Antitrypanosomal Activity of Natural Product-Inspired Chalcones and Dihydrochalcones: Computational Insights into a Potential Mechanism of Action

Chalcones (CHAs) and dihydrochalcones (DHCs) are flavonoid-related compounds with diverse biological activities. In this study, four chalcones (CHA-1–4) and their corresponding dihydrochalcones (DHC-1–4) were tested against intracellular forms of Trypanosoma cruzi, the cause of Chagas disease. CHA-3 was commercially available, while the other chalcones were synthesized using Claisen–Schmidt condensation, and the dihydrochalcones were obtained via selective hydrogenation. All compounds exhibited moderate antitrypanosomal activity, with IC50 values from 12.90 to 37.57 μM, and DHC-4 was the most potent derivative. A molecular modeling study indicated glyceraldehyde-3-phosphate dehydrogenase as a candidate T. cruzi target, presenting a strong correlation between predicted binding energies of the compounds and their experimental activities (R = 0.99). Additionally, in silico ADME-Tox analyses indicated favorable physicochemical and pharmacokinetic properties, providing a basis for developing more potent and selective antitrypanosomal agents based on chalcone and dihydrochalcone frameworks.