Anti-Trypanosoma cruzi action of a new benzofuran derivative based on amiodarone structure

Abstract

Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca concentration of T. cruzi.

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

“…More recently, a new benzofurane derivative with a construction design based on amiodarone's structure (Amioder) has been shown to display a potent effect on epimastigotes and cell-infected amastigotes from T. cruzi (Pinto-Martinez et al, 2018a). As expected, the mechanism of action, was similar to that of amiodarone, causing increased the [Ca 2+ ] i , collapsing the electrochemical membrane potential of the mitochondrion, and alkalinizing the acidocalcisomes of the parasite.…”

“…Amiodarone Mitochondria, Acidocalcisomes, Ergosterol synthesis Benaim et al, 2006;Serrano-Martín et al, 2009a,b;Benaim and Paniz-Mondolfi, 2012 Dronedarone Mitochondria, Acidocalcisomes, Ergosterol synthesis Benaim and Paniz-Mondolfi, 2012;SQ109 Mitochondria, Acidocalcisomes, Ergosterol synthesis Veiga-Santos et al, 2015García-García et al, 2016;Gil et al, 2020 Amioder (Benzofuran derivative) Mitochondria, Acidocalcisomes, Pinto-Martinez et al, 2018a;Martinez-Sotillo et al, 2019 Miltefosine Sph-activated Plasma membrane Ca 2+ -Channel, Mitochondria, Acidocalcisomes Pinto-Martinez et al, 2018b;Rodriguez-Duran et al, 2019 Posaconazole Elevation of intracellular Ca 2+ Benaim et al, 2006 channel (Rodriguez-Duran et al, 2019) which allows the opening of Ca 2+ currents in a similar fashion to the physiological activator of the channel sphingosine. Concomitantly, miltefosine has also been demonstrated to collapse the mitochondrial electrochemical membrane potential ( φ), and to induce a rapid alkalinization of the parasites acidocalcisomes through direct action (Pinto-Martinez et al, 2018b).…”

Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca2+ channel in Trypanosoma cruzi

“…Trypanosoma cruzi is the causative agent of Chagas disease or American trypanosomiasis. This human infection is considered a neglected disease causing a large mortality and morbidity in Latin America from Mexico to Argentina . More recently, with globalization, this human infection has begun to spread to North America and Europe.…”

“…Albeit both drugs are partially effective in the acute phase of the infection, they have little effect in the chronic phase (< 25%) which is the predominant form of this human infection. Furthermore, since their mechanism of action is based essentially on the formation of free radicals, both drugs possess several undesirable side effects, commonly driving to the arrest of the treatment . Thus, there is a continuous effort for the identification of new therapeutic targets.…”

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

“…Darifenacin had hydrophobic interactions with VAL-26, ILE-35, ILE-41, PHE-52, THR-80, ILE-84, and TYR-160 and formed a hydrogen bond with ILE-41. This compound is a benzofuran derivative; interestingly, this kind of compound has been proposed as anti- T. cruzi , acting on the mitochondrial electrochemical membrane potential [ 49 ].…”