期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 144, 期 -, 页码 572-581出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.052
关键词
Trypanosoma cruzi; Naphthoquinones; Trypanocidal activity; Chemotherapy
资金
- Oswaldo Cruz Institute of the Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
- Programa Estrategico de Apoio a Pesquisa em Saude (Papes VI)/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil [407729/2012-7]
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/010.001548/2014, E-26/110.553/2014]
The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihy-drofluorescein diacetate (H(2)DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC50 values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity. (C) 2017 Published by Elsevier Masson SAS.
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