Abstract
American trypanosomiasis is a parasitic illness of major public health relevance, resulting from infection with the protozoan Trypanosoma cruzi and predominantly impacting populations in low-resource settings. Current treatments, benznidazole and nifurtimox, are limited by their efficacy in the chronic phase, toxicity, and side effects, necessitating the search for new therapeutic agents. Cruzain, a key protease for parasite survival and infection, is a validated drug target. This work involved the synthesis and characterization of novel amides derived from 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. Their activity was evaluated against both cruzain and T. cruzi. The hydrochloride salts 4a and 4b showed moderate cruzain inhibition (60.2 ± 2.4% and 69.3 ± 2.6% inhibition at 100 μM, respectively). Notably, compound 3d and its hydrochloride salt 4d demonstrated significant antiparasitic activity with IC(50) values of 10.5 and 13.7 μM, respectively. However, their low cruzain inhibition (∼15%) suggests that their mechanism of action is likely through a different biological target.