Antiprotozoal Activity of the Cyclopalladated Complexes AgainstLeishmania amazonensisandTrypanosoma cruzi

Abstract

The present study describes the antiprotozoal activities of four cyclopalladated compounds, [Pd(dmba)(μ-Cl)] 2 , [Pd(dmba)(NCO)(isn)], [Pd(dmba)(N 3 )(isn)] and [Pd(dmba)(μ-NCO)] 2 , (dmba: N,N'-dimethylbenzylamine and isn: isonicotinamide), against the diseases leishmaniasis (Leishmania amazonensis and Leishmania infantum), Chagas disease (Trypanosoma cruzi) and human African trypanosomiasis (Trypanosoma brucei). [Pd(dmba)(μ-NCO)] 2 exhibited good leishmanicidal and trypanocidal activities against L. amazonensis and T. cruzi intracellular amastigote forms, with a 50% inhibitory concentration (IC 50 ) value of less than 9 μM and selectivity indexes of 14.47 and 28.42, respectively. Stability essays were conducted in phosphate buffer saline (PBS) pH 7.0 and showed that [Pd(dmba)(μ-NCO)] 2 is the most stable molecule. These findings indicate that this compound presented higher selectivity for these parasites than the other tested compounds. The data presented here suggest that this compound should be considered in the development of new and more potent drugs for the treatment of leishmaniasis and Chagas disease. 7 Pentavalent antimonial drugs are the most frequently prescribed treatments for leishmaniasis. 8 The main adverse effects that occur in systemic administration of these antimonials are arthralgias, myalgias, anorexia, and nausea, and other serious side effects include pancreatitis, liver-enzyme abnormalities, cardiac malfunctions and severe renal toxic effects. Other drugs, such as amphotericin B, pentamidine and miltefosine, are second choice drugs but they also produce side effects that can endanger the patient's life. KeywordsTrypanosoma cruzi is the causative agent of Chagas disease, which is present mainly in Latin America but also in North America. [10][11][12] Nifurtimox and benznidazole are the only drugs available to treat patients in the acute phase of the disease.13,14 However, these drugs are not Velásquez et al. 1033 Vol. 27, No. 6, 2016 effective against the chronic phase of the disease, and they present multiple side effects, from dermatitis to bone marrow depression. 15 HAT is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. 16Treatment of the hemolymphatic stage of HAT relies on suramin and pentamidine. In the meningoencephalitis stage, melarsoprol, a highly toxic arsenic-based drug that is effective against both T. b. gambiense and T. b. rhodesiense is used. Eflornithine is useful only against T. b. gambiense. An eflornithine/nifurtimox combined therapy has been used, but this also causes several side effects.17 In summary, the conventional drugs that have been employed to treat these diseases are antiquated, have high toxicity and are ineffective due to drug resistance. Therefore, is critical to develop new drugs for the treatment of these trypanosomiases.The use of transition metal-based drugs is increasing significantly in the therapy of cancer and tropical diseases; in fact, many organometallic compounds have been designed to specifically bind to a well-d...

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

“…amazonensis promastigotes and T. cruzi epimastigotes forms as previously described (47). Cells were plated in 96-well plates (TPP, Trasadingen, Switzerland) at a density of 10 7 parasites/ml (in a final volume of 100 μl) and incubated at 28°C in the presence of increasing concentrations of CP2 or reference drugs (from 0.5 to 100 μM) for 72 h for L.…”

“…The absorbance was then read in a plate reader (Robonik, Maharashtra, India) at 490 nm for Leishmania species according to the protocol as previously established in our laboratory and at 595 nm for T. cruzi (4, 47). The assays were carried out in triplicates, and data analysis and calculations of their IC 50 s were performed using the software Origin 7.0 (65).…”

Protective Cellular Immune Response Induction for Cutaneous Leishmaniasis by a New Immunochemotherapy Schedule

“…Therefore, it is imperative the development of new therapeutic alternatives for control of leishmaniasis and among them, the development of natural and synthetic products, molecular modifications of existing compounds and drug repositioning have shown different degrees of efficacy in the treatment of experimental leishmaniasis. Antitumor compounds have also shown activity against parasites, including palladacycle complexes that displayed trypanocidal and leishmanicidal effects (8)(9)(10)(11). Recent findings identified immunomodulators able to increase the efficacy of leishmanicidal compounds (12,13).…”

Solution-combustion synthesis of doped TiO 2 compounds and its potential antileishmanial activity mediated by photodynamic therapy

“…The cutaneous form of the disease is the most common manifestation, presenting an annual incidence of 0.7 to 1.3 million new cases [2,3]. The available therapeutic drugs for leishmaniasis treatment are still based on pentavalent antimonials, amphotericin B, miltefosine or paromomycin, which present several limitations such as toxicity, difficult route of administration and variable efficacy [4], and although many efforts have been made towards the discovery of new synthetic or natural antileishmanials [5][6][7][8][9][10][11][12], new therapeutic options are still needed. In recent years, photodynamic therapy (PDT) has been investigated as a potential alternative to control cutaneous leishmaniasis (CL) [13][14][15][16].…”