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Chagas disease, which is caused by the intracellular parasite Trypanosoma cruzi, is a neglected illness with 12-14 million reported cases in endemic geographic regions of Latin America. While the disease still represents an important public health problem in these affected areas, the available therapy, which was introduced more than four decades ago, is far from ideal due to its substantial toxicity, its limited effects on different parasite stocks, and its poor activity during the chronic phase of the disease. For the past 15 years, our group, in collaboration with research groups focused on medicinal chemistry, has been working on experimental chemotherapies for Chagas disease, investigating the biological activity, toxicity, selectivity and cellular targets of different classes of compounds on T. cruzi. In this report, we present an overview of these in vitro and in vivo studies, focusing on the most promising classes of compounds with the aim of contributing to the current knowledge of the treatment of Chagas disease and aiding in the development of a new arsenal of candidates with anti-T. cruzi efficacy.

Aromatic diamidines have been successfully used to combat a wide range of parasites that cause important human infections. Recently we reported that a N-phenyl-substituted analogue of furamidine (DB569) exerts a micromolar trypanocidal activity against Trypanosoma cruzi in vitro. Since DB569 also reduces the cardiac parasitism and increases the survival rates of T. cruzi-infected mice, our present aim was to analyze the potential protection of DB569 in the development of altered cardiac electrical conduction system during acute and chronic T. cruzi infection. In our experimental model of acute infection (Swiss mice inoculated with Y strain of T. cruzi), the prevailing disorder observed in electrocardiogram (ECG) analyses was sinus bradycardia. This ECG alteration was reverted in acutely infected mice treated with DB569. Interestingly, the DB569 treatment reduced significantly the numbers of CD8+ T cells in the cardiac infiltration. In addition, the noticed protection of DB569 in the ECG findings of acutely-infected animals was further extended to the chronic infection. Our data suggest that the reversion to and further maintenance of normal ECG profi le in the DB569-treated infected animals may be associated with the reduced cardiac CD8+ lymphocyte infiltration and parasitism that might be ultimately contributing to their increased survival rates.

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The baseline sensitivity of Botrytis cinerea to propamidine and assessment of the risk of propamidine resistance in vitro are presented in this article. The baseline sensitivities of 41 wild-type strains were distributed as a unimodal curve with EC values of mycelial growth ranging from 0.182 to 1.460 μg ml, with a mean of 0.79 ± 0.27 μg ml. A total of 10 resistant mutants, obtained from one parental strain, were induced by UV irradiation and selected for resistance to propamidine with an average frequency of 1.98 × 10 and 0.025 respectively. These mutants were divided into three classes of resistant phenotypes with low (LR), moderate (MR) and high (HR) levels of resistance, determined by the EC values of 5.0–15.0 μg ml, 15.1–75.0 μg ml and more than 75.0 μg ml respectively. Neither positive cross-resistance nor negative cross-resistance was detected between propamidine and the fungicides, benzimidazole carbendazim, anilino-pyrimidine pyrimethanil, dicarboximide iprodione or procymidone. All 10 propamidine-resistant mutants showed reduced mycelial growth in vitro, sporulation, spore germination and pathogenicity when compared with the parental strain. These studies demonstrated that propamidine possesses a low risk of resistance developing. However, as B. cinerea is a high-risk pathogen, appropriate precautions against resistance development should be taken. [ABSTRACT FROM AUTHOR]

Abstract: Canine leishmaniasis caused by Leishmania infantum is enzootic in the North American foxhound population. Currently available chemotherapy for canine leishmaniasis is not completely effective and relapses are common in treated dogs. Pentamidine and related aromatic diamidines possess broad spectrum antiprotozoal activity. The in vitro antileishmanial activities of 35 aromatic cationic molecules were determined, using pentamidine as the reference drug. The compounds were examined for activity against promastigotes of L. infantum isolated from a foxhound from Virginia. The compounds most active against Leishmania parasites were reversed amidines. Compound 9, a reversed amidine, exhibited the highest activity against L. infantum, with a 50% inhibitory concentration (IC50) of 0.0042μM compared with 14.2μM for pentamidine. Antileishmanial activities of nine compounds were at least 1000-fold higher relative to the reference drug. Results from this study indicate that several pentamidine-related compounds warrant further investigation as possible new agents for the treatment of canine leishmaniasis. [Copyright &y& Elsevier]

The aromatic diamidines are a series of chemicals with high basicity. Among other properties they have, is that of intervening in the metabolism and transport of polyamines, since they inhibit s-adenosyl-L-methionine decarboxylase (SAMDC) and diamine oxidase (DAO). They are of importance in pharmacology. Examples of this are: that pentamidine is used, for instance, in treating pneumonia in patients affected by the human immunodeficiency virus (HIV), that propamidine is utilized, among other things, to treat cornea infections, and that berenil is employed in veterinary medicine, though not in humans. Owing to their considerable interest, further chemicals belonging to this family are constantly being synthesized, with the aim of ensuring greater pharmacological capacities, better stability, and fewer secondary effects. It is essential to have available analytical methods for detecting these drugs in a range of media. In this study, attention was paid to nine aromatic diamidines that are heads of series: pentamidine, stilbamidine, DAPI, propamidine, hydroxystilbamidine, phenamidine, diampron, berenil, and dibromopropamidine, with the aim of proposing analytical methods employing HPLC. Use was made of ion-pairing for each of them, and for others of similar structure, in aqueous solutions and in biological media, such as serum and urine. To achieve the purpose of the study, the effects on the capacity factor k′ of varying the chief chromatographic parameters were tracked. These parameters were the influences exercised by: concentration and chain length of the ion-pair-forming agent, pH in the mobile phase, methanol percentage, buffer concentration, and temperature. The data obtained from this work suggest general conditions for the analysis of each of these substances in aqueous solution would be a mobile phase consisting of 25.0 mM citrate buffer, with pH = 3.25, methanol 45%, ultrasphere ODS column (5 µm particle size,15... [ABSTRACT FROM AUTHOR]

Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major "neglected" diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives.