| Autor: |
Tunes LG; Instituto René Rachou/Fiocruz Minas-Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Brasil., Morato RE; Instituto René Rachou/Fiocruz Minas-Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Brasil., Garcia A; Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brasil., Schmitz V; Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brasil., Steindel M; Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brasil., Corrêa-Junior JD; Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brasil., Dos Santos HF; Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brasil., Frézard F; Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brasil., de Almeida MV; Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brasil., Silva H; Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brasil., Moretti NS; Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo 04023-062, Brasil., de Barros ALB; Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brasil., do Monte-Neto RL; Instituto René Rachou/Fiocruz Minas-Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Brasil. |
| Abstrakt: |
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 IC 50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC 50 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. |
