# 2-Aminothiophene Derivative SB-83 Inhibits Trypanothione Reductase and Modulates Cytokine Production in Trypanosoma cruzi-Infected Cells

## TL;DR

A new compound, SB-83, shows strong anti-parasitic effects against Trypanosoma cruzi, the cause of Chagas disease, and could be a promising treatment.

## Contribution

SB-83 is a novel 2-aminothiophene derivative with potent trypanocidal activity and immune-modulating properties.

## Key findings

- SB-83 effectively inhibits T. cruzi at low concentrations with high selectivity for host cells.
- The compound modulates cytokine production and induces apoptosis in the parasite.
- SB-83 binds to trypanothione reductase and disrupts the parasite's redox balance.

## Abstract

Chagas disease remains a significant neglected tropical disease that predominantly affects vulnerable populations in rural, low-income areas of Latin America. The management of this condition is severely hindered by the limitations of current therapies, which are characterized by substantial toxicity, diminished efficacy during the chronic phase, and the emergence of parasitic resistance. Given the promising activity of SB-83 (a 2-aminothiophenic derivative) against Leishmania spp., the present study sought to evaluate its trypanocidal activity against Trypanosoma cruzi. The results showed that SB-83 exhibited potent inhibitory effects on the epimastigote forms of T. cruzi (IC50 = 6.23 ± 0.84 μM), trypomastigotes (EC50 = 7.31 ± 0.52 μM) and intracellular amastigotes (EC50 = 5.12 ± 0.49 μM). Furthermore, the cellular proliferation assay results indicated CC50 values of 77.80 ± 2.05 µM for LLC-MK2 CCL-7 and 24.21 ± 1.2 µM for Vero CCL-87, with a selectivity index above 10 for LLC-MK2 cells. In addition, the compound increased TNF-α, IL-12, nitric oxide, and ROS while decreasing IL-10. Moreover, in silico and in vitro assays confirmed its binding to trypanothione reductase, disrupting redox balance. Flow cytometry further revealed apoptosis induction in trypomastigotes, whereas electron microscopy showed cellular disruption and organelle disorganization. Therefore, SB-83 demonstrated potent activity against the TcI-resistant strain linked to Chagas cardiomyopathy at non-toxic concentrations for host cells, supporting its potential as a therapeutic candidate.