The drugs currently used to treat
leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the
gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All
gold(I) complexes were potent inhibitors of
trypanothione reductase (TR), with
enzyme IC50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced
reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of 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 L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or
AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and
miltefosine allowed for a 50% reduction in
miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further
drug development studies.
Gold(I) complexes are promising antileishmanial agents, with a potential for
therapeutic use, including in
leishmaniasis caused by
antimony-resistant parasites.