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Artículo

Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation

Chao, Maria NoeliaIcon ; Storey, Melissa; Li, Catherine; Rodriguez, Maricel GabrielaIcon ; Di Salvo, FlorenciaIcon ; Szajnman, Sergio HernanIcon ; Moreno, Silvia N. J.; Docampo, Roberto; Rodriguez, Juan BautistaIcon
Fecha de publicación: 10/2017
Editorial: Pergamon-Elsevier Science Ltd
Revista: Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Químicas

Resumen

The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents.
Palabras clave: Trypanosoma Cruzi , Squalene Synthase , Chagas Disease , Antiparasitic Agents
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/58899
DOI: https://dx.doi.org/10.1016/j.bmc.2017.10.016
URL: https://www.sciencedirect.com/science/article/pii/S0968089617317315
Colecciones
Articulos(INQUIMAE)
Articulos de INST.D/QUIM FIS D/L MATERIALES MEDIOAMB Y ENERGIA
Articulos(UMYMFOR)
Articulos de UNID.MICROANAL.Y MET.FISICOS EN QUIM.ORG.(I)
Citación
Chao, Maria Noelia; Storey, Melissa; Li, Catherine; Rodriguez, Maricel Gabriela; Di Salvo, Florencia; et al.; Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 25; 24; 10-2017; 6435-6449
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