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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Designing and exploring active N `-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients

Texto completo
Autor(es):
Palace-Berl, Fanny [1] ; Mesquita Pasqualoto, Kerly Fernanda [2] ; Jorge, Salomao Doria [3] ; Zingales, Bianca [4] ; Zorzi, Rodrigo Rocha [1] ; Silva, Marcelo Nunes [4] ; Ferreira, Adilson Kleber [3] ; de Azevedo, Ricardo Alexandre [3] ; Teixeira, Sarah Fernandes [3, 5] ; Tavares, Leoberto Costa [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Biochem & Pharmaceut Technol, Sao Paulo, SP - Brazil
[2] Butantan Inst, Biochem & Biophys Lab, Sao Paulo, SP - Brazil
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP - Brazil
[4] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, SP - Brazil
[5] Univ Sao Paulo, Sch Med, Cell & Mol Therapy Ctr NUCEL NETCEM, Sao Paulo, SP - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 96, p. 330-339, MAY 26 2015.
Citações Web of Science: 7
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
Linha de fomento: 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
Linha de fomento: Auxílio à Pesquisa - Regular