Acrylonitrile Derivatives against Trypanosoma cruzi: In Vitro Activity and Programmed Cell Death Study

Abstract

The neglected infection known as Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, results in more than 7000 deaths per year, with an increasing number of cases in non-endemic areas such as Europe or the United States. Moreover, with the current available therapy, only two compounds which are active against the acute phase of the disease are readily available. In addition, these therapeutic agents display multiple undesired side effects such as high toxicity, they are expensive, the treatment is lengthy and the resistant strain has emerged. Therefore, there is a need to find new compounds against Chagas disease which should be active against the parasite but also cause low toxicity to the patients. In the present work, the activity of novel acrylonitriles against Trypanosoma cruzi was evaluated as well as the analysis of the physiological events induced in the treated parasites related to the cell death process. Hence, the characteristic features of an apoptosis-like process such as chromatin condensation and mitochondrial membrane potential, among others, were studied. From the 32 compounds tested against the epimastigote stage of T. cruzi, 11 were selected based on their selectivity index to determine if these compounds were able to induce programmed cell death (PCD) in the treated parasites. Furthermore, acrylonitriles Q5, Q7, Q19, Q27 and Q29 were shown to trigger physiological events related in the PCD. Therefore, this study highlights the therapeutic potential of acrylonitriles as novel trypanocidal agents.

Acrylonitrile derivatives: In vitro activity and mechanism of cell death induction against Trypanosoma cruzi and Leishmania amazonensis

“…Previous studies demonstrate the induction of programmed cell death caused by acrylonitriles ( Sandes et al, 2010 , 2014 ). In addition, previous works by this group has demonstrated the existence of apoptosis like death caused by this type of compounds ( Bethencourt-Estrella et al, 2021 , 2022 ).…”

“…Previous reports demonstrate that acrylonitriles induce apoptosis when used to treat different pathologies ( Dang et al, 2018 ; Kim and Choi, 2020 ; Luo et al, 2022 ; Tretyakova et al, 2019 ), including leishmaniasis and Chagas disease ( Bethencourt-Estrella et al, 2021 , 2022 ). Apoptotic cell death is described as a type of programmed and controlled cell death, which, in the case of parasitosis, avoids the possible inflammatory response that would occur in the hosts.…”

In vitro activity and mechanism of cell death induction of cyanomethyl vinyl ethers derivatives against Trypanosoma cruzi

“…After incubating the epimastigotes with the IC 90 of the compounds at 26 °C for 24 h, centrifuging (825 g, 10 min, 4 °C) and resuspending in 50 μl of buffer, the kit was added at 5 μM concentration for 30 min at 26 °C. The measure of red cells concentration was carried out using the Countess II FL (ThermoFisher Scientific, Madrid, Spain) and the images were done using Cy5 light cube in the EVOS® FL Cell Imaging System (ThermoFisher Scientific, Madrid, Spain) ( Bethencourt-Estrella et al, 2021 ).…”

“…The use of compounds based on nitrile or cyano groups has been developed for decades against Trypanosoma spp. ( Bethencourt-Estrella et al, 2021 ; Quilles et al, 2020 ). In addition, these compounds have been linked to the inhibition of cystein proteases, more specifically against cruzain ( Beaulieu et al, 2010 ; Burtoloso et al, 2017 ; Fonseca Lameiro et al, 2021 ).…”

Antikinetoplastid Activity of Sesquiterpenes Isolated from the Zoanthid Palythoa aff. clavata

“…After incubating for 24 h, we performed centrifuging and resuspending in 50 µL of buffer with the CellROX kit, at a 5 µM concentration. Finally, fluorescence pictures were captured by using the EVOS ® FL Cell Imaging System (Thermo Fisher Scientific, MA, USA) with the Cy5 light cube [50].…”