The synthesis of dihydronaphthofurandione and dihydrofuroquinolinedione derivatives 4-11 was performed through Diels-Alder reactions of dihydrobenzofurandione 1 with several carbodienes and acrolein N,N-dimethylhydrazone. Then, the use of 5-bromobenzofurandione 2 toward 1,3-pentadiene and the 1-azadiene afforded quinones 6 and 11 with a total regioselectivity. All the prepared quinones were tested for trypanocidal activity in vitro against Trypanosoma epimastigotes, Tulahuen strain. Among the tested compounds, the furoquinolinediones 10 and 11 have shown potent trypanocidal activities but, only the 1,5-regioisomer (11) was found active as a redox cycling agent. Calculation of their stereoelectronic properties by the density-functional theory method provided a new insight for the trypanocidal activity of these heterocyclic quinones.