trypanocidal effect of the benzyl ester of npropyl oxamate a bipotential prodrug for the treatment of experimental chagas disease background chagas disease which is caused by trypanosoma cruzi is a major health problem in latin america and there are currently no drugs for the effective treatment of this disease the energy metabolism of t cruzi is an attractive target for drug design and we previously reported that inhibitors of hydroxy acid dehydrogenase hadhisozyme ii exhibit trypanocidal activity npropyl oxamate npox is an inhibitor of hadhisozyme ii and its nonpolar ethyl ester etnpox is cytotoxic to t cruzi a new derivative of npox has been developed in this study with higher trypanocidal activity which could be used for the treatment of chagas diseasemethods the benzyl ester of npox bnpox was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes in vitro as well as mice infected with t cruzi in vivo the activity of bnpox was also compared with those of etnpox benznidazole bz and nifurtimox nx ninoa miguz compostela nayarit and inc5t cruzi strains were used in this studyresults polar npox did not penetrate the parasites and exhibited no trypanocidal activity in contrast the hydrophobic ester bnpox exhibited trypanocidal activity in vitro and in vivo bnpox exhibited higher trypanocidal activity than etnpox bz and nx towards all five of the t cruzi strains the increased activity of bnpox was attributed to its hydrolysis inside the parasites to give npox and benzyl alcohol which is an antimicrobial compound with trypanocidal effects bnpox was also effective against two strains of t cruzi that are resistant to bz and nxconclusion bnpox exhibited higher in vitro 2 to 148fold and in vivo 22 to 45fold trypanocidal activity towards t cruzi than etnpox bnpox also exhibited higher in vitro 2 to 24fold and in vivo 19 to 15fold trypanocidal activity than bz and nx bnpox is more lipophilic than etnpox allowing for better penetration into t cruzi parasites where the enzymatic cleavage of bnpox would give npox and benzyl alcohol which are potent trypanocidal agents taken together with its low toxicity these results suggest that bnpox could be used as a potent prodrug for the treatment of chagas disease