Autor(es)

Palace-Berl, Fanny ; Mesquita Pasqualoto, Kerly Fernanda ; Jorge, Salomao Doria ; Zingales, Bianca ; Zorzi, Rodrigo Rocha ; Silva, Marcelo Nunes ; Ferreira, Adilson Kleber ; de Azevedo, Ricardo Alexandre ; Teixeira, Sarah Fernandes ; Tavares, Leoberto Costa

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 96, p. 10-pg., 2015-05-26.

Resumo

Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity. Lipinski's rules were considered in order to support drug-likeness designing. The set of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides was assayed against three T. cruzi strains, which represent the discrete typing units more prevalent in human patients: Y (TcII), Silvio X10 cl1 (TcI), and Bug 2149 cl10 (TcV). All the derivatives, except one, showed enhanced trypanocidal activity against the three strains as compared to BZD. In the Y strain 62% of the compounds were more active than NFX. The most active compound was N'((5-nitrofuran-2-yl) methylene)biphenyl-4-carbohydrazide (C20), which showed IC50 values of 1.17 +/- 0.12 mu M; 3.17 +/- 0.32 mu M; and 1.81 +/- 0.18 mu M for Y, Silvio X10 cl1, and Bug 2149 cl10 strains, respectively. Cytotoxicity assays with human fibroblast cells have demonstrated high selectivity indices for several compounds. Exploratory data analysis indicated that primarily topological, steric/geometric, and electronic properties have contributed to the discrimination of the set of investigated compounds. The findings can be helpful to drive the designing, and subsequently, the synthesis of additional promising drugs against Chagas disease. (C) 2015 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 13/13333-8 - Quimioterapia para a doença de Chagas: falhas terapêuticas para benznidazol e busca de candidatos para alternativas de tratamento
• Beneficiário: Bianca Silvana Zingales
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/06061-4 - Nitrocompostos com atividade em Trypanosoma cruzi: planejamento, síntese, avaliação da citotoxicidade e bioatividade in vitro e estudos de relações estrutura-atividade in silico
• Beneficiário: Leoberto Costa Tavares
• Modalidade de apoio: Auxílio à Pesquisa - Regular