Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites

Objectives The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. Methods Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy. Key-findings Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC50 < 3.0 mu g/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC50 = 15.9 mu g/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages. Conclusions Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.