A terpyridine derivative exhibits potent and selective anti-Toxoplasma gondii activity in BeWo cells.

Toxoplasmosis is a zoonosis widespread worldwide, although it primarily affects populations in underdeveloped countries. In humans, infection can lead to serious complications, particularly in immunocompromised individuals and pregnant women. Despite advances in the diagnosis of this disease, therapeutic regimens for treating toxoplasmosis are not fully effective, and new drugs are highly desirable. In this context, we evaluated 4'-(4-methylphenyl)-2,2':6',2''-terpyridine (L) and its previously reported Pt(II) complex (1) against Toxoplasma gondii. The free ligand L exhibited greater antiparasitic activity (IC50 < 0.78 μM) than 1 (IC50 = 2.4 μM), significantly reducing intracellular parasite proliferation in BeWo cells. Both compounds showed high selectivity toward host cells, with selectivity indices (SIs) exceeding 128 and 41 for L and complex 1, respectively. Molecular docking studies against TgCDPK1 and TgDHFR-TS were performed to investigate the potential binding modes of the compounds. Simulations suggested that both molecules can accommodate the ATP binding site of TgCDPK1 and the cofactor binding pockets of TgDHFR-TS. The free ligand L showed higher docking scores compared to the complex 1. This observation may be attributed to the greater conformational flexibility and lower steric hindrance of the free ligand, which potentially allows for a more optimized fit in the catalytic cavity under the simulated conditions. These findings indicate that terpyridine derivatives represent promising candidates for the development of new anti-T. gondii agents.