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Structural Design, Synthesis and Structure-Activity Relationships of Thiazolidinones with Enhanced Anti-Trypanosoma cruzi Activity

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

ChemMedChem, 2014-01, Vol.9 (1), p.177-188 [Periódico revisado por pares]

Weinheim: WILEY-VCH Verlag

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Título:
Structural Design, Synthesis and Structure-Activity Relationships of Thiazolidinones with Enhanced Anti-Trypanosoma cruzi Activity
Autor: 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
Assuntos: Animals ; antiprotozoal agents ; biological activity ; Cells, Cultured ; Crystallography, X-Ray ; Cysteine Endopeptidases - metabolism ; Drug Design ; Endoplasmic Reticulum - drug effects ; Female ; Golgi Apparatus - drug effects ; Hydrazines - chemical synthesis ; Hydrazines - chemistry ; Hydrazines - pharmacology ; hydrazones ; Macrophages - drug effects ; medicinal chemistry ; Mice ; Mice, Inbred BALB C ; Molecular Conformation ; Molecular Docking Simulation ; Protein Structure, Tertiary ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - metabolism ; Spleen - cytology ; Spleen - drug effects ; Structure-Activity Relationship ; Thiazolidinediones - chemical synthesis ; Thiazolidinediones - chemistry ; Thiazolidinediones - pharmacology ; Thiazolidines - chemical synthesis ; Thiazolidines - chemistry ; Thiazolidines - pharmacology ; thiazolidinones ; Trypanocidal Agents - chemical synthesis ; Trypanocidal Agents - chemistry ; Trypanocidal Agents - pharmacology ; Trypanosoma cruzi ; Trypanosoma cruzi - drug effects
É parte de: ChemMedChem, 2014-01, Vol.9 (1), p.177-188
Notas: ark:/67375/WNG-R70C24DL-H
ArticleID:CMDC201300354
istex:BD9D55179F95CA018A39A427AAA20FC359E261DF
Fundação de Amparo à Pesquisa do estado de Minas Gerais (FAPEMIG, Brazil)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil)
Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB, Brazil)
European Union consortium ChemBioFight
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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 μM, while they did not display host cell toxicity up to 200 μM. 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. Stop the cycle! The attachment of an aryl ring to the iminic carbon produced thiazolidinones that are conformationally more restricted than first‐generation thiazolidinones. This enhanced the potency of antiparasitic thiazolidinones, as observed under treatment with compound 4 h where parasite development and invasion in host cells were substantially reduced.
Editor: Weinheim: WILEY-VCH Verlag
Idioma: Inglês;Alemão

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Structural Design, Synthesis and Structure-Activity Relationships of Thiazolidinones with Enhanced Anti-Trypanosoma cruzi Activity

Weinheim: WILEY-VCH Verlag

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