Anti-Trypanosoma Activity and Synergistic Effects of Natural and Semi-Synthetic Triterpenes and Predominant Cell Death through Autophagy in Amastigote Forms

Abstract

Chagas' disease is a parasitic disease with unsatisfactory treatment, mainly in chronic stage. This study aimed to evaluate the trypanocidal activity and action mechanisms of α/β-amyrin and its semisynthetic derivatives, together with four isolated natural triterpenes, tested against trypomastigote and amastigote forms. The structure-activity relationship was suggested and cytotoxicity was measured. In general, greater polar compounds may have improved the selectivity to the protozoan. Action mechanisms were only performed for the amastigotes of Trypanosoma cruzi by evaluating the ultrastructural alterations, membrane permeability, mitochondrial membrane potential and cell volume, since the majority of compounds displayed promising antiamastigote activities. Triterpenes promoted changes on mitochondrial membrane potential and ultrastructural features that suggest autophagy processes. Both combinations between α/β-amyrin and 3-O-acetyl-11-oxo-α/β-amyrin and 3-O-acetyl-α/β-amyrin with benznidazole displayed synergistic effects against amastigotes and antagonistic effects on LLCMK 2 cells. The antiamastigote activities, chemical derivatization, drug combinations and action mechanisms revealed to be crucial approaches toward this chronic disease.

Semisynthetic triterpenes led to the generation of selective antitrypanosomal lead compounds

“…A series of semisynthetic derivatives of α‐ and β‐amyrins were tested against trypomastigotes forms of T . cruzi being the most active compound 3‐O‐fumaryl‐α/β‐amyrin presenting an IC 50 of 25.2 μM (Bossolani et al, 2017). The antiparasitic activity observed in the compounds of the present study corroborates those previous studies of these triterpenes, where we brought derivatives with unprecedented modifications to α‐ and β‐amyrins and with similar or even more potent activity against parasites in vitro.…”

“…Active compounds against T. cruzi and T. brucei have already been reported, such as Tingenin B (IC 50 0.25 μM), which is the most active (Maregesi et al, 2010), and against several species of Leishmania, such as maesabalide III for L. infatum IC 50 0.25 µM (Germonprez et al, 2005). A series of semisynthetic derivatives of αand βamyrins were tested against trypomastigotes forms of T. cruzi being the most active compound 3-O-fumaryl-α/βamyrin presenting an IC 50 of 25.2 μM (Bossolani et al, 2017). The antiparasitic activity observed in the compounds of the present study corroborates those previous studies of these triterpenes, where we brought derivatives with unprecedented modifications to α-and β-amyrins and with similar or even more potent activity against parasites in vitro.…”

“…Molecular docking studies demonstrated that the triterpenes αand βamyrin had an affinity for Leishmania infantum CYP51 (Ogungbe & Setzer, 2013), and different β-amyrin fatty esters (behenate, eicosanoate, stearate, lignonate, and palmitate) were selective for Trypanosoma cruzi CYP51 (Warfield et al, 2014), suggesting an antiparasitic potential for these triterpenes and their derivatives. In a previous study, derivatives of α-and β-amyrin showed an excellent activity against T. cruzi (Bossolani et al, 2017).…”

“…In a previous study, derivatives of α‐ and β‐amyrin showed an excellent activity against T . cruzi (Bossolani et al, 2017).…”

A terpenoid-rich extract from Clethra fimbriata exhibits anti-Trypanosoma cruzi activity and induces T cell cytokine production

“…Additionally, when cytotoxicity was assessed in mammalian conjunctive cells, a low toxicity was observed, reaching a selectivity index of 5.7 [ 58 ]. Other triterpenes such as α and β amyrin together with their semi-synthetic derivatives have been described as having trypanocidal activities on trypomastigotes and amastigotes, whose mechanisms of action seems to be related to mitochondrial membrane potential changes and ultrastructural features suggesting autophagy processes [ 59 ].…”