Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives

Maya, Juan Diego; Bollo, Soledad; Núñez‐Vergara, Luis J.; Squella, J.A.; Repetto, Yolanda; Morello, Antonio; Périé, Jacques; Chauvière, G.

doi:10.1016/s0006-2952(02)01663-5

Cited by 159 publications

(131 citation statements)

References 33 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Thus, the nitro derivative 6 and the diacetamide 12 presented IC 50 values of 155 µM and 48.5 µM, respectively. Many nitrofuran derivatives have been reported to act as subversive substrate for TR, a class of inhibitors that produce free radicals once reduced by the enzyme, thereby subverting its physiological role (JockersScherübl et al 1989, Paulino et al 2002, Maya et al 2003, Chibale & Musonda 2003, Aguirre el al. 2004).…”

Section: Resultsmentioning

confidence: 99%

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Oliveira

Vaz

Alves

et al. 2006

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

The natural lignans veraguensin and grandisin have been reported to be active against Trypanosoma cruzi bloodstream forms. Aiming at the total synthesis of these and related compounds, we prepared three 2-arylfurans and eight 2,5-diarylfurans. They were evaluated for their potential as T. cruzi trypanothione reductase (TR) 60% at 20 µg/ml (59 and 90 µM, respectively). On the other hand, none of the compounds was significantly active against the parasite bloodstream forms even at 250 µg/ml (0.6-1.5 mM).Key words: tropical diseases -Chagas disease -arylfurans -trypanothione reductase Chagas disease, caused by the flagellate protozoan Trypanosoma cruzi, affects 18 million people in Latin America and is responsible for 13,000 deaths every year (WHO 2002). The treatment relies on only two available drugs, nifurtimox and benznidazole, which are relatively efficient in the acute phase of the disease, but almost ineffective in the chronic phase. Nowadays, one of the most important mechanisms of Chagas disease transmission in many countries is by blood transfusion (Schmuñis 1991). In highly endemic areas it is strongly recommended the use of chemoprophylatic measures such as the addition of gentian violet to clear trypomastigotes from blood banked for transfusion (Moraes-Souza et al. 1995). Although effective, this triphenylmethane dye is not well accepted because of undesirable effects such as coloring the skin and possible mutagenicity (Wendel 1993). Thus, new drugs to treat or prevent Chagas disease are still needed.Trypanosoma cruzi enzymes such as the trypanothione reductase (TR) represent a potential drug targets because they play an essential role in the life of this parasite. TR and its substrate trypanothione, the disulfide of a glutathione-spermidine conjugate [N 1 , N 8 -bis(glutathionyl)spermidine, T(SH) 2 ] 1, help to protect the parasite from oxidative stress by maintaining an intracellular reducing environment in a manner analogous to glutathione reductase (GR) and glutathione [L-γ-glutamyl-Lcysteiylglycine, GSH] 2 (Fig. 1a) in mammalian cells (Schmidt & Krauth-Siegel 2002). TR catalyses the NADPHdependent reduction of trypanothione disulfide TS 2 to its dithiol form, T(SH) 2 . Trypanothione may be oxidized back to TS 2 (Fig. 1b) following reaction with potentially damaging radicals and oxidants generated by aerobic metabolism. Another aspect that makes TR an even more attractive target is its structural differences from the human counterpart GR. GR has a narrow positively charged active site, to accommodate the glycine carboxylates of its substrate glutathione, whereas TR has a wider, noncharged, and more hydrophobic active site (Bond et al. 1999). These differences allowed the discovery of several promising selective inhibitors of TR (Schmidt & KrauthSiegel 2002).Lignans is a class of natural products that possess important biological properties (Jensen et al. 1993). Lopes et al. (1998) showed that the tetrahydrofuran lignans veraguensin 3 and grandisin 4 (Fig. 2) were active in vitro at 5 µg/ml aga...

