Targeting Trypanosoma cruzi with silver and gold-based N-heterocyclic carbene complexes: insights into parasite death and trypanothione reductase interaction

Chagas disease remains a major public health challenge, and there is a need for new therapeutic agents. N-heterocyclic carbene (NHC) complexes, particularly those linked to silver or gold, have shown significant anticancer, antimicrobial, and antiparasitic activities. This study aimed to evaluate the efficacy of four NHC compounds (QMT3, QMT4, QMT7, and QMT8) against Trypanosoma cruzi, the causative agent of Chagas disease. In vitro assays revealed that QMT3 and QMT8 exhibited the strongest antiparasitic effects, with QMT3 showing the highest potency and stability over time (IC₅₀ = 10.3 µg/mL at 24 h). Both compounds induced rapid, irreversible cell death in epimastigotes, primarily through late apoptotic-like and necrotic pathways, as evidenced by Annexin V/PI labeling. Additionally, treatment with QMT3 and QMT8 led to significant increases in intracellular reactive oxygen species (ROS), particularly superoxide (SO). Notably, both compounds displayed high specificity for the parasite with low cytotoxicity towards mammalian cells, although QMT8 was less toxic to host cells than QMT3 at short exposure times. Molecular modeling studies revealed that QMT3, and QMT8 bind to the active site of TryR, a crucial player in maintaining redox homeostasis in trypanosomatids, potentially competing with its natural ligand and disrupting its enzymatic function. These findings suggest that QMT3 and QMT8, silver- and gold-based NHC complexes, act through redox system disruption and TryR inhibition, positioning them as promising candidates for the development of new treatments for Chagas disease.