Sertraline as a Scaffold for Antitrypanosoma Cruzi DrugDevelopment: Design of Novel Derivatives and Computational Target Screening

Abstract

Due to the advantages of drug repurposing, the discovery of newchemotherapeutic agents for the treatment of Chagas diseasebased on approved drugs has become a strategy for identifyingnew candidates. In this work, the antidepressant drug sertraline isreported, with an IC50 of 7.8 1.7 μM against the amastigoteforms of Trypanosoma cruzi. The optimization of activity throughthe formation of tertiary amides results in a small library of com-pounds, where two compounds, SMBT and SM04, show increasesof 4.3 and 2.7 times in vitro activity against the amastigote form ofthe parasite, and a safety index of >55.6 and 25.4, respectively,compared to sertraline. Due to hindered rotation around the(O)CN bond, the tertiary amides exist as a mixture of E/Z rotamers,typically inseparable, which display separate signals in their NMRspectra. The differential assignment of the 1 H resonances of theE/Z rotamers is based on the magnitude of anisotropic solvent-induced shift effects and confirmed by 2D nuclear Overhausereffect spectroscopy. Computational analysis of the hit com-pounds reveals that SMBT showed significant affinity for threetargets (galactopyranose mutase, dihydrofolate reductase, andsqualene synthase), while SM04 displays notable interaction withone (squalene synthase). These results not only suggest a plausi-ble mechanism of action for the studied compounds but also pro-vide valuable insights for the rational design of new derivativeswith potentially enhanced trypanocidal activity