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Malaria and Chagas disease, caused by <i>Plasmodium</i> spp. and <i>Trypanosoma cruzi</i> parasites, remain important global health problems. Available treatments for those diseases present several limitations, such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti-<i>P. falciparum</i> and anti-<i>T. cruzi</i> activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose–response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against <i>T. cruzi</i> were tested against intracellular amastigote forms. Purines <b>33</b> (IC₅₀ = 19.19 µM) and <b>76</b> (IC₅₀ = 18.27 µM) were the most potent against <i>P. falciparum</i>. On the other hand, <b>6D</b> (IC₅₀ = 3.78 µM) and <b>34</b> (IC₅₀ = 4.24 µM) were identified as hit purines against <i>T. cruzi</i> amastigotes. Moreover, an in silico docking study revealed that <i>P. falciparum</i> and <i>T. cruzi</i> hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites.