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Due to the rudimentary antioxidant defenses in  Trypanosoma cruzi , disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in  T. cruzi  infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to  Trypanosoma cruzi  infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac  β -adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and  T. cruzi  death  in vitro  or the antiparasitic potential of these drugs when tested in preclinical models of  T. cruzi  infection. The divergence of in silico,  in vitro , and  in vivo  findings indicated that the anti- T. cruzi  effects of the analyzed drugs were not restricted to TR inhibition. As  in vivo  studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.

oxidative medicine and cellular longevity

Relevance of Trypanothione Reductase Inhibitors on <i>Trypanosoma cruzi</i> Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach

Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach