nifuroxazide and Chagas-Disease

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.

Topics: Cell Line; Chagas Disease; Drug Design; Humans; Models, Molecular; Nitrofurans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

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.

Topics: Antiprotozoal Agents; Cells, Cultured; Chagas Disease; Dose-Response Relationship, Drug; Drug Design; Fibroblasts; Humans; Hydrazines; Hydrazones; Models, Molecular; Molecular Structure; Nitrofurans; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanosoma cruzi