Chagas disease and trichomoniasis are two neglected parasitic infections (NPIs) in need for new therapies that address both the toxicity and limited bioavailability impacting on the effectiveness of benznidazole (BZ) and nifurtimox, the only drugs available for treating the infection caused by
Trypanosoma
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Chagas disease and trichomoniasis are two neglected parasitic infections (NPIs) in need for new therapies that address both the toxicity and limited bioavailability impacting on the effectiveness of benznidazole (BZ) and nifurtimox, the only drugs available for treating the infection caused by
Trypanosoma cruzi, as well as the resistance that
Trichomonas vaginalis has developed to 5-nitroimidazoles. Herein, we report the outcomes of the primary screening of a series of eighteen quinoxaline-1,4-di-
N-oxides (QdNOs) carried out against both protozoan parasites. Computational approaches revealed that these derivatives have adequate oral bioavailability and do not pose toxicity risks associated with their chemical structures. Meanwhile, biological studies disclosed that compounds
4b and
4m exhibit considerable activity against
T. cruzi at the highest concentration tested, showing
4m a trypanocidal profile (IC
50 = 23.66 µM) similar to that of BZ (IC
50 = 21.66 µM), and a selectivity index (SI) > 5.32. Regarding the activity on
T. vaginalis, derivative
4n stands out with an IC
50 value of 9.85 µM, showing no cytotoxicity towards mammalian cells. However, their potency decreases when tested over resistant parasites. Alterations in either the hydrogenosomal membrane potential or the production of reactive oxygen species (ROS) were also explored. The findings suggest that the trichomonacidal activity of compound
4n is not mediated by a direct disruption of hydrogenosomal bioenergetics or a pro-oxidant effect. Altogether, these preliminary results support that the QdNO scaffold could be introduced as a proper template for developing novel trypanocidal and trichomonacidal agents.
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