In Vitro Activity of Pterocarpanquinone LQB-118 on Trypanosoma cruzi and Its Impact on Parasite Bioenergetics

The hemoflagellate protozoan Trypanosoma cruzi is the etiologic agent of Chagas disease, one of the neglected tropical diseases endemic to Latin America with a high socioeconomic impact. Treatment remains restricted to two drugs, benznidazole and nifurtimox, which present several side effects and are ineffective in the chronic phase of the disease. The synthetic pterocarpanquinone LQB-118, a hybrid molecule synthesized from lapachol and pterocarpan, exhibits several biological activities, including antiparasitic effects similar to those of its precursors. The present study aimed to investigate the in vitro activity of LQB-118 on T. cruzi and its effect on the parasite's mitochondrion. For an initial evaluation of the antiparasitic effect, intracellular amastigotes, epimastigotes, and metacyclic trypomastigotes were incubated with LQB-118, and the IC₅₀ values were 4.2, 2.5, and 38.1 μM, respectively. DNA fragmentation analysis by TUNEL labeling showed that treatment with LQB-118 induced selective fragmentation of amastigote nuclei, while macrophage nuclei remained intact. In addition, treatment of metacyclic trypomastigotes with LQB-118 reduced the infectivity of peritoneal macrophages. LQB-118 also induced changes in parasite mitochondrial function, causing H₂O₂ production and increasing O₂ consumption in mitochondrial respiration states. Corroborating these results, LQB-118 exposure led to severe ultrastructural disruption, especially in the parasite's single mitochondrion, which exhibited swelling and disorganization. Additionally, other cellular changes, such as autophagic vacuoles, nuclear chromatin condensation, and shrinkage, were observed. These results indicate that LQB-118 exerts its antiparasitic action on T. cruzi by disrupting mitochondrial physiology, leading to mitochondrial reactive oxygen species production, oxidative stress, and parasite death.