From Chemistry to Biology: Zinc(II)–1,10-Phenanthroline-5,6-dione Complex Exhibits Potent Activity against Mammalian Stages of Trypanosoma cruzi with Controlled Host Cell Toxicity

Chagas disease, caused by Trypanosoma cruzi, affects 6–7 million people worldwide and causes ∼12,000 deaths annually. Treatments are limited to benznidazole and nifurtimox, both associated with toxicity, adverse effects, and frequent treatment discontinuation, highlighting the need for new therapeutic strategies. Here, a coordination compound was synthesized and evaluated against cell-derived trypomastigotes and intracellular amastigotes of T. cruzi. The compound, [Zn(1,10-phenanthroline-5,6-dione)3](ClO4)2·6H2O (Zn-phendione), consists of a hexacoordinated Zn(II) center bound to three phendione ligands, forming a dicationic complex. The anti-T. cruzi activity of Zn-phendione was initially evaluated in trypomastigotes, in which it reduced parasite viability in a dose-dependent manner after 24 h, with an LD50 of 3.30 nM. This activity was higher than that of the free ligand phendione (LD50 = 7.56 nM) and was 388-fold greater than benznidazole (LD50 = 1,280 nM), whereas the zinc salt alone showed no activity. Zn-phendione-treated trypomastigotes, as observed by optical and scanning electron microscopy, exhibited pronounced morphological alterations, including cell twisting, swelling, and partial or complete loss of the unique flagellum. Notably, 1-h exposure to Zn-phendione decreased trypomastigote infectivity by ∼50% at the LD50. Moreover, Zn-phendione dose-dependently inhibited intracellular amastigote replication after 72 h (IC50 = 36 nM), outperforming benznidazole (IC50 = 210 nM), while showing no toxicity to the host cells used for amastigote maintenance. For trypomastigotes, 24-h exposure resulted in selectivity index (SI) values of >312.5 for benznidazole and 64,800 for Zn-phendione, whereas for amastigotes, 72-h exposure yielded SI values of >238.1 and 83.3, respectively. These findings highlight Zn-phendione as a promising candidate for the development of new therapeutic strategies against T. cruzi.