The preparation and evaluation as potential anti-protozoal agents of molecules bearing an endocyclic hydrazine moiety is presented. The synthetic route to this new series of compounds is straightforward, involving a hetero Diels-Alder reaction between different benzotropolone esters and diethyl azodicarboxylate (DEAD). While they show limited or no in vitro activity against Leishmania donovani, Plasmodium falciparum and Trypanosoma brucei rhodesiense, several of the compounds have activities against Trypanosoma cruzi in the 15.8-41.0 microM range. These activities are comparable to that of benznidazole (IC50 6.0 microM), the main chemotherapy employed in the treatment of T. cruzi infections. In addition, all but one of the new bicyclic hydrazine esters are virtually non-toxic, one of the most important drawbacks of currently available trypanocidal drugs.