Electrochemical Reduction Using Glassy Carbon Electrode in Aqueous Medium of a Potential Anti-Chagas Drug: NFOH

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hydroxymethylnitrofurazone Is Active in a Murine Model of Chagas' Disease

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.

Interaction between nitroheterocyclic compounds with beta-cyclodextrins: Phase solubility and HPLC studies

Chagas disease is a serious health problem for Latin America. Nitrofurazone (NF) and Hidroxymethylnitrofurazone (NFOH) are active against Trypanosoma cruzi. The effect of beta-cyclodextrin (beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD) complexation on the UV absorption and retention time of nitrofurazone (NF) and its hydroxymethylated analog (NFOH) were studied in solution. The retention behavior was analyzed on a reversed phase C(18) column and the mobile phase used was acetonitrile-water (20/80 v/v), in which cyclodextrins (beta-CD or DM-beta-CD) were incorporated as a mobile phase additive. The decrease in the retention times of NF (or NFOH) with increasing concentration of HP-beta-CD enables the cleternnination of the complex stability constants by HPLC. A phase-solubility Study was performed. according to the method reported by Higuchi and Connors, to evaluate the changes of NF/NFOH in the complexation state, and the diagrams obtained suggested that it forms complexes with a stoichiometry of 1 : 1. This is an important Study for the characterization of potential formulations to be used as therapeutic options for the treatment of Chagas disease. (c) 2008 Elsevier B.V. All rights reserved.

Study of the interaction between hydroxymethylnitrofurazone and 2-hydroxypropyl-beta-cyclodextrin

Chagas disease is a serious health problem in Latin America. Hidroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug more active than nitrofurazone against Trypanosoma cruzi. However, NFOH presents low aqueous solubility, high photodecomposition and high toxicity. The present work is focused on the characterization of an inclusion complex of NFOH in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The complexation with HP-beta-CD was investigated using reversed-phase liquid chromatography, solubility isotherms and nuclear magnetic resonance. The retention behavior was analyzed on a reversed-phase C-18 column, using acetonitrile-water (20/80, v/v) as the mobile phase, in which HP-beta-CD was incorporated as a mobile phase additive. The decrease in the retention times with increasing concentrations of HP-beta-CD enables the determination of the apparent stability constant of the complex (K = 6.2 +/- 0.3 M-1) by HPLC. The solubility isotherm was studied and the value for the apparent stability constant (K = 7.9 +/- 0.2 M-1) was calculated. The application of continuous variation method indicated the presence of a complex with 1:1 NFOH:HP-beta-CD stoichiometry. The photostability study showed that the formation of an inclusion complex had a destabilizing effect on the photodecomposition of NFOH when compared to that of the "free" molecule in solution. The mobility investigation (by NMR longitudinal relaxation time) gives information about the complexation of NFOH with HP-beta-CD. In preliminary toxicity studies, cell viability tests revealed that inclusion complexes were able to decrease the toxic effect (p < 0.01) caused by NFOH. (c) 2008 Elsevier B.V. All rights reserved.

Preparação e caracterização inicial de complexo de inclusão entre nitrofurazona e 2-hidroxipropil-β-ciclodextrina

Nitrofurazone (NF), 5-nitro-2-furaldehyde semicarbazone, a broad-spectrum antibiotic, has reported toxic effects and low solubility in water. It would be of great interest to form inclusion complexes between NF and a cyclodextrin, to develop more effective and safer antibiotic formulations. This paper focuses on the preparation of inclusion complexes of NF with 2-hydroxypropyl-β- cyclodextrin (HP-β-CD) and their initial characterization by evaluating rates of complex formation, photostability, solubility isotherms, release rate profiles, stoichiometry of the complexes and their morphology, as revealed by scanning electron microscopy. The kinetic tests of complex formation revealed that 17,3 h is enough for stabilization of the NF-cyclodextrin complex. The solubility isotherm studies showed that the isotherm changes from type A to type B, as a function of temperature. The photostability experiments showed that the insertion of the NF in the HP-β-CD cavity protects the drug from photodecomposition. The release kinetic tests showed that the profile of NF release from the complex is altered by the presence of HP-β-CD in the medium. A Job's plot indicated that the stoichiometry of the complex was 1:1 NF:HP-β-CD. The scanning electron micrographs showed changes in the crystal structure of NF in the complex. This study focused on the physicochemical properties of drug-delivery formulations that could potentially be developed into a novel type of therapy with NF.

Toxicidade de fármacos nitrofurânicos

During the structural designing of new drugs, it is possible predict the influence of specific chemical groups on pharmacological activity. Among these, the nitro group has potential antiparasitic activity, being present in many antimicrobial drugs, such as metronidazole, nitrofurazone, furazolidone, oxamniquine and chloramphenicol. Also, the introduction of the nitro group into a molecule can modify the physicochemical and electronic properties of the substance. Besides antimicrobial drugs, this group is also found in other drug classes, such as antiulcer, anti-inflamatory and anxiolytic. However, the use of the nitro group in drug design has encountered restrictions, due to the associated toxicity. This article is a review of the toxicity of nitrofuran compounds, as well the possible mechanisms involved and the strategy of latentiation by molecular modification to decrease their toxicity.

Farmacocinética pré-clínica do hidroximetilnitrofural (NFOH) – potencial pró-fármaco antichagásico

Pós-graduação em Ciências Farmacêuticas - FCFAR

Avaliação da presença do grupo nitro na atividade antichagásica e mutagênica do candidato a fármaco hidroximetilnitrofural (NFOH)

Pós-graduação em Ciências Farmacêuticas - FCFAR

Preparação e determinação da atividade toxicológica do pró-fármaco hidroximetilnitrofural, potencialmente antichagásico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Planejamento e estudo da viabilidade de obtenção do pró-fármaco recíproco nitrofural-alendronato potencialmente antichagásico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Planejamento, sintese e avaliação biológica de derivados furoxânicos e benzofuroxânicos potencialmente antichagásicos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Síntese e avaliação biológica de novos compostos das séries LAPDESF FUR-PQ E LAPDESF FUR-TS contra Trypanosoma cruzi

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Síntese e avaliação biológica de novos compostos das séries LAPDESF FUR-PQ E LAPDESF FUR-TS contra Trypanosoma cruzi

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Medicinal Chemistry of ureido derivatives as Antiinfectives

Ureides are compounds, which essentially incorporate urea as a substructural component either in open or cyclic form. Ureido derivatives are one of the oldest classes of bioactives, widely used as antiinfective agents. Several of these compounds, including aminoquinuride, aminocarbalide, imidurea, cloflucarban, nitrofurazone, urosulfan, viomycin are used in clinical situations. One of the ureides, the triclocarban is compulsorily used as antibacterial agent in cleansing and disinfecting solutions in hospital, household, cosmetics, toys, textile and plastics. It disables the activity of ENR, an enzyme vital for building the cell wall of the bacteria and fungus. Besides, the ureido-penicillins in clinical use there have been several ureido-lactam derivatives which have been reported to exhibit significant antibacterial activity. A urea containing dipeptide TAN-1057A isolated from Flexibacter spp. has potent bioactivity against MRSA. The metal complexes of sulphonyl ureido derivatives are effective antifungal agents by inhibiting the activity of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls. There have been number of ureides including the cyclic ureas which are potent HIV protease inhibitors and display significant anti-HIV activity. The urea derivative, merimepodip that has been derived using structure based design, is potent inhibitor of IMPDH and is active against Hepatitis-C infection. This review will primarily focus on the significant work reported for this class of compounds including design, synthesis and biological activity.