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

Abstract

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 (IC 50 < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC 50 = 15.9 µg/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.

Chlorogenic acid acts upon Leishmania donovani arresting cell cycle and modulating cytokines and nitric oxide in vitro

“…In the present report, antileishmanial role of purified CGA is shown on both promastigotes and intracellular amastigotes of L. donovani in in vitro cultures. In vitro studies for the activities of other antileishmanal agents on free promastigotes and intracellular amastigotes are reported elsewhere 23,24 . In the present study, CGA in increasing doses (0 to 120 μmol/L) gradually retarded the normal growth of the promastigotes.…”

Antileishmanial compounds from Connarus suberosus: Metabolomics, isolation and mechanism of action

“…Compounds 1, 2, 3 and the benzoquinones: raponone (4), suberonone (5) and embelin (6), previously isolated by our group [12], were tested against L. infantum and L. amazonensis promastigotes and L. amazonensis amastigotes. Compounds 2 and 3 presented an IC 50 33.8 μM and 11.4 μM for L. amazonensis; and 44.3 μM and 13.3 μM for L. infantum, promastigotes respectively. For L. amazonensis amastigotes, the IC 50 of compound 2 was 20.4 μM with a selectivity index (SI) 5.7, while the IC 50 of compound 3 was 2.9 μM (SI 6.3).…”

“…infantum promastigotes (IC 50 11.4 μM/13.3 μM) and L. amazonensis amastigotes (IC 50 2.9 μM). The latter was in fact more active against the intracellular stage than the miltefosine positive control (IC 50 12.7 μM). Compounds 1 and 2 exhibited moderate activity against amastigotes (IC 50 31.6 μM/ 20.4 μM) whereas compounds 4, 5 and 6 were inactive.…”

“…aforementioned extract (Table 1). Due to its activity (IC 50 12.1 μg/mL) and yield, Fraction A was submitted to a silica column, resulting in 29 (A1-A29) fractions. The highest yielding fraction (A22), together with the five adjacent upstream and downstream fractions (A17-A27), were tested against L. amazonensis promastigotes with 24 h exposure at 100 μg/mL (S1A Fig).…”

“…Fraction A22 was the most active with 91.1% inhibition and was analyzed by LC-MS, with the major ion the same as that pinpointed by metabolomic analysis (m/z 391.2284; C 26 H 32 O 3 -H + [M-H] -). Therefore, A22 was fractionated in a Sephadex LH-20 column, yielding compound 3 (Fig 3), with an IC 50 20 , error = -3.8 ppm). The IR spectra showed signals at 3300 cm -1 (OH), 2912 cm -1 (aliphatic chains), 1504 cm -1 (aromatic) and 1200 cm -1 (ether group).…”