Voltammetric behavior of nitrofurazone and its hydroxymethyl prodrug with potential anti-Chagas activity

Abstract

A doença de Chagas é um grave problema de saúde pública para a América Latina, situação agravada pela inexistência de quimioterapia eficiente. Os dois fármacos comercialmente encontrados, benznidazol e nifurtimox, são eficazes apenas na fase aguda da doença. A nitrofurazona é ativa contra Trypanosoma cruzi, entretanto, a alta toxicidade impede seu uso na parasitose. A hidroximetilnitrofurazona é um pró-fármaco da nitrofurazona, que apresenta maior atividade contra Trypanosoma cruzi, além de ser menos tóxico. Estudou-se o comportamento voltamétrico da nitrofurazona por voltametria cíclica, varredura linear e pulso diferencial, comparando-o ao do metronidazol e do cloranfenicol. Os coeficientes de difusão dos três fármacos foram estimados aplicando-se a equação de Wilke-Chang. Este artigo também apresenta o estudo do derivado hidroximetilnitrofurazona por voltametria cíclica. A redução de nitrofurazona é pH-dependente e em meio ácido o derivado hidroxilamínico, envolvendo quatro elétrons, é o principal produto formado. Em meio alcalino e com prévio tratamento do eletrodo de carbono vítreo, a redução de nitrofurazona ocorre em duas etapas: a primeira envolve um elétron para formar o nitro-radical aniônico e a segunda etapa corresponde à formação da hidroxilamina. Hidroximetilnitrofurazona possui comportamento voltamétrico semelhante e, de forma análoga, apresentou a mesma eletroatividade e capacidade de estabilização do nitro-radical, indicando que a modificação molecular de nitrofurazona não introduziu alterações no seu comportamento voltamétrico. Uma breve discussão das diferenças de atividade biológica entre os compostos também é apresentada.Chagas' disease is a serious health problem for Latin America. The situation is worsened by the lack of efficient chemotherapy. The two available commercial drugs, benznidazole and nifurtimox, are more effective in the acute phase of the disease. Nitrofurazone is active against Trypanosoma cruzi, however its high toxicity precludes its current use in parasitosis. Hydroxymethylnitrofurazone is a prodrug of nitrofurazone. It is more active against Trypanosoma cruzi than nitrofurazone, besides being less toxic. This work shows the voltammetric behavior of nitrofurazone and a comparison with those of metronidazole and chloramphenicol using cyclic, linear sweep and differential pulse voltammetries. For these drugs also the prediction of the diffusion coefficients using Wilke-Chang equation was performed. The reduction of nitrofurazone is pH-dependent and in acidic medium the hydroxylamine derivative, involving four electrons, is the principal product formed. In aqueousalkaline medium and with a glassy carbon electrode pre-treatment the reduction of nitrofurazone occurs in two steps, the first involving one electron to form the nitro-radical anion and the second corresponding to the hydroxylamine derivative formation. Hydroxymethylnitrofurazone presented the same voltammetric behavior and electroactivity, indicating that the molecular modification performed in nitrofurazone did no...

Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: investigation of a new target inTrypanosoma cruzi

“…Atomic charges calculated for the two molecules as represented in Figure 4A show a very similar distribution in the nitrofuran ring, thus indicating that nitro radical formation is not favored in one compound over the other. This was previously demonstrated by voltammetric studies, in which NFOH presented the same behavior as NF in terms of electroactivity 32 .…”

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

“…Fig. The cytotoxic mechanism of NFOH was suggested to be the same as that of NF (10). Chemical structure of the mutual prodrug of nitrofurazone (10) and primaquine (74) and its conversion to the parent drugs by cruzipain.…”

“…5-nitro-2furaldehyde semicarbazone, also known as nitrofurazone (10), was synthesized in 1944 by Dodd and Stilman, and was the first nitrofuran derivative used therapeutically [66]. Several nitrofurans have been marketed worldwide for human and veterinary use.…”

“…(22). In 2005, La-Scalea and colleagues reported the voltammetric behavior of nitrofurazone (10), and its hydroxymethyl derivative (75), on a glassy carbon electrode in aqueous media [10]. in maintaining undetectable parasitemia throughout the 60 days of treatment.…”

“…The examples below describe the application of this strategy to modulate the physico-chemical properties and reduce the genotoxicity of metronidazole (9) and nitrofurazone (10). In this case, strategies using a prodrug approach can reduce the toxicity of nitroimidazole derivatives.…”