Ruthenium Complexes Containing Thiobenzamide Act as Potent and Selective Anti- <i>Trypanosoma cruzi</i> Agents through Apoptotic Cell Death

Chagas disease remains a significant global health concern, with current therapies limited to benznidazole and nifurtimox, which have adverse effects and show reduced efficacy in the chronic phase. This study investigated ruthenium complexes with or without thiobenzamide (Tbz). FOR0012A and FOR0212A, both containing Tbz, showed potent trypanocidal activity, with IC₅₀ values of 0.13 and 0.09 μM for trypomastigotes, and 1.8 and 0.32 μM for amastigotes. Electron microscopy revealed shrinkage, blebbing, and severe mitochondrial/kinetoplast damage, indicating apoptosis-like cell death, as confirmed by flow cytometry. Docking studies demonstrated strong binding to trypanothione reductase, suggesting oxidative stress induction, further supported by mitochondrial superoxide production and membrane depolarization. In a murine model, FOR0212A (20 mg/kg) reduced parasitemia by 50.2% during the acute phase without any toxicity. These findings identify FOR0212A as a promising therapeutic candidate for Chagas disease, acting via oxidative stress and apoptosis-like mechanisms in <i>T. cruzi</i>.