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Pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate, have been used for more than half a century in the therapy of the parasitic disease leishmaniasis. Even though antimonials are still the first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of antimonials, their metabolism and mechanism of action are still being investigated. Some recent studies suggest that pentavalent antimony acts as a prodrug that is converted to active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data suggest that the biomolecules, thiols and ribonucleosides, may mediate the actions of these drugs. This review will summarize the progress to date on the chemistry and biochemistry of pentavalent antimony. It will also present the most recent works being done to improve antimonial chemotherapy. These works include the development of simple synthetic methods for pentavalent antimonials, liposome-based formulations for targeting the Leishmania parasites responsible for visceral leishmaniasis and cyclodextrin-based formulations to promote the oral delivery of antimony. [ABSTRACT FROM AUTHOR]

Two bismuth(III) porphyrins-5,10,15,20-tetrakis(phenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(TPP)]NO, and the unprecedent 5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(T4CMPP)]NO, and two unprecedented antimony(V) porphyrins dichlorido(5,10,15,20-tetrakis(phenyl)porphyrinato)antimony(V) bromide, [Sb(V)(TPP)Cl]Br, and dibromido(5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinato)antimony(V) bromide, [Sb(V)(T4CMPP)Br]Br,-were synthesized by reacting the corresponding porphyrin ligand with Bi(NO)·5HO or SbCl. All compounds were characterized by UV-vis, H NMR spectroscopy, and mass spectrometry. The new compounds were also characterized by elemental analysis. Because antimony and bismuth compounds have been widely applied in medicine, the activity of these complexes was tested against Sb-sensitive and -resistant Leishmania amazonensis parasites. [Sb(V)(T4CMPP)Br]Br was more active against the promastigote form of Sb-resistant mutant strain as compared to the sensitive parental strain, with IC in the micromolar range. These data contrasted with those obtained using the Sb(III) drug potassium antimony tartrate, which displayed IC of 110 μmol L against the Sb-sensitive parasite and was almost inactive against the Sb-resistant strain. The HT4CMPP ligand also showed antileishmanial activity against Sb-resistant and -sensitive strains, but with IC at least tenfold greater than that of the complex. The Sb(V)-porphyrin complex was also active against intracellular amastigotes and showed a higher selectivity index than the conventional Sb(V) drug glucantime, in both Sb-sensitive and -resistant strains. The greater antileishmanial activity of this complex could be attributed to an increased cellular uptake of Sb. Thus, [Sb(V)(T4CMPP)Br]Br constitutes a new antileishmanial drug candidate. [ABSTRACT FROM AUTHOR]

Background:: Visceral leishmaniasis (VL) is a chronic debilitating disease endemic in tropical and subtropical areas, caused by protozoan parasites of the genus Leishmania. Annually, it is estimated the occurrence of 0.2 to 0.4 million new cases of the disease worldwide. Considering the lack of an effective vaccine the afflicted population must rely on both, an accurate diagnosis and successful treatment to combat the disease. Here we propose to evaluate the efficacy of trivalent antimonial encapsulated in conventional liposomes, in association with ascorbic acid, by monitoring its toxicity and efficacy in BALB/c mice infected with Leishmania infantum. Methodology/Principal Findings:: Infected mice were subjected to single-dose treatments consisting in the administration of either free or liposome-encapsulated trivalent antimony (SbIII), in association or not with ascorbic acid. Parasite burden was assessed in the liver, spleen and bone marrow using the serial limiting dilution technique. After treatment, tissue alterations were examined by histopathology of liver, heart and kidney and confirmed by serum levels of classic biomarkers. The phenotypic profile of splenocytes was also investigated by flow cytometry. Treatment with liposome-encapsulated SbIII significantly reduced the parasite burden in the liver, spleen and bone marrow. Co-administration of ascorbic acid, with either free SbIII or its liposomal form, did not interfere with its leishmanicidal activity and promoted reduced toxicity particularly to the kidney and liver tissues. Conclusions/Significance:: Among the evaluated posological regimens treatment of L. infantum-infected mice with liposomal SbIII, in association with ascorbic acid, represented the best alternative as judged by its high leishmanicidal activity and absence of detectable toxic effects. Of particular importance, reduction of parasite burden in the bone marrow attested to the ability of SbIII-carrying liposomes to efficiently reach this body compartment. [ABSTRACT FROM AUTHOR]

Abstract: Novel trivalent antimony complexes with the nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen) or dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) have been synthesized by the reaction with SbCl3 or PhSbCl2. The crystal structures of [Sb(phen)Cl3] and [PhSb(phen)Cl2]CH3COOH were determined and shown to adopt a distorted square pyramid geometry with a five-coordinated Sb center. Surprisingly, all the complexes, the ligands and PhSbCl2 showed very high antileishmanial activities, with IC50 in the nanomolar range against SbIII-sensitive and -resistant Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis strains. These compounds were much more active against these Leishmania strains than the old trivalent drug potassium antimonyl tartrate. [PhSb(phen)Cl2]CH3COOH complex was found to be the most active compound and the lack of cross-resistance of PhSbCl2 suggests that the transport pathways of this compound across the cell membrane differ from those responsible for the resistance of Leishmania to Sb(OH)3. In the case of the complexes with PhSbCl2, our data supports the model that both ligand and metal contributed to the overall activity of the complex. Furthermore, among the complexes with SbCl3, only bipy showed an improved activity upon complexation. Cytotoxicity evaluations of these compounds against murine peritoneal macrophages showed high selective indexes in the range of 7–70 for [Sb(phen)Cl3], [Sb(bipy)Cl3] and [Sb(dpq)Cl3] complexes, being much more selective than potassium antimonyl tartrate. In conclusion, this study presents a set of new antileishmanial agents including one of the most active Sb-based compounds ever reported, which can contribute to the development of new chemotherapeutic strategies against leishmaniasis including Sb-resistant cases. [Copyright &y& Elsevier]

This work investigated the use of water extract of green propolis (WEP) and its association with free or liposomal meglumine antimoniate (MA) for the treatment of murine visceral leishmaniasis. Mice infected with Leishmania infantum were treated with oral doses of WEP associated or not with a single dose of liposomal MA by intraperitoneal route. Parasite burden was assessed in the liver and spleen by limiting dilution assay, and alterations in the spleen cellular phenotype were evaluated by flow cytometry. Tissue damage was assessed by determination of biochemical markers of the liver, heart, and kidney function and histopathological analysis of the liver and spleen. Our data showed that treatment with WEP was able to reduce parasite load in the liver but not in the spleen. On the other hand, liposomal MA reduced parasite load in both organs. Unexpectedly, there was no synergism with the combination of WEP and liposomal MA in reducing the parasite load. The histopathological analysis showed that administration of WEP, liposomal MA, or their association was able to protect the liver and spleen from lesions caused by infection. No alteration in the profile of spleen cells by flow cytometry or in the liver, heart, and kidney functions by biochemical markers due to any of the treatments was observed. These results demonstrate that although WEP was able to significantly reduce the liver parasite load, its association with liposomal MA did not lead to significant improvement in reducing parasite load. On the other hand, treatment with WEP and/or liposomal MA protected the liver and spleen from lesions caused by the infection. [ABSTRACT FROM AUTHOR]