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Título: | Discovery and pharmacological studies of 4-hydroxyphenyl-derived phosphonium salts active in a mouse model of visceral Leishmaniasis |
Autor: | Manzano, José Ignacio CSIC ORCID; Cueto-Díaz, Eduardo J. CSIC ORCID; Olías-Molero, Ana Isabel; Perea, Ana; Herraiz Tomico, Tomás CSIC ORCID ; Torrado, Juan J.; Alunda, José María; Gamarro, Francisco; Dardonville, Christophe CSIC ORCID | Fecha de publicación: | 2019 | Editor: | American Chemical Society | Citación: | Journal of Medicinal Chemistry 62(23): 10664-10675 (2019) | Resumen: | We report the discovery of new 4-hydroxyphenyl phosphonium salt derivatives active in the submicromolar range (EC from 0.04 to 0.28 μM, SI > 10) against the protozoan parasite Leishmania donovani. The pharmacokinetics and in vivo oral efficacy of compound 1 [(16-(2,4-dihydroxyphenyl)-16-oxohexadecyl)triphenylphosphonium bromide] in a mouse model of visceral leishmaniasis were established. Compound 1 reduced the parasite load in spleen (98.9%) and liver (95.3%) of infected mice after an oral dosage of four daily doses of 1.5 mg/kg. Mode of action studies showed that compound 1 diffuses across the plasma membrane, as designed, and targets the mitochondrion of Leishmania parasites. Disruption of the energetic metabolism, with a decrease of intracellular ATP levels as well as mitochondrial depolarization together with a significant reactive oxygen species production, contributes to the leishmanicidal effect of 1. Importantly, this compound was equally effective against antimonials and miltefosine-resistant clinical isolates of Leishmania infantum, indicating its potential as antileishmanial lead. | Versión del editor: | https://doi.org/10.1021/acs.jmedchem.9b00998 | URI: | http://hdl.handle.net/10261/203458 | DOI: | 10.1021/acs.jmedchem.9b00998 | Identificadores: | doi: 10.1021/acs.jmedchem.9b00998 e-issn: 1520-4804 issn: 0022-2623 |
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