Enzymatic Inhibitory Activity and Trypanocidal Effects of Extracts and Compounds from Siphoneugena densiflora O. Berg and Vitex polygama Cham.

Gallo, Margareth Borges Coutinho; Marques, Anna Sylvia Ferrari; Vieira, Paulo C.; Silva, Maria Fátima das Graças Fernandes da; Fernandes, João B.; Silva, Márcio; Güido, Rafael Victório Carvalho; Oliva, Glaucius; Thiemann, Otávio Henrique; Albuquerque, Sérgio de; Fairlamb, Alan H.

doi:10.1515/znc-2008-5-611

Cited by 17 publications

(8 citation statements)

References 24 publications

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“…Compounds from natural sources have been investigated as trypanothione reductase selective inhibitors in several previous studies (Bond et al 1999;Gallo et al 2008). Trypanosomatids possess a unique thiol metabolism based on trypanothione, which plays a crucial role in regulating the redox balance and also in the defence against oxidative stress in a pathway not shared by the human host (reviewed in Müller et al 2003).…”

Section: Resultsmentioning

confidence: 99%

Croton cajucara crude extract and isolated terpenes: activity on Trypanosoma cruzi

et al. 2010

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Croton cajucara is a plant found in the Amazon region and is known for its medicinal properties. The effects of the methanolic extract of the stem bark of C. cajucara (MCC) and of the isolated terpenes, trans-dehydrocrotonin (t-DCTN) and acetyl aleuritolic acid (AAA), were investigated using four isolates of Trypanosoma cruzi. In assays with trypomastigotes, the extract was more active than the isolated compounds, presenting IC(50) in the range of 10 to 50 μg/mL. The trypanocidal effect of MCC, AAA and benznidazole was significantly higher in the GLT291 and C45 strains, which were recently isolated from wild animals. MCC and AAA caused a dose-dependent inhibition of epimastigote proliferation. In assays using intracellular amastigotes, AAA and MCC reduced the percent of infection and the endocytic index after 96 h of treatment, at concentrations that were non-toxic to the host cells. MCC inhibited the trypanothione reductase pathway in both epimastigotes and trypomastigotes of all the subpopulations. The absence of AAA activity on the trypanothione reductase pathway in epimastigotes of Dm28c suggests heterogeneity of the biochemical profile between this clone and the three strains. Epimastigotes and trypomastigotes (GLT291) were treated for 24 h with MCC or AAA, and both induced alterations of the plasma membrane, while AAA-treated epimastigotes also displayed mitochondrial damage.

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Section: Resultsmentioning

confidence: 99%

Croton cajucara crude extract and isolated terpenes: activity on Trypanosoma cruzi

et al. 2010

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“…In recent years several different classes of compounds have been reported as TryR inhibitors 15–52. However, with the exception of the antimonials,8 none of these compounds are currently used clinically against trypanosomiases or leishmaniases.…”

Section: Introductionmentioning

confidence: 99%

“…In recent years several different classes of compounds have been reported as TryR inhibitors. 15 – 52 However, with the exception of the antimonials, 8 none of these compounds are currently used clinically against trypanosomiases or leishmaniases. To address the need for new compounds and new compound classes, we initiated a screening of 1266 pharmacologically active compounds from the Sigma–Aldrich LOPAC1280 library.…”

Section: Introductionmentioning

confidence: 99%

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

et al. 2009

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Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (Ki=330 nm) with an improved potency against T. brucei (EC50=775 nm).

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“…Among some other active compounds, a series of flavonoids showed interesting activity at initial concentration of 25 µM. The most potent compounds were flavones 1 and 2 (Figure 1), isolated from Vitex polygama (Verbenaceae) 28 and Lonchocarpus subglaucescens (Leguminoseae), 29 respectively, with IC 50 ) 2.5 and 13.5 µM. The IC 50 values correspond to the concentration of compound required for 50% inhibition of cathepsin V, and were determined from collected data by non-linear regression analysis.…”

Section: Resultsmentioning

confidence: 99%

Solution Phase Synthesis of a Combinatorial Library of Chalcones and Flavones as Potent Cathepsin V Inhibitors

et al. 2010

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Cathepsin V is a papain-like cysteine protease. It is involved in the control of human T cells (responsible for cell immunity), and presents the largest elastolytic activity among the proteolytic enzymes. Therefore, cathepsin V is a potential molecular target for the treatment of atherosclerosis. In the present work, natural flavonoids were screened against cathepsin V, and two flavones were identified as potent inhibitors of cathepsin V. On the basis of this result, a combinatorial library of chalcones and flavones was prepared, in solution phase employing a scavenger reagent, and fully evaluated.

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Enzymatic Inhibitory Activity and Trypanocidal Effects of Extracts and Compounds from Siphoneugena densiflora O. Berg and Vitex polygama Cham.

Cited by 17 publications

References 24 publications

Croton cajucara crude extract and isolated terpenes: activity on Trypanosoma cruzi

Croton cajucara crude extract and isolated terpenes: activity on Trypanosoma cruzi

Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

Solution Phase Synthesis of a Combinatorial Library of Chalcones and Flavones as Potent Cathepsin V Inhibitors

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