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

Due to the advantages of drug repurposing, the discovery of new chemotherapeutic agents for the treatment of Chagas disease based on approved drugs has become a strategy for identifying new candidates. In this work, the antidepressant drug sertraline is reported, with an IC₅₀ of 7.8 ± 1.7 µM against the amastigote forms of Trypanosoma cruzi. The optimization of activity through the formation of tertiary amides results in a small library of compounds, where two compounds, SMBT and SM04, show increases of 4.3 and 2.7 times in vitro activity against the amastigote form of the 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 NMR spectra. The differential assignment of the ¹H resonances of the E/Z rotamers is based on the magnitude of anisotropic solvent-induced shift effects and confirmed by 2D nuclear Overhauser effect spectroscopy. Computational analysis of the hit compounds reveals that SMBT showed significant affinity for three targets (galactopyranose mutase, dihydrofolate reductase, and squalene synthase), while SM04 displays notable interaction with one (squalene synthase). These results not only suggest a plausible mechanism of action for the studied compounds but also provide valuable insights for the rational design of new derivatives with potentially enhanced trypanocidal activity.