title: Designing and exploring active N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients.
abstract: 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 μM; 3.17 ± 0.32 μM; and 1.81 ± 0.18 μM 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.
authors.affiliation: Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil. Electronic address: palaceberlf@usp.br.
authors.forename: Fanny
authors.initials: F
authors.lastname: Palace-Berl
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.affiliation: Department of Immunology, Biomedical Sciences Institute, University of São Paulo, SP, Brazil.
authors.forename: Salomão Dória
authors.initials: SD
authors.lastname: Jorge
authors.affiliation: Department of Biochemistry, Chemistry Institute, University of São Paulo, SP, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Zingales
authors.affiliation: Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil.
authors.forename: Rodrigo Rocha
authors.initials: RR
authors.lastname: Zorzi
authors.affiliation: Department of Biochemistry, Chemistry Institute, University of São Paulo, SP, Brazil.
authors.forename: Marcelo Nunes
authors.initials: MN
authors.lastname: Silva
authors.affiliation: Department of Immunology, Biomedical Sciences Institute, University of São Paulo, SP, Brazil.
authors.forename: Adilson Kleber
authors.initials: AK
authors.lastname: Ferreira
authors.affiliation: Department of Immunology, Biomedical Sciences Institute, University of São Paulo, SP, Brazil.
authors.forename: Ricardo Alexandre
authors.initials: RA
authors.lastname: de Azevedo
authors.affiliation: Department of Immunology, Biomedical Sciences Institute, University of São Paulo, SP, Brazil; Cell and Molecular Therapy Center - NUCEL/NETCEM, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Sarah Fernandes
authors.initials: SF
authors.lastname: Teixeira
authors.affiliation: Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil.
authors.forename: Leoberto Costa
authors.initials: LC
authors.lastname: Tavares
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006835:Hydrazones / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009581:Nitrofurans / Q000737:chemistry*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D006834:Hydrazines; D006835:Hydrazones; D009581:Nitrofurans
keywords: Chagas disease; Exploratory data analysis; N′-[(5-nitrofuran-2-yl) methylene] substituted hydrazides; Trypanosoma cruzi strains