Investigating the structure-activity relationships of N '-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds

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Palace-Berl, Fanny ; Mesquita Pasqualoto, Kerly Fernanda ; Zingales, Bianca ; Moraes, Carolina Borsoi ; Bury, Mariana ; Franco, Caio Haddad ; da Silva Neto, Adelson Lopes ; Murayama, Joao Sussumu ; Nunes, Solange Lessa ; Silva, Marcelo Nunes ; Tavares, Leoberto Costa

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 144, p. 12-pg., 2018-01-20.

Abstract

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. (C) 2017 Elsevier Masson SAS. All rights reserved. (AU)

• 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 Opportunities: Regular Research Grants
• 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 Opportunities: Regular Research Grants