Antiparasitic Activity of Coumarin-Chalcone (3-cinnamoyl-2H-chromen-2-ones) Hybrids

Coumarin-chalcone hybrids are promising compounds that could be used as lead structures in the fight against parasitic diseases. In this work, sixteen hybrids of coumarin-chalcone (3-cinnamoyl-2H-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-2H-chromen-2-one (H25) and (E)-7-(diethylamino)-3-(4-(methoxyphenyl)acryloyl)-2H-chromen-2-one (H12) showed the highest antileishmanial activity with EC50 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 H25 hybrid also demonstrated the greatest antitrypanosomal activity, with an EC50 value of 13.2±0.4 µM. Notably, the H25 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 in account the high antiparasitic activity of H25, 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.