Nitro-compounds with Trypanosoma cruzi activity: design, synthesis, evaluation of cytotoxicity and bioactivity in vitro and studies of structure-activity relationships in silico

• Grant number: 14/06061-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2014
• End date: July 31, 2016
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Leoberto Costa Tavares
• Grantee: Leoberto Costa Tavares
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Bianca Silvana Zingales

Abstract

Considered as a neglected disease, Chagas' disease affects around 10 million people in Latin America and an increasing number of new cases in non-endemic areas. The search for therapeutic alternatives for this disease has an important role, since the current options are limited, and and only benznidazole is available in Brazil, which is the only active drug for the chronic phase of the disease. In this sense, nitro - heterocyclic compounds, that have activity against the etiologic agent of the disease, Trypanosoma cruzi, are considered very promising compounds. As a result, this project aims to identify compounds with optimal pharmacological activity against T. cruzi. This investigation will include design, synthesis, evaluation of anti-T. cruzi activity, cytotoxicity and computational studies in order to build quantitative models of structure-activity relationships (QSAR multivariate), which should identify the physico-chemical parameters related to anti-T. cruzi activity. This approach is aligned with many scientific papers in the field of medicinal chemistry focused on the search for new drug candidates for the treatment of neglected diseases. The study of nitro compounds with bioactivity in T. cruzi involves the steps of synthesis and identification of compounds, evaluation of activity against different parasite clones in your epimastigote form, cytotoxicity evaluation, and activity against the amastigote form of the parasite. Also, this research involves computational studies with the purpose of building quantitative models of structure-activity relationships (QSAR) which may help predict new structures with optimized pharmacological profile, and to investigate the possible mechanisms of action of these compounds. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOARES PETRI E SILVA, SIMONE CAROLINA; PALACE-BERL, FANNY; TAVARES, LEOBERTO COSTA; CASTRO SOARES, SANDRA REGINA; LAULETTA LINDOSO, JOSE ANGELO. Effects of nitro-heterocyclic derivatives against Leishmania (Leishmania) infantum promastigotes and intracellular amastigotes. Experimental Parasitology, v. 163, p. 68-75, APR 2016. (14/06061-4)

PALACE-BERL, FANNY; MESQUITA PASQUALOTO, KERLY FERNANDA; JORGE, SALOMAO DORIA; ZINGALES, BIANCA; ZORZI, RODRIGO ROCHA; SILVA, MARCELO NUNES; FERREIRA, ADILSON KLEBER; DE AZEVEDO, RICARDO ALEXANDRE; TEIXEIRA, SARAH FERNANDES; TAVARES, LEOBERTO COSTA. Designing and exploring active N '-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 96, p. 10-pg., 2015-05-26. (13/13333-8, 14/06061-4)

PALACE-BERL, FANNY; MESQUITA PASQUALOTO, KERLY FERNANDA; JORGE, SALOMAO DORIA; ZINGALES, BIANCA; ZORZI, RODRIGO ROCHA; SILVA, MARCELO NUNES; FERREIRA, ADILSON KLEBER; DE AZEVEDO, RICARDO ALEXANDRE; TEIXEIRA, SARAH FERNANDES; TAVARES, LEOBERTO COSTA. Designing and exploring active N `-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 96, p. 330-339, MAY 26 2015. (14/06061-4, 13/13333-8)

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; et al. Investigating the structure-activity relationships of N `-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 144, p. 29-40, JAN 20 2018. (14/06061-4, 13/13333-8)

DIAS MENDONCA, DAIANE BARROS; COSTA SILVA, RENATA ELLEN; PALACE-BERL, FANNY; TAKAKURA, CLEUSA F. H.; SOARES, SANDRA REGINA C.; ALMEIDA BRAZ, LUCIA MARIA; TAVARES, LEOBERTO COSTA; LAULETTA LINDOSO, JOSE ANGELO. Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 25, MAR 11 2019. (14/06061-4)

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; et al. Investigating the structure-activity relationships of N '-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 144, p. 12-pg., 2018-01-20. (13/13333-8, 14/06061-4)

Filed patent(s) as a result of this research project