Antileishmanial Activity and Immunomodulatory Effects of Tricin Isolated from Leaves of Casearia arborea (Salicaceae).

Bioactivity-guided fractionation of antileishmanial active extract from leaves of Casearia arborea led to isolation of three metabolites: tricin (1), 1',6'-di-O-ß-d-vanilloyl glucopyranoside (2) and vanillic acid (3). Compound 1 demonstrated the highest activity against the intracellular amastigotes of Leishmania infantum, with an IC50 value of 56 µm. Tricin (1) demonstrated selectivity in mammalian cells (SI > 7) and elicited immunomodulatory effect on host cells. The present work suggests that tricin modulated the respiratory burst of macrophages to a leishmanicidal state, contributing to the parasite elimination. Therefore, the natural compound tricin could be further explored in drug design studies for leishmaniasis treatment.

Gibbilimbol analogues as antiparasitic agents--Synthesis and biological activity against Trypanosoma cruzi and Leishmania (L.) infantum.

The essential oils from leaves of Piper malacophyllum (Piperaceae) showed to be mainly composed by two alkenylphenol derivatives: gibbilimbols A and B. After isolation and structural characterization by NMR and MS data analysis, both compounds were evaluated against promastigote/amastigote forms of Leishmania (L.) infantum as well as trypomastigote/amastigote forms of Trypanosoma cruzi. The obtained results indicated that gibbilimbol B displayed potential against the tested parasites and low toxicity to mammalian cells, stimulating the preparation of several quite simple synthetic analogues in order to improve its activity and to explore the preliminary structure-activity relationships (SAR) data. Among the prepared derivatives, compound LINS03003 (n-octyl-4-hydroxybenzylamine) displayed the most potent IC50 values of 5.5 and 1.8 µM against amastigotes of T. cruzi and L. (L.) infantum, respectively, indicating higher activity than the natural prototype. In addition, this compound showed remarkable selectivity index (SI) towards the intracellular forms of Leishmania (SI=13.1) and T. cruzi (SI=4.3). Therefore, this work indicated that preparation of synthetic compounds structurally based in the bioactive natural products could be an interesting source of novel and selective compounds against these protozoan parasites.

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.

Antiprotozoal activity of extracts and isolated triterpenoids of 'carnauba' (Copernicia prunifera) wax from Brazil.

CONTEXT: 'Carnauba' wax is a natural product obtained from the processing of the powder exuded from Copernicia prunifera (Miller) H. E. Moore (Arecaceae). This material is widely used in the Brazilian folk medicine, including the treatment of rheumatism and syphilis. OBJECTIVE: To investigate the antiprotozoal activity of hexane and EtOH extracts from the 'carnauba' wax as well as from the isolated compounds from the bioactive extracts. MATERIAL AND METHODS: Two different samples of 'carnauba' (C. prunifera) waxes - types 1 and 4 - were individually extracted using hexane (EH) and EtOH (EE). Aliquots of hexane (type 1 - EH-1 and EH-4) and EtOH (type 4 - EE-1 and EE-4) extracts were tested against promastigote (2-200 µg/mL in DMSO during 48 h at 24 °C) and amastigote (3-150 µg/mL in DMSO during 120 h at 37 °C) forms of Leishmania infantum as well as against trypomastigote (3-150 µg/mL in DMSO during 24 h at 37 °C) forms of Trypanosoma cruzi. Bioactive extracts EH-1 and EE-4 were subjected to a bioactivity-guided fractionation to afford three dammarane-type triterpenoids (1-3). The in vitro antiprotozoal activities of the obtained compounds were evaluated as described above. Additionally, the cytotoxicity activity of compounds 1-3 against mammalian conjunctive cells (NCTC - 2-200 µg/mL in DMSO during 48 h at 37 °C) was determined. RESULTS: From the bioactive hexane and EtOH extracts from the 'carnauba' (C. prunifera) wax, were isolated three dammarane-type triterpenoids: (24R*)-methyldammar-25-ene-3ß,20-diol (carnaubadiol, 1), (24R*)-methyldammara-20,25-dien-3-one (2) and (24R*)-methyldammara-20,25-dien-3α-ol (3). These compounds were identified based on the analysis of NMR and MS spectroscopic data. Compounds 1-3 were effective against the intracellular amastigotes of L. infantum, with IC50 values ranging from 8 to 52 µM, while compounds 1 and 3 displayed activity against trypomastigote forms of T. cruzi with IC50 values of 15 and 35 µM, respectively. The mammalian cytotoxicity assay demonstrated no damage to NCTC conjunctive cells up to 200 µM, except for compound 1, which demonstrated a CC50 value of 34 µM. CONCLUSION: Based on the results, it was possible to conclude that the detected antiprotozoal bioactivity of 'carnauba' (C. prunifera) wax extracts could be related to the presence of the natural dammarane triterpenoid derivatives. The results suggested that these compounds could be used as promising scaffolds for drug design studies for leishmaniasis and Chagas disease.