Synthesis and Biological Evaluation of Tetrahydroisoquinoline Derivatives as Trypanocidal Agents

American trypanosomiasis is a parasitic illness of major public health relevance, resulting from infection with the protozoan <i>Trypanosoma cruzi</i> 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 <i>T. cruzi</i>. The hydrochloride salts <b>4a</b> and <b>4b</b> showed moderate cruzain inhibition (60.2 ± 2.4% and 69.3 ± 2.6% inhibition at 100 μM, respectively). Notably, compound <b>3d</b> and its hydrochloride salt <b>4d</b> demonstrated significant antiparasitic activity with IC₅₀ 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.