Journal
CHEMMEDCHEM
Volume 9, Issue 1, Pages 177-188Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300354
Keywords
antiprotozoal agents; biological activity; hydrazones; medicinal chemistry; thiazolidinones; Trypanosoma cruzi
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Funding
- Brazilian agencies Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB, Brazil)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil)
- Fundacao de Amparo a Pesquisa do estado de Minas Gerais (FAPEMIG, Brazil)
- European Union consortium ChemBioFight
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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 (4a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10M, while they did not display host cell toxicity up to 200M. Thiazolidinone 4h 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 (4a-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.
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