Repurposing of terconazole as an anti Trypanosoma cruzi agent

CHANTAL REIGADA; MARIANA R. MIRANDA; EDWARD A. VALERA VERA; MELISA SAYÉ; CLAUDIO A. PEREIRA

Heliyon

Elsevier Ltd

Año: 2019 vol. 5

2405-8440

Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America.Currently there are no effective treatments for the chronic phase of the disease, when most patients are diagnosed,therefore the development of new drugs is a priority area. Several triazoles, used as fungicides, exhibit trypanocidalactivity both in vitro and in vivo. The mechanism of action of such drugs, both in fungi and in T. cruzi, reliesin the inhibition of ergosterol biosynthesis affecting the cell viability and growth. Among them, terconazole wasthe first triazole antifungal drug for human use. In this work, the trypanocidal activity of terconazole was evaluatedusing in vitro assays. In epimastigotes of two parasites strains from different discrete typing units (Y andDm28c) the calculated IC50 were 25.7 μM and 21.9 μM, respectively. In trypomastigotes and amastigotes (theclinically relevant life-stages of T. cruzi) a higher drug susceptibility was observed with IC50 values of 4.6 μM and5.9 μM, respectively. Finally, the molecular docking simulations suggest that terconazole inhibits the T. cruzicytochrome P450 14-α-demethylase, interacting in a similar way that other triazole drugs. Drug repurposing toChagas disease treatment is one of the recommended approach according to the criterion of international healthorganizations for their application in neglected diseases.