In vitro and in vivo antitrypanosomatid activity of 5-nitroindazoles.

Previously, we have identified a series of 5-nitroindazoles with good antiprotozoal activities, against Trypanosoma cruzi epimastigotes and Trichomonas vaginalis. Most of them have shown very low unspecific toxicity on macrophage cell lines. In the present work, we assayed these compounds on T. cruzi bloodstream trypomastigotes and Leishmania promastigotes (Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum). Derivatives 1, 2, 7 and 8 displayed remarkable trypanocidal activity (>80% lysis) equivalent to gentian violet. Derivatives 2 and 10, as Pentamidine, caused the complete lysis of promastigotes of Leishmania. An oxidative stress-mediated mechanism of action was confirmed for derivatives 1, 10 and 12 on T. cruzi epimastigotes. Supported by the in vitro activities, derivatives 1 and 2 were submitted to in vivo assays using an acute model of Chagas' disease and a short-term treatment. None of the animals treated with derivatives 1 and 2 died, unlike the untreated control and Benznidazole groups.

2H-benzimidazole 1,3-dioxide derivatives: a new family of water-soluble anti-trypanosomatid agents.

Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-benzimidazole 1,3-dioxides displayed remarkable in vitro activities against both parasites, with derivatives 28, 29, and 32 being the most potent (IC50 < 5 microM) against the epimastigote form of T. cruzi and 28, 33, and 35 the most potent against the promastigote form of Leishmania spp. Unspecific cytotoxicity was evaluated using murine macrophages, and derivative 33 was not toxic at a concentration 30 times that of its IC50 against T. cruzi that was completely toxic for Leishmania spp., implying that the series of 2H-benzimidazole 1,3-dioxides is selective toward both trypanosomatid parasites. Derivatives 33 and 35 were submitted to an in vivo assay using an acute model of Chagas' disease and a short-term treatment (30 mg/kg/day orally administrated as aqueous solution, during 10 days). While in the control (untreated) and Benznidazole (50 mg/kg/day) groups survival fraction was 60.0% and 87.5%, respectively, none of the animals treated with derivatives 33 and 35 died. From the preliminary structure-activity relationship studies reduction potential and electrophilicity were found relevant to anti-T. cruzi activity. Active compounds are better electrophiles and more easily reduced than inactive ones.

Efficacy of orally administered 2-substituted quinolines in experimental murine cutaneous and visceral leishmaniases.

We report in this study the in vivo efficacy of nine 2-substituted quinolines on the Leishmania amazonensis cutaneous infection murine model and on the Leishmania infantum and Leishmania donovani visceral infection murine models. In the case of the L. amazonensis model, quinolines were administered orally at 25 mg/kg twice daily for 15 days. Quinolines 1, 2, 3, and 7 reduced by 80 to 90% the parasite burdens in the lesion, whereas N-methylglucamine antimoniate (Glucantime), administered by subcutaneous injections at 100 mg [28 mg Sb(V)] per kg of body weight daily, reduced the parasite burdens by 98%. In visceral leishmaniasis due to L. infantum, mice treated orally at 25 mg/kg daily for 10 days with quinolines 1, 4, 5, and 6 showed a significant reduction of parasite burdens in the liver and spleen. These quinolines were significantly more effective than meglumine antimoniate to reduce the parasite burden in both the liver and spleen. Also, the oral in vivo activity of three quinolines (quinolines 4, 5, and 2-n-propylquinoline) were determined against L. donovani (LV 9) at 12.5 and 25 mg/kg for 10 days. Their activity was compared with that of miltefosine at 7.5 mg/kg. Miltefosine, 2-n-propylquinoline, and quinoline 5 at 12.5 mg/kg significantly reduced the parasite burdens in the liver by 72, 66, and 61%, respectively. From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis. The double antileishmanial and antiviral activities of these compounds suggest that this series could be a potential treatment for coinfection of Leishmania-human immunodeficiency virus.