Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi.

摘要: Abstract The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. mainstay of treatment is chemotherapy, however the drugs choice, which include benznidazole miltefosine, are toxic have numerous side effects. Safe effective therapies urgently needed. Marine alpha-pyrones been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples 3-substituted 4-hydroxy-6-methyl were synthesized their antiparasitic efficacy evaluated against Leishmania (L.) infantum Trypanosoma cruzi order to evaluate structure-activity relationships within series. mechanism action in vivo most selective compound T. cruzi different techniques. In vitro data indicated that compounds 8, 15, 25, 26 28 presented IC50 values range between 13 54 μM L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was potent, Selectivity Index (SI) > 14. Fifteen trypomastigotes, 3-undecanoyl (11) 3-tetradecanoyl (12) pyrones being potent 1 2 μM, respectively, SI higher 70. Using flow cytometry fluorescent-based assays, 12 found induce hyperpolarization mitochondrial membrane T. cruzi, without affecting plasma permeability. An experimental acute phase-murine model, demonstrated dosing (30 mg/kg/day; 5 days), had no at first parasitemia onset but reduced second by 55% (p