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Title

Discovery and pharmacological studies of 4-hydroxyphenyl-derived phosphonium salts active in a mouse model of visceral Leishmaniasis

AuthorsManzano, José Ignacio; Cueto-Díaz, E. J.; Olías-Molero, Ana Isabel; Perea, Ana; Herraiz Tomico, Tomás ; Torrado, Juan J.; Alunda, José María; Gamarro, Francisco; Dardonville, Christophe
Issue Date2019
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 62(23): 10664-10675 (2019)
AbstractWe 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.
Publisher version (URL)https://doi.org/10.1021/acs.jmedchem.9b00998
URIhttp://hdl.handle.net/10261/203458
Identifiersdoi: 10.1021/acs.jmedchem.9b00998
e-issn: 1520-4804
issn: 0022-2623
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