Antileishmania and immunomodulatory potential of cashew nut shell liquid and cardanol.

Conventional treatments for leishmaniasis have caused serious adverse effects, poor tolerance, development of resistant strains. Natural products have been investigated as potential therapeutic alternatives. The cashew nut shell liquid (CNSL) is a natural source of phenolic compounds with several biological activities, where cardanol (CN) is considered one of the most important and promising compounds. This study aimed to evaluate antileishmanial, cytotoxic and immunomodulatory activities of CNSL and CN. Both showed antileishmanial potential, with IC50 for CNSL and CN against Leishmania infantum: 148.12 and 56.74 µg/mL; against Leishmania braziliensis: 85.71 and 64.28 µg/mL; against Leishmania major: 153.56 and 122.31 µg/mL, respectively. The mean cytotoxic concentrations (CC50) of CNSL and CN were 37.51 and 31.44 µg/mL, respectively. CNSL and CN significantly reduced the percentage of infected macrophages, with a selectivity index (SI) >20 for CN. CNSL and cardanol caused an increase in phagocytic capacity and lysosomal volume. Survival rates of Zophobas morio larvae at doses of 3; 30 and 300 mg/kg were: 85%, 75% and 60% in contact with CNSL and 85%, 60% and 40% in contact with CN, respectively. There was a significant difference between the survival curves of larvae when treated with CN, demonstrating a significant acute toxicity for this substance. Additional investigations are needed to evaluate these substances in the in vivo experimental infection model.

Isopropyl Gallate, a Gallic Acid Derivative: In Silico and In Vitro Investigation of Its Effects on Leishmania major.

Isopropyl gallate (IPG) is a polyphenol obtained from alterations in the gallic acid molecule via acid catalysis with previously reported leishmanicidal and trypanocidal activities. The present study aims to evaluate in silico binding activity towards some targets for antileishmanial chemotherapy against Leishmania major species, and ADMET parameters for IPG, as well as in vitro antileishmanial and cytotoxic effects. Molecular docking was performed using AutoDockVina and BIOVIA Discovery Studio software, whereas in silico analysis used SwissADME, PreADMET and admetSAR software. In vitro antileishmanial activity on promastigotes and amastigotes of Leishmania major, cytotoxicity and macrophages activation were assessed. IPG exhibited affinity for pteridine reductase (PTR1; -8.2 kcal/mol) and oligopeptidase B (OPB; -8.0 kcal/mol) enzymes. ADMET assays demonstrated good lipophilicity, oral bioavailability, and skin permeability, as well as non-mutagenic, non-carcinogenic properties and low risk of cardiac toxicity for IPG. Moreover, IPG inhibited the in vitro growth of promastigotes (IC50 = 90.813 µM), presented significant activity against amastigotes (IC50 = 13.45 µM), promoted low cytotoxicity in macrophages (CC50 = 1260 µM), and increased phagocytic capacity. These results suggest IPG is more selectively toxic to the parasite than to mammalian cells. IPG demonstrated acceptable in silico pharmacokinetics parameters, and reduced infection and infectivity in parasitized macrophages, possibly involving macrophage activation pathways and inhibition of leishmania enzymes.

Limonene-carvacrol: A combination of monoterpenes with enhanced antileishmanial activity.

BACKGROUND: Leishmaniasis is a parasitosis with a wide incidence in developing countries. The drugs which are indicated for the treatment of this infection usually are able to promote high toxicity. PURPOSE: A combination of limonene and carvacrol, monoterpenes present in plants with antiparasitic activity may constitute an alternative for the treatment of these diseases. METHODS: In this study, the antileishmania activity against Leishmania major, cytotoxicity tests, assessment of synergism, parasite membrane damage tests as well as molecular docking and immunomodulatory activity of limonene-carvacrol (Lim-Car) combination were evaluated. RESULTS: The Lim-Car combination (5:0; 1:1; 1:4; 2:3; 3:2; 4:1 and 0:5) showed potential antileishmania activity, with mean inhibitory concentration (IC50) ranging from 5.8 to 19.0 µg.mL-1. They demonstrated mean cytotoxic concentration (CC50) ranging from 94.1 to 176.0 µg.mL-1, and did not show significant hemolytic effect. In the investigation of synergistic interaction, the 4:1 Lim-Car combination showed better fractional inhibitory concentration (FIC) index as well as better activity on amastigotes and IS. The samples caused considerable damage to the parasite membrane this monoterpene activity seems to be more related to Trypanothione Reductase (TryR) enzyme interaction, demonstrated in the molecular docking assay. In addition, the 4:1 Lim-Car combination stimulated macrophage activation, and showed at was the best association, with reduction of infection and infectivity of parasitized macrophages. CONCLUSION: The 4:1 Lim-Car combination appears to be a promising candidate as a monotherapeutic antileishmania agent.

Garcinielliptone FC: Selective anti-amastigote and immunomodulatory effects on macrophages infected by Leishmania amazonensis.

The present study was directed to the in vitro antileishmanial, cytotoxic and immunomodulatory effects of Garcinielliptone FC (GFC) against promastigote and macrophage-internalized amastigote forms of Leishmania amazonensis. GFC showed in vitro cytotoxicity against BALB/c peritoneal macrophages with CC50 of 74.90 µM. The hemolytic activity against sheep erythrocytes only demonstrated a decrease of 20.42% in cell viability at the highest tested concentration tested (1326.0 µM). GFC promoted in vitro growth inhibition of both promastigote and intracellular amastigotes with IC50 values of 14.06 and 1.91 µM, respectively, with 7.3-fold higher Selectivity Index (SI) for intracellular amastigotes (SI = 39.21) than for promastigotes (SI = 5.33). Interestingly, the pre-treatment of macrophages or promastigotes with GFC promoted decrease of infected macrophages and number of recovered amastigotes, respectively. Also, GFC was able to markedly promote macrophages activation by increase of phagocytic capability and nitrite production at concentrations able to solve infection of macrophages by L. amazonensis, suggesting the possible involvement of immunomodulatory modulation of macrophages leading to solve the infection. GFC is an emerging and promising chemical compound for the studies focused on the assessment of its therapeutic potential on in vivo experimental models of leishmaniasis.