Contribution to the Chemotherapy of Human Trypanosomiasis: Design, Synthesis, and Biological Evaluation of Dimeric 2-Nitroimidazoles against <i>Trypanosoma cruzi</i> Amastigotes and Bloodstream <i>Trypanosoma brucei</i>

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 <i>Trypanosoma cruzi</i> (Tulahuen C2C4-<i>LacZ</i>). Notably, longer-chain dimers exhibited remarkable potency (IC₅₀ < 1.0 μM). These compounds also showed significant activity against <i>T. b. brucei</i> 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.