Biological and Medicinal Chemistry

GoldLeish: gold(I) Complexes as Oral Drug Candidates to Treat Leishmaniasis are Potent Trypanothione Reductase Inhibitors and Exert in vivo Efficacy


The drugs currently used to treat leishmaniasis have limitations concerning cost, efficacy and safety, making urgent the search for new therapeutic approaches. Here we report the antileishmanial activity of 14 gold(I) complexes. We found that the complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All complexes were potent inhibitors of trypanothione reductase (TR), with IC50 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 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. 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 potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.


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