Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection

Infection with the protozoan parasite <i>Trypanosoma cruzi</i> causes human Chagas disease. Benznidazole (BNZ) and nifurtimox are the current drugs for the treatment; however, they induce severe adverse side effects in patients; therefore, there is a need to improve the treatment effectiveness and efficiency of these drugs for its safer use. <b>Background/Objective</b>: Glyburide, glipizide, and gliquidone, hypoglycemic drugs for diabetes treatment, were previously predicted to bind to dihydrofolate reductase-thymidylate synthase from <i>T. cruzi</i> by in silico docking analysis; they also showed antiproliferative effects against <i>T. cruzi</i> epimastigotes, the stage of the insect vector. In the present study, the potential parasiticidal effect of these antidiabetic drugs was tested in monotherapy and bi-therapy with BNZ in human cells in vitro and in animals. <b>Methods</b>: Evaluation was performed in (a) a model of in vitro infection of <i>T. cruzi</i> trypomastigotes using human fibroblasts as host cells and (b) in mice infected with <i>T. cruzi</i>. <b>Results:</b> The antidiabetic drugs in monotherapy showed antiparasitic effects in preventing infection progression (trypomastigotes release), with an IC₅₀ of 8.4–14.3 µM in comparison to that of BNZ (0.26 µM) in vitro. However, in bi-therapy, the presence of just 0.5 or 1 µM of the antidiabetics decreased the BNZ IC₅₀ by 5–10 times to 0.03–0.05 µM. Remarkably, the antidiabetic drugs in monotherapy decreased the infection in mice by 40–60% in a similar extent to BNZ (80%). In addition, the combination of BNZ plus antidiabetics perturbed the antioxidant metabolites in epimastigotes. <b>Conclusions</b>: These results identified antidiabetics as potential drugs in combination therapy with BNZ to treat <i>T. cruzi</i> infection.