Discovery of new phosphonium salts active in vivo against Leishmania parasites

Abstract

We report the discovery of new phosphonium lead compound (1) showing a strong in vivo activity by oral dosage in a mouse model of visceral leishmaniasis. A focused screening of an in-house series of trypanocidal compounds against L. donovani parasites resulted in the discovery of potent leishmanicides. Three 4-hydroxyphenyl-derived phosphonium salts displaying EC50 < 0.2 µM against promastigotes and intracellular amastigotes of L. donovani, and satisfactory selectivities (SI > 10), were selected for further studies. Since the selected compounds contain a hydrolysable ester bond, which may potentially limit its in vivo efficacy, more metabolically stable analogues 1¿3 were synthesized. The new compounds showed high efficacy (EC50 < 0.28 µM) against promastigote and intracellular amastigote forms of L. donovani with SI > 20. Compound 1 (EC50 = 90 nM and SI = 31), which was equally effective against antimonials and miltefosine-resistant clinical isolates of L. infantum, was selected for in vivo assays in a mouse model of visceral leishmaniasis. 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 and targets the mitochondrion of Leishmania parasites. Disruption of the energy metabolism (i.e. decrease of intracellular ATP levels and mitochondrial depolarization) together with a significant ROS production contributes to the leishmanicidal effect of 1.