Abstract
A promising strategy for developing novel therapies against tropical diseases, including malaria, leishmaniasis, and trypanosomiasis, is to detect biological targets such as trypanothione reductase, a vital parasite enzyme that regulates oxidative stress. This enzyme is highly selective and conserved in the Trypanosotidae family and has an ortholog in the Plasmodium genus. Previous studies have established that an isosteric replacement of naphthoquinone's carbonyl group with a sulfone group leads to compounds with high bioactivity and selectivity (half-maximal inhibitory concentration = 3 μM against intracellular amastigotes of L. panamensis, selectivity index = 153 over monocytes U-937). In this study, we analyzed the reactive oxygen species (ROS) levels of parasites through indirect measurements of the tryparedoxin system after treatment with these isosteric compounds. This strategy proved that a significant increase in the ROS levels and strong mitochondrial perturbation led to the death of parasites due to cell homeostatic imbalance, confirming the compounds' effectiveness in disrupting this important metabolic pathway. To improve understanding of the parasite-molecule interaction, 27 new compounds were synthesized and assessed against parasites of the three principal tropical diseases (malaria, leishmaniasis, and trypanosomiasis), displaying an EC50 below 10 μM and good correlation with in-silico studies, indicating that the 4H-thiochromen-4-one 1,1-dioxide core is a special allosteric modulator. It can interact in the binding pocket through key amino acids like Ser-14, Leu-17, Trp-21, Ser-109, Tyr-110, and Met-113, leading to interhelical disruption.