Hydroxymethylnitrofurazone Is Active in a Murine Model of Chagas' Disease

Abstract

The addition of a hydroxymethyl group to the antimicrobial drug nitrofurazone generated hydroxymethylnitrofurazone (NFOH), which had reduced toxicity when its activity against Trypanosoma cruzi was tested in a murine model of Chagas' disease. Four groups of 12 Swiss female mice each received 150 mg of body weight/kg/day of NFOH, 150 mg/kg/day of nitrofurazone (parental compound), 60 mg/kg/day of benznidazole (BZL), or the solvent as a placebo. Treatments were administered orally once a day 6 days a week until the completion of 60 doses. NFOH was as effective as BZL in keeping direct parasitemia at undetectable levels, and PCR results were negative. No histopathological lesions were seen 180 days after completion of the treatments, a time when the levels of anti-T. cruzi antibodies were very low in mice treated with either NFOH or BZL. Nitrofurazone was highly toxic, which led to an overall rate of mortality of 75% and necessitated interruption of the treatment. In contrast, the group treated with its hydroxymethyl derivative, NFOH, displayed the lowest mortality (16%), followed by the BZL (33%) and placebo (66%) groups. The findings of histopathological studies were consistent with these results, with the placebo group showing the most severe parasite infiltrates in skeletal muscle and heart tissue and the NFOH group showing the lowest. The present evidence suggests that NFOH is a promising anti-T. cruzi agent.In 1909, Carlos Chagas described the protozoan parasite Trypanosoma cruzi as the causative agent of a widespread disease in Brazil that involved cardiac alterations and megaorgans. The parasite and its insect vectors were described in the original paper on the disease (7), and the parasite was soon confirmed to be present in patients throughout Latin America. Recent reports estimate the number of infected people to be between 9.8 million and 15 million in the Americas (29), with 28 million more being at risk of infection (26). In this scenario, congenital transmission of infection is a major problem in urban areas, along with risks from blood transfusion and migration of infected patients to areas of nonendemicity (28). In spite of the reduction in the number of new infections and the increased knowledge about the parasite, treatment of Chagas' disease relies on two drugs developed during the early 1970s: benznidazole (BNZ; Radanil, Roche) and nifurtimox (NFX; Bayer) (35). Both drugs are generally well tolerated by children but cause many undesirable side effects in adults and are not effective during the chronic phase of the disease. A well-tolerated, safe, and therapeutically efficient drug is not yet available. Several attempts have been made to create new drugs with more specificity toward the parasite and less toxicity for the mammalian host. Such attempts included inhibitors of cruzain (13, 14), C-14␣-demethylase (5, 10, 32), and chemical modifications of molecules with known trypanocidal activity, such as aromatic nitroheterocyclic compounds (1, 2). Nitrofurazone is an antimicrobial drug that is eff...

Abordagem da Latenciação de Fármacos como Ferramenta para Descoberta de novos Antichagásicos

“…A mutagenicidade e a possível carcinogenicidade dos nitrofuranos devem-se, provavelmente, à presença de dois grupos potencialmente reativos: o nitro na posição 5 e os substituintes (R) na posição 2 do anel furânico (MCCALLA, 1983;KOBIERSKA-SZELIGA & CZECZOT, 1994;MECCA & DIAZ & CASTRO, 2002;HIRAKU et al, 2004;DAVIES et al, 2010).…”

“…O NFOH apresenta estabilidade in vitro, e é metabolizado em plasma (humano e de ratos) e também, provavelmente, pelo fígado. O NFOH, através dos estudos realizados, aliado à estabilidade química favorecida pela sua estrutura, é um potencial candidato a fármaco antichagásico para os estudos clínicos (SERAFIM, 2008;DAVIES et al, 2010;SANTOS;MATOS;FERREIRA, 2011).…”

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

“…New therapeutic drugs have been obtained by using the prodrug design strategy (4,6,7,9,10,11,12,13). The prodrugs have been an effective way of overcoming absorption, distribution, metabolism, and elimination (ADME) barriers that restrict the application of many chemical compounds as orally administered drugs (14,15).…”

Candidatos a leishmanicidas, antichagásicos e tuberculostáticos: estudo da síntese de fármacos dirigidos de hidroximetilnitrofural com manana para liberação específica em macrófagos

“…Dessa forma, é de grande importância o desenvolvimento de uma terapia mais eficaz para esta patologia (TROSSINI et al, 2010a;DAVIES et al, 2010;CARRILERO et al, 2011;COURA, BORGES-PEREIRA, 2012). …”