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

Due to the rudimentary antioxidant defenses in , 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 infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to 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 -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 death or the antiparasitic potential of these drugs when tested in preclinical models of infection. The divergence of in silico, , and findings indicated that the anti- effects of the analyzed drugs were not restricted to TR inhibition. As studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.