Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensisand Its Inhibitory Effect on Topoisomerase 1B

Autor: Velásquez, Angela Maria Arenas, Ribeiro, Willian Campos, Venn, Vutey, Castelli, Silvia, Camargo, Mariana Santoro de, de Assis, Renata Pires, de Souza, Rodrigo Alves, Ribeiro, Aline Rimoldi, Passalacqua, Thaís Gaban, da Rosa, João Aristeu, Baviera, Amanda Martins, Mauro, Antonio Eduardo, Desideri, Alessandro, Almeida-Amaral, Elmo Eduardo, Graminha, Marcia A. S.
Zdroj: Antimicrobial Agents and Chemotherapy; May 2017, Vol. 61 Issue: 8
Abstrakt: ABSTRACTLeishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmaniagenus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N′-dimethylbenzylamine (Hdmba) against Leishmania amazonensis. The compound [Pd(dmba)(μ-N3)]2(CP2) inhibits promastigote growth (50% inhibitory concentration [IC50] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitroincubated macrophages (IC50= 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against T. cruziintracellular amastigotes (IC50= 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivoassays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovanitopoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)
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