Some of the most hazardous tropical diseases, including malaria, leishmaniasis, and trypanosomiasis, are caused by Plasmodium and trypanosomatids. The incidence of these diseases is high, with approximately 1 million people affected worldwide annually. A promising strategy for developing novel therapies is to detect biological targets such as trypanothione reductase, a vital parasite enzyme regulating oxidative stress. This enzyme is highly selective and conserved in the Trypanosotidae family and has an ortholog in the Plasmodium genus. In contrast, naphthoquinone-like compounds have been widely demonstrated as inhibitors of glutathione reductase, although their biological activity against parasite enzymes has not been studied extensively. Previous studies have established that an isosteric replacement of naphthoquinone’s carbonyl group by sulfone group leads to compounds with high bioactivity and selectivity (half maximal inhibitory concentration = 3 µM, selectivity index = 153). In this study, we analyzed reactive oxygen species (ROS) levels of parasites and electrochemical behavior of candidate compounds and performed computational studies to elucidate the parasite–molecule interaction and effectiveness of the compounds in inducing cell homeostatic imbalance. For this purpose, 27 compounds were synthetized and assessed against parasites of three principal tropical diseases (malaria, leishmaniasis, and trypanosomiasis), followed by analysis of ROS levels and redox behavior. The results indicate that the 4H-thiochromen-4-one 1,1-dioxide core is a unique allosteric modulator in this class of compounds.