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

Abstract

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...

Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

“…A cell viability test was performed to evaluate the cytotoxicity of the compounds against the murine fibroblast L-929 cell line [39,40]. The concentrations that caused 50% inhibition of the parasite growth (IC 50 ) were evaluated for the more potent compounds (those presenting more than 70% inhibition in the initial screening at 100 µM) ( Table 3).…”

Benznidazole Nanoformulates: A Chance to Improve Therapeutics for Chagas Disease

“…Their use in obtaining complexes of different drugs with trypanocidal action has been explored. [25][26][27][28][29] The aims of the present work were 1) to determine the in vitro trypanocidal activity of new nanostructured formulations of BNZ:small unilamellar vesicles (SUVs) (conventional nanoLPs and quatsomes [QS], lipid nanoparticles [solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs)]) and nanostructured CD complexes; and 2) to explore the toxicity of these agents in two cultured mammal cell lines.…”

Multiple Spectroscopic and Theoretical Approaches to Study the Interaction between HSA and the Antiparasitic Drugs: Benznidazole, Metronidazole, Nifurtimox and Megazol

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