Rapid test for the evaluation of the activity of the prodrug hydroxymethylnitrofurazone in the processing of Trypanosoma cruzi messenger RNAs

Barbosa, C.F.; Okuda, E.S.; Chung, M.C.; Ferreira, Elizabeth Igne; Cicarelli, Regina Maria Barretto

doi:10.1590/s0100-879x2007000100005

Cited by 10 publications

(9 citation statements)

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“…NFOH presented the same voltammetric behavior and electroactivity, indicating that the molecular modification performed in NF did not change its capacity to be reduced [15] . We and others have shown NFOH has 2-fold more cytotoxic activity than the parental compound NF against T. cruzi [15] , [16] . The mechanism of action of NFOH against T. cruzi is not completely clear; however, like all nitroheterocyclic compounds, it is enzymatically reduced at the nitro group resulting in the generation of nitroanion (RNO 2 •− ) and hydronitroxide (RNHO •− ) free radicals [17] .…”

Section: Introductionmentioning

confidence: 67%

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

et al. 2014

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BackgroundTreatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known.MethodsHepG2 cells dose response to NFOH and BZL (5–100 µM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored.ResultsHepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-α), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT) and a 20–40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment.ConclusionsNFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted.

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Section: Introductionmentioning

confidence: 67%

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

et al. 2014

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“…The literature showed that the inhibition of the trypanothione reductase was a possible mechanism of action of nitrofurazone (22,23,24); Trossini and coworkers (16) showed cruzipain inhibition and an increase of 30% in affinity for the enzyme. In addition, the most interesting and important point is the simplicity of the NFOH synthesis and its high yield (10), suggesting a very cheap compound for chemical scale-up.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Hydroxymethylnitrofurazone, a Promising New Prodrug for Chagas' Disease Treatment

Serafim

Silva

Moreno

et al. 2013

Antimicrob Agents Chemother

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dHydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (T max ) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [C max] ‫؍‬ 0.83 g/ml; area under the concentration-time curve from 0 to 12 h [AUC 0 -12] ‫؍‬ 5.683 g/ml · h) than observed for administered NF (C max ‫؍‬ 2.78 g/ml; AUC 0 -12 ‫؍‬ 54.49 g/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas' disease drug candidate.

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“…The native conformation of dUTpase from T. cruzi was determined and it revealed stumpy structural similarities with human dUTpase. This suggests certain specificity, making this enzyme another potential therapeutic target until today; however, no drug had demonstrated potential inhibition [145].…”

Section: Other Promising Targetsmentioning

confidence: 99%

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

Oliveira¹,

Mendes²,

Almeida³

et al. 2014

CRJ

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Abstract:Chagas disease is an infectious illness with a broad distribution throughout the South American and African continents, importantly influencing human morbidity and mortality and a controversial relationship with the onset of cancers, especially of the gastrointestinal tract system. In addition, it is listed by the World Health Organization (WHO) as one ofthe most neglected tropical diseases. Although Chagas disease (CD) was discovered more than 100 years ago, the existing therapies show low efficacy and serious side effects and developing safer and more effective drugs remains a hard challenge. Thus, this review highlights the main, novel and promising treatments against Trypanosoma cruzi, including biomacromolecules, natural products, vaccines, and metabolic pathway targets and highlights a worsening of esophageal cancer prognosis in chagasic patients. Moreover, we also discuss the perspectives of obtaining original optimized drugs that take advantage of organic and inorganic medicinal chemistry advances, as well as molecular modeling and biotechnology.

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Rapid test for the evaluation of the activity of the prodrug hydroxymethylnitrofurazone in the processing of Trypanosoma cruzi messenger RNAs

Cited by 10 publications

References 9 publications

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

Pharmacokinetics of Hydroxymethylnitrofurazone, a Promising New Prodrug for Chagas' Disease Treatment

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

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