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

07:00 EST 8th November 2019 | BioPortfolio

Summary of "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 (EC50 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 4 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 ROS 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.

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Name: Journal of medicinal chemistry
ISSN: 1520-4804
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