3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

Couto, Marcos; Sánchez, Carina; Dávila, Belén; Machín, Valentina; Varela, Javier; Álvarez, Guzmán; Cabrera, Mauricio; Celano, Laura; Aguirre-López, Beatriz; Cabrera, Nallely; Gómez‐Puyou, Marietta Tuena de; Gómez‐Puyou, Armando; Pérez‐Montfort, Ruy; Cerecetto, Hugo; González, Mercedes

doi:10.3390/molecules200814595

Cited by 13 publications

(6 citation statements)

References 29 publications

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“…Tbf showed squalene and lanosterol accumulation and ergosterol depletion as expected because Tbf is a known SBI [38]. These results seem to corroborate the inhibitory activity of terbinafine on the enzymes squalene-2,3-epoxidase and CYP51 described in the literature [8,39].…”

Section: Application Of the Methods To Real Samplessupporting

confidence: 86%

Development, validation and application of a GC–MS method for the simultaneous detection and quantification of neutral lipid species in Trypanosoma cruzi

Santivañez-Veliz

Moreno‐Viguri

Pérez‐Silanes

et al. 2017

Journal of Chromatography B

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The development and validation of an analytical method for the simultaneous analysis of five neutral lipids in Trypanosoma cruzi epimastigotes by GC-MS is presented in this study. The validated method meets all validation parameters for all components and the chromatographic conditions have been optimized during its development. This analytical method has demonstrated good selectivity, accuracy, within-day precision, recovery and linearity in each of the established ranges. In addition, detection and quantification limits for squalene, cholesterol, ergosterol and lanosterol have been improved and it is worth highlighting the fact that this is the first time that squalene-2,3-epoxide validation data have been reported. The new validated method has been applied to epimastigotes treated with compounds with in vitro anti-T.cruzi activity. This new methodology is straightforward and constitutes a tool for screening possible sterol biosynthesis pathway inhibitors in Trypanosoma cruzi, one of the most studied targets in Chagas disease treatment. Therefore, it is an interesting and useful contribution to medicinal chemistry research.

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Section: Application Of the Methods To Real Samplessupporting

confidence: 86%

Development, validation and application of a GC–MS method for the simultaneous detection and quantification of neutral lipid species in Trypanosoma cruzi

Santivañez-Veliz

Moreno‐Viguri

Pérez‐Silanes

et al. 2017

Journal of Chromatography B

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“…Spectral intensities were scaled to internal standard and reduced to integrated regions of equal width (0.04) corresponding to the region of δ 0.0–10.0 by AMIX software. The region of δ 4.85–4.95 ppm was excluded from the analysis because of the residual signal of H 2 O [38,52,53,54,55].…”

Section: Methodsmentioning

confidence: 99%

Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers

et al. 2019

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Different strategies have been used to mitigate greenhouse gas emissions from domesticated ruminants, including the removal of protozoa (defaunation). The objective of the present work was to analyze the potential of different N-oxide-containing aromatic heterocycles with known antiprotozoal activity as rumen-gas-abating agents. Nineteen pure compounds, belonging to seven different N-oxide chemotypes from our chemo-library were studied together with monensin in an in vitro rumen simulation assay. Fermentation profiles, i.e., gas production, pH, and short carboxylic acid concentrations, were compared to an untreated control at 96 h post inoculation. In our study, we investigated whole-ruminal fluid, with and without compound treatments, by NMR spectroscopy focusing on concentrations of the metabolites acetate, propionate, butyrate, and lactate. From data analysis, three of the compounds from different N-oxide chemotypes, including quinoxaline dioxide, benzofuroxan, and methylfuroxan, were able to diminish the production of gases such as monensin with similar gas production lag times for each of them. Additionally, unlike monensin, one methylfuroxan did not decrease the rumen pH during the analyzed incubation time, shifting rumen fermentation to increase the molar concentrations of propionate and butyrate. These facts suggest interesting alternatives as feed supplements to control gas emissions from dairy ruminants.

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“…This compound exhibited IC 50 ¼ 4.9 mM and SI ¼ 12.8, but the mechanistic studies were not able to correlate its activity with TcTIM (glycolytic enzyme triosephosphate isomerase), cruzipain or membrane sterol biosynthesis (Fig. 8) [43].…”

Section: Phenotype-based Screeningmentioning

confidence: 99%

Current advances in drug discovery for Chagas disease

Scarim

Jornada

Chelucci

et al. 2018

European Journal of Medicinal Chemistry

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Chagas disease, also known as American trypanosomiasis, is one of the 17 neglected tropical diseases (NTDs) according to World Health Organization. It is estimated that 8-10 million people are infected worldwide, mainly in Latin America. Chagas disease is caused by the parasite Trypanosoma cruzi and is characterized by two phases: acute and chronic. The current therapy for Chagas disease is limited to drugs such as nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease. In addition, several side effects ranging from hypersensitivity to bone marrow depression and peripheral polyneuropathy have been associated with these drugs. Therefore, the current challenge is to find new effective and safe drugs against this NTD. The aim of this review is to describe the advances in the medicinal chemistry of new anti-chagasic compounds reported in the literature in the last five years. We report promising prototypes for drug discovery identified through target-based and phenotype-based strategies and present some important targets for the development of new synthetic compounds.

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3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

Cited by 13 publications

References 29 publications

Development, validation and application of a GC–MS method for the simultaneous detection and quantification of neutral lipid species in Trypanosoma cruzi

Development, validation and application of a GC–MS method for the simultaneous detection and quantification of neutral lipid species in Trypanosoma cruzi

Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers

Current advances in drug discovery for Chagas disease

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