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

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. 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 vitro incubated 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. 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 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 donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)

Leishmanicidal and Immunomodulatory Activities of the Palladacycle Complex DPPE 1.1, a Potential Candidate for Treatment of Cutaneous Leishmaniasis

“…Treatment with 3.5 and 7 mg/kg of DPPE 1.1 led to a reduction of parasite load in foot lesions of 93 and 99%, respectively. In comparison with in vivo treatment with CP2, our data indicate the higher efficacy of DPPE 1.1 over this cyclopalladated compound since at the same concentration (7 mg/kg) mice treated with DPPE 1.1 and CP2 displayed a decrease of parasite load of 99 and 55%, respectively ( Velásquez et al, 2017 ). Furthermore, treatment with DPPE 1.1 did not result in toxicity in L. (L.) amazonensis -infected BALB/c mice as demonstrated by hepatic and renal assays after treatment with this compound, corroborating literature data that showed the low toxicity of these palladacycle complexes in the treatment of mice against tumor cells ( Rodrigues et al, 2003 ).…”

“…Other palladacycles were tested against Leishmania and showed an effective activity only on promastigote growth ( Fricker et al, 2008 ) and previous data from our group showed the in vitro and in vivo efficacy of the palladacycle complex DPPE 1.2 on L. (L.) amazonensis ( Paladi et al, 2012 ). More recently the leishmanicidal activity of a series of palladacycles on intracellular amastigotes of L. (L.) amazonensis was also demonstrated and among them a binuclear palladacycle complex named CP2 showed an effective action on L. (L.) amazonensis infection ( Velásquez et al, 2016 , 2017 ). The leishmanicidal activity of DPPE 1.1 is comparable to that observed with CP2.…”

“…The leishmanicidal activity of DPPE 1.1 is comparable to that observed with CP2. However, a concentration 44-times higher of CP2 was used to destroy L. (L.) amazonensis amastigotes in vitro in comparison to DPPE 1.1 ( Velásquez et al, 2017 ).…”

Synthesis, Characterization and Cytotoxicity Evaluation of New Biimidazole Palladium(II) Complexes with Thioureas

“…Motivated by the aforementioned findings, and as a part of our continuing research program in the field of coordination and biological chemistry of Pd(II) complexes, [16][17][18][19][20][21] we present herein the synthesis, characterization and cytotoxic evaluation of the compounds [PdL 2 (tm-biimH 2 )]Cl 2 ·nH 2 O, where L is thiourea (2), N-methylthiourea (3), N-phenylthiourea (4), N,N'-dimethylthiourea (5), N,N'-diphenylthiourea (6); n = 3-5; tmbiimH 2 is 2,2'-bis(4,5-dimethylimidazole).…”

Potential application of rLc36 protein for diagnosis of canine visceral leishmaniasis

“…For quantitative PCR assays, we used mouse peritoneal macrophages collected from adult male Swiss albino mice, infected with L. infantum as previously described ( Velásquez et al 2017 ), except that the assay was performed in 25-cm 2 cell culture flasks (Nunc™, Roskilde, Denmark). These assays were approved by the Ethics Committee for Animal Experimentation (Protocol CEUA/FCF/CAr no.…”