Drug repurposing for Chagas disease: Trying to overcome the hit-to-preclinical candidate stage

Hugo Cerecetto^1*Claudia Veira¹Belén Dávila¹Elva Serna²Nilda Portillo²Gloria Yaluff²Guzmán Alvarez¹Elena Aguilera^1*

• ¹Universidad de la República, Montevideo, Uruguay
• ²Universidad Nacional de Asuncion, San Lorenzo, Paraguay

Building upon our previous work in drug repurposing and the use of binary combinations as anti-Chagas agents, herein we detail the efforts undertaken to advance the most promising repositioned compounds and binary mixtures, identified in vitro, beyond the hit-to-preclinical candidate stage. Five repositioned active principles and 4 binary combinations of these agents, selected for their in vitro isobolographic behavior, were evaluated in a murine model of the acute disease. In the study, these 9 systems were administered orally, along with the negative and positive controls (benznidazole), for 15 days. Changes over time in parasitemia levels and animal survival were evaluated together with levels of anti-Trypanosoma cruzi antibodies at the end of the trials. Gabapentin was the most notable of the repositioning drugs; it significantly decreased parasitemia and anti-T. cruzi antibodies while also improving modestly, the animal's survival. When it was combined with naftazone, the best animal survival profile was achieved. Naftazone, combined with the red clover extract trademarked in Uruguay as Climodin, was another noteworthy binary combination. This combination exhibited a consistent parasitemia reduction profile, with the best antibody reduction; however, it did not yield the best animal survival profile, which is in line with our previous in vitro results. Furthermore, to advance preclinical studies, the mutagenicity of both binary combinations was studied, both with and without metabolic activation, and no mutagenic effects were observed.