The available treatment for the prevention and cure of Chagas disease, caused by the protozoan Trypanosoma
cruzi, is still unsatisfactory. Thus, there is an urgent need to develop new drugs. In the last few years, our research group
has focused on finding a new chemical entity able to target the infectious bloodstream trypomastigotes. In this study, we
assayed 16 β-lapachone analogous with modifications in the pyran and aromatic ring to find a new prototype with high
trypanocidal activity. Interestingly, two ortho-naphthoquinones presented the best trypanocidal profile (8c and 8d with an
IC50/24 h of 26.9 ± 1.3 and 23.5 ± 2.5 μM, respectively), which were 4 to 17 times more effective than β-lapachone (391.5
± 16.5 μM) and the standard drug benznidazole (103.6 ± 0.6 μM). The introduction of a hydroxyl group on the
compounds’ aromatic ring modulated their biological profile by increasing their activity not only for cancer cells (MDAMB435),
as previously described in literature, but also against T. cruzi. The Structure-Activity Relationship (SAR) study
indicated that this introduction modulated HOMO and MEP parameters, improving the trypanocidal activity.
Keywords: Pyran naphthoquinone, Trypanosoma cruzi, Chagas disease, Chemotherapy, SAR, Molecular modeling.
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