In vitro evaluation of the activity of aromatic nitrocompounds against Trypanosoma cruzi

Oliveira, Renata Barbosa de; Passos, Ana Paula F.; Alves, Rosana; Romanha, Álvaro J.; Prado, Maria Auxiliadora Fontes; Filho, José Dias de Souza; Alves, Ricardo José

doi:10.1590/s0074-02762003000100018

Cited by 14 publications

(13 citation statements)

References 11 publications

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“…Several studies have reported the efficacy of compounds that possess one or more nitro groups against many pathogens (60,61,62). Thus, as expected, A3K2A3, which contains two nitro groups in its structure, had better trypanocidal activity than A3K2A1, which contains only one nitro group.…”

Section: Discussionmentioning

confidence: 51%

Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System

Lazarin-Bidóia

Desoti

Martins

et al. 2016

Antimicrob Agents Chemother

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Despite ongoing efforts, the available treatments for Chagas' disease are still unsatisfactory, especially in the chronic phase of the disease. Our previous study reported the strong trypanocidal activity of the dibenzylideneacetones A3K2A1 and A3K2A3 against Trypanosoma cruzi (Z. Ud Din, T. P. Fill, F. F. de Assis, D. Lazarin-Bidóia, V. Kaplum, F. P. Garcia, C. V. Nakamura, K. T. de Oliveira, and E. Rodrigues-Filho, Bioorg Med Chem 22:1121-1127, 2014, http://dx.doi.org/10.1016/j.bmc.2013.12.020). In the present study, we investigated the mechanisms of action of these compounds that are involved in parasite death. We showed that A3K2A1 and A3K2A3 induced oxidative stress in the three parasitic forms, especially trypomastigotes, reflected by an increase in oxidant species production and depletion of the endogenous antioxidant system. This oxidative imbalance culminated in damage in essential cell structures of T. cruzi, reflected by lipid peroxidation and DNA fragmentation. Consequently, A3K2A1 and A3K2A3 induced vital alterations in T. cruzi, leading to parasite death through the three pathways, apoptosis, autophagy, and necrosis.

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Section: Discussionmentioning

confidence: 51%

Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System

Lazarin-Bidóia

Desoti

Martins

et al. 2016

Antimicrob Agents Chemother

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“…The trypanocidal activity of aromatic non-imidazole nitrocompounds was previously described by us (Oliveira et al 2003). All compounds tested displayed lower activity against trypomastigote forms of T. cruzi (IC 50 > 450 µM) when compared to the activity of MTZ-I (111 µM).…”

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confidence: 72%

The activity of a metronidazole analogue and its β-cyclodextrin complex against Trypanosoma cruzi

Lopes

Júnior

Lopes

et al. 2011

Mem. Inst. Oswaldo Cruz

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Chagas disease is a potentially life-threatening illness caused by the flagellate protozoan Trypanosoma cruzi. In Brazil, benznidazole is the only drug available for the treatment of Chagas disease, but it has toxic side effects and is only active in the acute phase of the illness (Urbina 1999). With such an unfavourable treatment, the development of new drugs to fight Chagas disease becomes increasingly important.Because nitroaromatics have been found to be active against T. cruzi (Maya et al. 2003), we decided to evaluate the trypanocidal activity of a metronidazole (MTZ) analogue [1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I)] (Fig. 1) previously synthesised in our laboratory (Busatti et al. 2007) and its beta-cyclodextrin (β-CD) inclusion complex. We also investigated the differences in toxicity between free MTZ-I and its β-CD inclusion complex. It has been well demonstrated that inclusion complexes decrease the toxic effect of some therapeutic agents (Corrêa et al. 2005). Furthermore, the complexation of MTZ-I with CD may improve the bioavailability of MTZ-I by enhancing its water solubility.The solubility of the complex was evaluated in relation to MTZ-I with a phase solubility study. The phase solubility diagram of MTZ-I and β-CD was obtained by plotting the changes in guest solubility as a function of β-CD concentration. The solubility curve can be classified as a B s curve according to Higuchi and Connors (1965). The complex exhibits higher solubility than the guest molecule, but its limit was reached within the CD concentration ranges that were tested. Increasing the amount of available CD-molecules did not lead to a rise in solubility. However, the MTZ-I solubility increased considerably with an equimolar ratio of MTZ-I:β-CD.The solid-state inclusion complex was characterised using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). A comparison between the IR spectra of MTZ-I, β-CD, MTZ-I and β-CD in a simple 1:1 physical mixture (PM) and MTZ-I and β-CD as a complex shows some significant changes in the shape and position of the absorbance bands of the MTZ-I functional groups. Analysis of the IR spectra of the inclusion complexes revealed the most frequent changes to be in the range of 700-660 cm -1 , which were interpreted as the band corresponding to the vibration of the C-I bond. Differences were also found in the 1,526 and 1,356 cm -1 regions, which were attributed to the skeleton vibrations of the C-NO 2 group. Less pronounced changes were observed in the IR spectrum of the PM. The DSC thermal behaviours of MTZ-I, β-CD, the MTZ-I:β-CD complex and the MTZ-I:β-CD PM were also studied. The DSC curve for MTZ-I showed a typical pure crystalline substance profile with a sharp endothermic peak at 101.2ºC. The DSC curve of β-CD showed a broad endothermic peak in the range of 75-85ºC, which can be attributed to desolvation, followed by a small endothermic peak at 220.16ºC. The formation of an inclusion complex was suggested by the absence of a melting endothermic peak for MTZ-I in...

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“…The antitrypanosomals considered on this study are representatives of families with diverse structural patterns. [29][30][31][32][33][34][35][36][37][38] Figure 2 shows the whole active set collected from the literature for this work. The selected inactive group included antivirals, sedative/hypnotics, diuretics, anticonvulsivants, hemostatics, oral hypoglycemics, antihypertensives, antihelminthics, anticancer compounds as well as some other kinds of drugs, guaranteeing at the same time a great structural variability.…”

Section: Resultsmentioning

confidence: 99%

A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds

Montero-Torres

Gómez²,

Marrero-Ponce

et al. 2005

Bioorganic & Medicinal Chemistry

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In vitro evaluation of the activity of aromatic nitrocompounds against Trypanosoma cruzi

Abstract: Fourteen compounds were evaluated for their activity against Trypanosoma cruzi blood stream forms at the concentration of 500 µg/ml. Six compounds were active and re-tested at lower concentrations.

Cited by 14 publications

References 11 publications

Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System

Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System

The activity of a metronidazole analogue and its β-cyclodextrin complex against Trypanosoma cruzi

A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds

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