Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent trypanothione reductase inhibitors.

The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy and safety, making urgent the search for new therapeutic approaches. We found that the complexes were active against and intracellular amastigotes with IC values ranging from 0.5 to 5.5 μM. All complexes were potent inhibitors of trypanothione reductase (TR), with IC ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced ROS production and decreased mitochondrial respiration after 2 h exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing or and treated orally with 12.5 mg/kg/day of AdT Et () or AdO Et () presented reduced lesion size and parasite burden, as revealed by bioimaging. Combination of () and miltefosine allowed for a 50 % reduction in miltefosine treatment time. Complexes () and () presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.