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

Abstract

BACKGROUND: Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi. 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. OBJECTIVES: Our aim was to explore the trypanosomicidal effect of BTZ alone or in combination with benznidazole (BZ) against T. cruzi. METHODS and FINDINGS: Our in vitro assays validated the low cytotoxicity of BTZ and high potency on amastigotes (EC50 = 0.075 μM), being 23-fold more potent than BZ. Washout assays demonstrated the sterilization 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 parasitemia but ensured the animal survival. BTZ plus BZ reduced parasitemia and provided higher survival rates than monotherapies. However, 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. CONCLUSIONS: Our dataset reinforces the relevance of drug repurposing and combination strategies to advance into the development of novel therapeutic approaches for CD.