show abstract

Section: Resultsmentioning

confidence: 99%

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Oliveira

Vaz

Alves

et al. 2006

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

show abstract

“…Both are trypanocidal to all forms of the parasite (Maya et al, 2007;Maya et al, 1997;Urbina, 2009b). Nx and Bz act through the formation of free radicals and/or electrophilic metabolites, affecting all macromolecules of the parasite (Maya et al, 2003). However, therapy is not always successful.…”

Section: Treatment Of Chagas Diseasementioning

confidence: 99%

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

et al. 2010

Self Cite

View full text Add to dashboard Cite

There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.

show abstract

“…En este sentido, hoy en día se están haciendo muchos esfuerzos por entender los mecanismos de acción del benzonidazol y el nifurtimox, con el fin de mejorar el uso de estos medicamentos (7,12,13,39,40). Si bien es cierto que se han producido algunos avances en este sentido (7,12,13,41,42), en la actualidad aún no se han podido esclarecer parámetros tales como cuáles son las concentraciones del medicamento para considerar las cepas como resistentes y cuál es la relación entre los mecanismos de resistencia natural y la inducida.…”

Section: Discussionunclassified

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

Mejía-Jaramillo¹,

Fernández²,

Montilla³

et al. 2012

biomedica

View full text Add to dashboard Cite

Introducción. La enfermedad de Chagas, causada por Trypanosoma cruzi, es uno de los problemas más graves de salud pública en el continente americano. El benzonidazol es uno de los dos medicamentos utilizados para tratar la enfermedad de Chagas. Sin embargo, la variación de la sensibilidad del parásito a este medicamento es una de las principales causas del fracaso del tratamiento. Objetivo. Evaluar la sensibilidad in vitro al benzonidazol de cepas colombianas de T. cruzi de diferentes orígenes y procedencia geográfica. Materiales y métodos. Treinta y tres cepas colombianas de T. cruzi aisladas de humanos, vectores y mamíferos, se analizaron in vitro mediante el micrométodo enzimático de MTT para determinar la concentración inhibitoria 50 (CI 50 ) al benzonidazol. Se estudió la correlación entre la sensibilidad in vitro al medicamento y diferentes parámetros biológicos y eco-epidemiológicos. Resultados. El análisis de sensibilidad al medicamento indicó que el 36 % de las cepas eran sensibles, el 48 %, parcialmente resistentes y, el 16 %, resistentes al benzonidazol. Los análisis de correlación entre las CI 50 con algunos parámetros biológicos y eco-epidemiológicos, mostraron diferencias en cuanto a la sensibilidad según el origen biológico y el área geográfica de procedencia de la cepa. Conclusiones. Existe una gran variabilidad en cuanto a la sensibilidad al benzonidazol de las cepas circulantes de T. cruzi en Colombia, lo cual sugiere la presencia de cepas naturalmente resistentes en el país. Palabras clave:Trypanosoma cruzi, enfermedad de Chagas/terapia, inmunidad innata, Colombia. Trypanosoma cruzi strains resistant to benznidazole occurring in ColombiaIntroduction. Chagas disease caused by Trypanosoma cruzi is one of the most serious public health problems in the Americas. Benznidazole is one of two drugs used to treat Chagas' disease. However, the variation in susceptibility of the parasite to this drug is one of the main causes of treatment failure. Objective. The in vitro susceptibility to benznidazole was assessed in Colombian strains of T. cruzi from several sources and geographical regions. Materials and methods. Thirty-three Colombian T. cruzi strains were isolated from humans, vectors and mammals. These were analyzed in vitro by the MTT enzymatic micromethod to determine the IC 50 to benznidazole. Additionally, the in vitro susceptibility was correlated with several biological and ecoepidemiological parameters. Results. Thirty-six percent of the strains were considered to be sensitive, 48% partially resistant, and 16% were resistant. Correlations between the IC 50 and several biological and eco-epidemiological parameters indicated that differences in susceptibility depended on the biological source and geographical origin of the strain. Conclusions. A high degree of variability exists in the susceptibility to benznidazole of T. cruzi strains in Colombia. The distribution data indicate the presence and circulation of naturally resistant strains.

show abstract

Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives

Cited by 159 publications

References 33 publications

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

Contact Info

Product

Resources

About