Antiparasitic Activity of Coumarin–Chalcone (3‐Cinnamoyl‐2 H ‐Chromen‐2‐Ones) Hybrids

ABSTRACT Coumarin–chalcone hybrids are promising compounds that could be used as lead structures in the fight against parasitic diseases. In this work, 16 hybrids of coumarin–chalcone (3‐cinnamoyl‐2 H ‐chromen‐2‐ones) were synthesized, and their in vitro biological activity was evaluated against intracellular amastigotes of Leishmania braziliensis and Trypanosoma cruzi , as well as their cytotoxicity in the U‐937 cell line. Compounds ( E )‐3‐(3‐(3‐ethoxy‐4‐hydroxyphenyl)acryloyl)‐7‐methoxy‐2 H ‐chromen‐2‐one ( H 25 ) and ( E )‐7‐(diethylamino)‐3‐(4‐(methoxyphenyl)acryloyl)‐2 H ‐chromen‐2‐one ( H 12 ) showed the highest antileishmanial activity with EC 50 values of 18.6 ± 3.5 and 25.6 ± 0.4 µM, respectively. In general, all 16 compounds exhibited moderate‐to‐high antitrypanosomal activity. The H 25 hybrid also demonstrated the greatest antitrypanosomal activity, with an EC 50 value of 13.2 ± 0.4 µM. Notably, the H 25 hybrid displayed activity similar to that of benznidazole, which is known for its antiparasitic effects against T. cruzi . The results indicated that all compounds met the drug‐like properties criteria. Taking into account the high antiparasitic activity of H 25 , a molecular docking study with the enzyme trypanothione reductase was performed. The substituent at C7 in the coumarinyl system is an important structural requirement for the antileishmanial and antitrypanosomal activities.