Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity.

Abstract

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.

• Authors: Diogo Rodrigo Magalhães Moreira, Ana Cristina Lima Leite, Marcos Verissimo Oliveira Cardoso, Rajendra Mohan Srivastava, Marcelo Zaldini Hernandes, Marcelo Montenegro Rabello, Luana Faria da Cruz, Rafaela Salgado Ferreira, Carlos Alberto de Simone, Cássio Santana Meira, Elisalva Teixeira Guimaraes, Aline Caroline da Silva, Thiago André Ramos dos Santos, Valéria Rêgo Alves Pereira, Milena Botelho Pereira Soares
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 1 Pg. 177-88 (Jan 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 24203393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• (2-(2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono)-5-ethylthiazolidin-4-one
• Hydrazines
• Protozoan Proteins
• Thiazolidinediones
• Thiazolidines
• Trypanocidal Agents
• Cysteine Endopeptidases
• cruzain, Trypanosoma cruzi

Topics

• Animals
• Cells, Cultured
• Crystallography, X-Ray
• Cysteine Endopeptidases (metabolism)
• Drug Design
• Endoplasmic Reticulum (drug effects)
• Female
• Golgi Apparatus (drug effects)
• Hydrazines (chemical synthesis, chemistry, pharmacology)
• Macrophages (drug effects)
• Mice
• Mice, Inbred BALB C
• Molecular Conformation
• Molecular Docking Simulation
• Protein Structure, Tertiary
• Protozoan Proteins (antagonists & inhibitors, metabolism)
• Spleen (cytology, drug effects)
• Structure-Activity Relationship
• Thiazolidinediones (chemical synthesis, chemistry, pharmacology)
• Thiazolidines (chemical synthesis, chemistry, pharmacology)
• Trypanocidal Agents (chemical synthesis, chemistry, pharmacology)
• Trypanosoma cruzi (drug effects)