolide showed significant activity against L. On the other hand, scandenolide was not active against this parasite stage.

Background

Steric and electronic factors could also influence the anti- T. The four isolated compounds differ from each other in the number of epoxy groups, in the presence or absence of the exocyclic double bond and in the presence of an OAc group at C In comparing the results of activity obtained for mikanolide and dihydromikanolide on the different T.

Despite the different number of epoxy groups present in mikanolide and deoxymikanolide structures, both compounds showed similar activity on this parasite. On the other hand, the presence of the exocyclic double bond seems to be important for the leishmanicidal activity, since mikanolide and deoxymikanolide were active, while dihydromikanolide was moderately active. Scandenolide did not show any antiprotozoal activity, suggesting that the presence of an OAc at C-3 could be responsible for the decrease of such activity.

A strong correlation between biological activity and cytotoxicity of STLs has been reported [ 29 ]. Although many of them display a considerable cytotoxic activity against mammalian cells, some of these compounds show more selectivity against the parasites [ 31 ]. Deoxymikanolide presented a CC 50 that was approximately four times higher than mikanolide, thus proving to be more selective for the parasite.

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There are previous reports describing the presence of mikanolide, dihydromikanolide, deoxymikanolide and scandenolide in M. Although these sesquiterpene lactones have been evaluated for other activities [ 20 , 22 , 32 ], this is the first study that describes their trypanocidal and leishmanicidal effects. Herein, the STLs of M. An optimal response to treatment of trypanosomatid diseases is strongly linked to an efficient immune response.

The biological activities of lactones, including sesquiterpenoids are largely due to their inhibitory effects on the activity of a plethora of enzymes of prokaryotic organisms and eukaryotic cells [ 37 ]. Sesquiterpene lactones have proved to be potent inhibitors of different transcription factors [ 38 , 39 ].

These effects are presumed to be related to molecular mechanisms determining the immune activity of sesquiterpene lactones. Harmatha et al. Based on its activity and selectivity, we selected deoxymikanolide for the evaluation of its immunomodulatory activity on macrophage cells, which are the first line of defense against T. Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide were isolated from M. With the exception of scandenolide, all the sesquiterpene lactones showed trypanocidal and leishmanicidal activities. Deoxymikanolide was the most promising compound based on its activity, selectivity and its capacity to stimulate cytokine production.

Besides, this compound was also active in a murine model of T.

Biosynthesis of thiocarboxylic acid-containing natural products

This finding makes it an interesting lead molecule which may be useful for the development of new drugs, alone or in combination with actual therapy, for the treatment of trypanosomatid diseases, in order to reduce side effects. Trypanocidal activity of the reference drug benznidazol determined by in vitro assays against: epimastigotes A , trypomastigotes B and amastigotes C of T. In vivo treatment with benznidazol in a murine model of T. Area under curve AUC was determined. Abstract Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts.


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Author summary Chagas' disease and Leishmaniasis are parasitic diseases that affect especially poor people in developing countries. Materials and methods Plant material The aerial parts of Mikania variifolia Hieron. Parasites Trypanosoma cruzi epimastigotes RA strain were grown in a biphasic medium. Preparation of extracts The extraction of the aerial parts of M. Bioassay-guided fractionation of M. Isolation of compounds from Mikania micrantha The fractionation procedure of M.

HPLC analysis of M. In vitro trypanocidal activity The evaluation of T. In vitro leishmanicidal activity The growth inhibition of Leishmania braziliensis promastigotes was evaluated by the MTT method. Cytokine production RAW Animal model of T.

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Results Trypanocidal activity and fractionation of Mikania variifolia dichloromethane extract The Mikania variifolia dichloromethane extract was evaluated for its trypanocidal activity on T. Isolation and identification of compounds from fractions 3 and 4 of Mikania micrantha From the active fractions MM3 and MM4 of the organic extract of Mikania micrantha , four compounds 1—4 were isolated. Download: PPT.