Synthesis of ferrocenyl benzimidazole derivatives as novel anti-Toxoplasma gondii agents

Toxoplasmosis, a disease caused by the apicomplexan parasite Toxoplasma gondii, affects up to one third of the global population. Although immunocompetent individuals rarely experience severe symptoms, those with immunodeficiencies may potentially face fatal disease. The frontline treatments are currently sulphadiazine and pyrimethamine, which suffer from adverse side effects, and lack efficiency in clearing parasite cysts from the muscles and brain of patients. To address the need for novel, more effective, and less toxic treatments, four new ferrocenyl benzimidazole complexes 15-18 were synthesised and evaluated against the ΔKu80:mNeonGreen strain of T. gondii. Complexes 15 and 17 were found to be active with EC₅₀ values of 17.9 and 17.5 μM respectively, with comparable activity to pyrimethamine, which had an EC₅₀ value of 13.8 μM, and less effective than sulphadiazine, which had an EC₅₀ value of 2.56 μM. Additionally, the compounds were found to be relatively non-toxic against HEK 293T and PNT1A human cell lines. Further investigations found that the complexes act by generating reactive oxygen species (ROS) through the ferrocenyl moiety. These complexes show potential for the development of new treatments against Toxoplasmosis.