Antiparasitic effect of stilbene and terphenyl compounds againstTrypanosoma cruziparasites
Authors: Bruno Federica , Castelli Germano , Vitale Fabrizio , Catanzaro Simone , Vitale Badaco Valeria , Roberti Marinella , Colomba Claudia , Cascio Antonio , Tolomeo Manlio 
Published: February 2021

Background

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasiteTrypanosoma cruzi. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago and is considered very aggressive and may cause several adverse effects. Currently, this drug has severe limitations, including high frequency of undesirable side effects and limited efficacy and availability and the research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products.

Methodology/Principal Findings

This study evaluated the in vitro antiparasitic activity inT. cruziepimastigotes and intracellular amastigotes of a series of stilbene and terphenyl compounds previously synthesized. The action of the most selective compounds has been investigated by flow cytometry analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasome were assayed in macrophages infected withT. cruziafter treatment comparing with Nifurtimox.

Conclusions/Significance

The stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase of parasites positive to Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation in infected macrophages of caspase-1, a conserved enzyme which plays a main role in controlling parasitemia, host survival, and the onset of adaptive immune response in Trypanosoma infection. The antiparasitic activity of ST18 together to its ability to activate caspase-1 in infected macrophages and its low toxicity on normal cells makes this compound interesting for further clinical investigations.

Author Summary

Chagas disease is a pathology caused by the protozoan parasiteTrypanosoma cruzi.No progress in the treatment of this pathology has been made since benznidazole and Nifurtimox were introduced more than fifty years ago. However, these drugs have severe limitations and the research to discover new drugs for the treatment of Chagas disease is imperative. We evaluated thein vitroantiparasitic activity inT. cruziepimastigotes of a series of stilbene and terphenyl compounds previously synthesized. The stilbene ST18 was the most potent compound of the series. It was slightly less active than nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase of parasites positive to Annexin V and monodansylcadaverine. Moreover, this compound induced the activation in infected macrophages of caspase-1, an evolutionarily conserved enzyme which plays a main role in controlling parasitemia, host survival, and the onset of adaptive immune response inT. cruziinfection. The antiparasitic activity of ST18 together to its ability to activate caspase-1 in infected macrophages and its low toxicity on normal cells makes this compound interesting for further clinical investigations.