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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 10
[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
Total Affiliations: 5
Document type: Journal article
Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 96, p. 330-339, MAY 26 2015.
Web of Science Citations: 7

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)

FAPESP's process: 14/06061-4 - Nitro-compounds with Trypanosoma cruzi activity: design, synthesis, evaluation of cytotoxicity and bioactivity in vitro and studies of structure-activity relationships in silico
Grantee:Leoberto Costa Tavares
Support type: Regular Research Grants
FAPESP's process: 13/13333-8 - Chemotherapy for Chagas Disease: therapeutic failures to benznidazole and screening of candidates for treatment alternatives
Grantee:Bianca Silvana Zingales
Support type: Regular Research Grants