Abstract Chalcones are a group of natural products with many recognized biological activities, including antiparasitic activity. Although a lot of chalcones have been synthetized and assayed against parasites, the number of structural features known to be involved in this biological property is small. Thus, in the present study, 21 chalcones were synthesized to determine the effect of substituents in the A and B rings on the activity against Leishmania braziliensis, Trypanosoma cruzi , and Plasmodium falciparum . The compounds were active against L. braziliensis in a structure‐dependent manner. Only one compound was very active against T. cruzi , but none of them had a significant antiplasmodial activity. The electron‐donating substituents in ring B and the hydrogen bonds at C‐2′ with carbonyl affect the antiparasitic activity.