chagas' disease, a parasitic infection widely distributed throughout latin america, is a major public health problem with devastating consequences in terms of human morbidity and mortality. the enzyme cruzain is the major cysteine protease from trypanosoma cruzi, the etiologic agent of american trypanosomiasis or chagas' disease, and has been selected as an attractive target for the development of novel trypanocidal drugs. in the present work, we describe the synthesis and inhibitory effects of a series of thirty-three chalcone and seven hydrazide derivatives against the enzyme cruzain from t. cruzi. most of the compounds showed promising in vitro inhibition (ic50 values in the range of 20-60 μm), which suggest the potential of these compounds as lead candidates for further development. twelve compounds have not been reported before, and four of them (7, 13, 16 e 18) are among the most potent inhibitors of the series.