# In vitro and in vivo studies on the activity and selectivity of butoconazole in experimental infection by Trypanosoma cruzi

## TL;DR

This study explores butoconazole as a potential treatment for Chagas disease, finding it effective in lab settings and when combined with another drug.

## Contribution

The study identifies butoconazole as a potent and low-toxic compound against Trypanosoma cruzi, with insights into combination therapy efficacy.

## Key findings

- Butoconazole showed high potency against T. cruzi amastigotes with low cytotoxicity.
- Combining butoconazole with benznidazole showed additive effects in reducing parasitaemia and improving survival in mice.
- Despite combination therapy benefits, no parasitological cure was achieved as parasite DNA remained in the heart tissue.

## Abstract

The protozoan Trypanosoma cruzi causes Chagas disease (CD). There are two drugs available for the treatment with limited efficacy, especially in the later stage. Focusing on drug repurposing by virtual screening of chemical databases, butoconazole (BTZ) was identified as promising hit.

Our aim was to explore the trypanosomicidal effect of BTZ alone or in combination with benznidazole (BZ) against T. cruzi.

Our in vitro assays validated the low cytotoxicity of BTZ and high potency on amastigotes (EC50 = 0.07 μM), being 24-fold more potent than BZ. Washout assays demonstrated the sterilisation capacity of BTZ, whereas its combination with BZ gave an additive interaction (xƩFICI = 0.66). In a mouse model of acute T. cruzi infection, BTZ was unable to suppress parasitaemia but ensured the animal survival. BTZ plus BZ reduced parasitaemia and provided higher survival rates than monotherapies. However, quantitative polymerase chain reaction (qPCR) revealed that BTZ + BZ protocol gave 100% of lack of parasitological cure, as parasite satDNA was amplified in the heart of all surviving animals.

Our dataset reinforces the relevance of drug repurposing and combination strategies to advance into the development of novel therapeutic approaches for CD.