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Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐ Trypanosoma cruzi Activity
Author(s) -
Moreira Diogo Rodrigo Magalhães,
Lima Leite Ana Cristina,
Cardoso Marcos Verissimo Oliveira,
Srivastava Rajendra Mohan,
Hernandes Marcelo Zaldini,
Rabello Marcelo Montenegro,
da Cruz Luana Faria,
Ferreira Rafaela Salgado,
de Simone Carlos Alberto,
Meira Cássio Santana,
Guimaraes Elisalva Teixeira,
da Silva Aline Caroline,
dos Santos Thiago André Ramos,
Pereira Valéria Rêgo Alves,
Pereira Soares Milena Botelho
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300354
Subject(s) - benznidazole , trypanosoma cruzi , chagas disease , antiparasitic , mechanism of action , pharmacology , chemistry , toxicity , nifurtimox , programmed cell death , biochemistry , biology , in vitro , parasite hosting , apoptosis , virology , medicine , organic chemistry , pathology , world wide web , computer science
Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti‐ Trypanosoma cruzi thiazolidinones ( 4 a – p ). (2‐[2‐Phenoxy‐1‐(4‐bromophenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one ( 4 h ) and (2‐[2‐phenoxy‐1‐(4‐phenylphenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one ( 4 l ) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μ M , while they did not display host cell toxicity up to 200 μ M . Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti‐ T. cruzi thiazolidinones ( 4 a – p ) led to the identification of compounds with enhanced potency and selectivity compared to first‐generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.