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 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.