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.

The antileishmanial efficacies of 2-n-propylquinoline, chimanines B and D, 2-n-pentylquinoline, 2-phenylquinoline, 2-(3,4-methylenedioxyphenylethyl) quinoline, and two total alkaloidal extracts of Galipea longiflora were evaluated in BALB/c mice infected with Leishmania amazonensis or Leishmania venezuelensis. Animals were treated for 4 to 6 weeks postinfection with a quinoline by the oral route at 50 mg/kg of body weight twice daily for 15 days or by five intralesional injections at intervals of 4 days with a quinoline at 50 mg/kg of body weight. The reference drug, N-methylglucamine antimonate (Glucantime), was administered by subcutaneous or intralesional injection (regimens of 14, 28, or 56 mg of pentavalent antimony [Sbv] per kg of body weight daily). Twice-daily oral treatment with chimanine B at 50 mg/kg resulted in a decrease in lesion weight by 70% (P < 0.001) and a decrease in the parasite loads by 95% (P < 0.001). Five injections of chimanine B at intervals of 4 days reduced the lesion weight by 74% and the parasite loads in the lesion by 90% compared with the values for the group of untreated mice. Subcutaneous administration of N-methylglucamine antimonate at 28 mg of Sbv kg per day for 15 days reduced the parasite burden by 95% (P < 0.001), and five intralesional injections at the same concentration reduced the parasite burden by 96% (P < 0.001). Other 2-substituted quinolines, 2-n-propylquinoline administered by the oral and intralesional routes, 2-phenylquinoline administered by the oral route, 2-n-pentylquinoline administered by intralesional injection, and two total alkaloidal extracts of G. longiflora administered by the oral route, had intermediate effects. These findings suggest that chimanine B may be chosen as a lead molecule in the development of oral therapy against leishmaniasis.

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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.