Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. 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. Here we report 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 (IC50 = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (CC50 = 506.0 ± 10.7 μM). Additionally, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 μM, Selective Index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load when compared to infected and non-treated 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 donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite.

Velásquez, A., Ribeiro, W., Venn, V., Castelli, S., Santoro, M., de Assis, R., et al. (2017). Efficacy of a Binuclear Cyclopalladated Compound Therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis and its inhibitory effect on Topoisomerase 1B. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61(8), AAC.00688-17 [10.1128/AAC.00688-17].

Efficacy of a Binuclear Cyclopalladated Compound Therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis and its inhibitory effect on Topoisomerase 1B

VENN, VUTEY;CASTELLI, SILVIA;DESIDERI, ALESSANDRO;
2017-05-15

Abstract

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. 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. Here we report 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 (IC50 = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (CC50 = 506.0 ± 10.7 μM). Additionally, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 μM, Selective Index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load when compared to infected and non-treated 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 donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite.
15-mag-2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Velásquez, A., Ribeiro, W., Venn, V., Castelli, S., Santoro, M., de Assis, R., et al. (2017). Efficacy of a Binuclear Cyclopalladated Compound Therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis and its inhibitory effect on Topoisomerase 1B. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61(8), AAC.00688-17 [10.1128/AAC.00688-17].
Velásquez, A; Ribeiro, W; Venn, V; Castelli, S; Santoro, M; de Assis, R; de Souza, R; Ribeiro, A; Passalaqua, T; da Rosa, J; Baviera, A; Mauro, A; Desideri, A; Almeida Amaral, E; Graminha, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/185097
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