Synthesis of a cytotoxic dihydrochalcone, first isolated from a traditional Amazonian medicinal plant Iryanthera juruensis Warb (Myristicaceae), followed by a comprehensive SAR analysis of saturated and unsaturated chalcone synthetic intermediates, led to the identification of analogues with selective and significant in vitro anti-Trypanosoma cruzi activity. Further SAR studies were undertaken with the synthesis of 21 new chalcones containing two allyloxy moieties that resulted in the discovery of 2′,4′-diallyloxy- 6′-methoxy chalcones with improved selectivity against this parasite at concentrations below 25 μM, four of which exhibited a selectivity index greater than 12. © 2008 American Chemical Society.