Contribution to the Chemotherapy of Human Trypanosomiasis: Design, Synthesis, and Biological Evaluation of Dimeric 2‑Nitroimidazoles against Trypanosoma cruzi Amastigotes and Bloodstream Trypanosoma brucei.

Effective and safe treatments for neglected tropical diseases caused by parasites, such as Chagas disease and sleeping sickness, remain lacking, posing a significant challenge for researchers worldwide. The rational design of dimeric compounds inspired solely by the pharmacophoric core of benznidazole (2-nitroimidazole) has proven to be a promising strategy for antiparasitic development. Thus, in the present work, it was increased the linker between the active units (2-nitroimidazole) to improve the interaction with TcNTR, facilitating the bioactivation of the longest dimers. Biological assays confirmed this, demonstrating that all compounds were active against replicative intracellular amastigotes of Trypanosoma cruzi (Tulahuen C2C4-LacZ). Notably, longer-chain dimers exhibited remarkable potency (IC50 < 1.0 μM). These compounds also showed significant activity against T. b. brucei and demonstrated very low cytotoxicity in mammalian cells, highlighting their selectivity, especially among the longer-chain dimers. These findings support the development of dimeric 2-nitroimidazole derivatives as selective agents against trypanosomes.