C-1 functionalization of the marinoquinoline scaffold generates novel and selective inhibitors of Toxoplasma gondii and Trypanosoma cruzi.

Toxoplasmosis and Chagas disease are parasitic diseases for which current treatments are limited by toxicity and suboptimal efficacy. Marinoquinolines have recently emerged as promising antiparasitic scaffolds, although structural modifications at position 1 of the marinoquinoline core remain unexplored. Herein, we report the synthesis and biological evaluation of 13 novel C-1-functionalized marinoquinoline derivatives. The compounds were obtained through Pictet-Spengler cyclization, halogenation, and Heck coupling reactions and evaluated against intracellular Toxoplasma gondii tachyzoites and intracellular Trypanosoma cruzi amastigotes. Cytotoxicity was assessed in human foreskin fibroblasts (HFFs), and in silico ADME and toxicity properties were predicted. All derivatives exhibited activity against T. gondii, with EC50 values ranging from 0.61 to 8.29 μM and selectivity index (SI) ranging from 15 to above 327. Against T. cruzi, the compounds showed EC50 values between 6 and 98 μM and SI values ranging from 1 to above 21. More than half of the derivatives showed CC50 values above 200 μM, indicating low cytotoxicity toward host cells. Most compounds were predicted to exhibit high gastrointestinal absorption, while three compounds showed predicted blood-brain barrier permeability. These findings demonstrate that position-1 functionalization is well tolerated within the marinoquinoline scaffold and led to compounds with potent antiparasitic activity and favorable selectivity profiles. Moreover, this study provides the first evidence of anti-T. cruzi activity for marinoquinolines, highlighting this scaffold as a promising platform for antiparasitic drug discovery.