Discovery and pharmacological studies of 4-hydroxyphenyl-derived phosphonium salts active in a mouse model of visceral Leishmaniasis
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.
| Main Authors: | , , , , , , , , |
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| Other Authors: | |
| Format: | artículo biblioteca |
| Published: |
American Chemical Society
2019
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| Online Access: | http://hdl.handle.net/10261/203458 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100011033 |
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