Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 163, Issue -, Pages 569-582Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.12.005
Keywords
Ferrocene; Mannich bases; Chagas disease; Trypanosoma cruzi; In vitro studies; Superoxide dismutase
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Funding
- Obra Social la CAIXA
- Fundacion Caja Navarra
- Ministry of Economy and Competitiveness [Consolider Ingenio CSD2010-00065]
- Ministry of Education of Spain [FPU14/01537]
- Asociacion de Amigos de la Universidad de Navarra
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Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2, 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC50) value around 5 mu M in both amastigote and trypomastigote forms of T. cruzi and SI values higher than 13, being the best value on the trypomastigote forms of the Arequipa strain (SI = 41.7). Moreover, 2 decreased the number of infected cells and was not genotoxic. Furthermore, its possible mechanism of action was studied through the alteration of the metabolites excreted by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase (SOD). Finally, docking studies were executed to analyze the binding mode of the studied compounds to Fe-SOD enzyme. (C) 2018 Elsevier Masson SAS. All rights reserved.
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