title: Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease.
abstract: 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 α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) 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 disease.
  
  
  METHODS
  The benzyl ester of NPOx (B-NPOx) 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 B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.
  
  
  RESULTS
  Polar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.
  
  
  CONCLUSIONS
  B-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. charlywong@icloud.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Wong-Baeza
authors.affiliation: Parasitology Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. bnogueda@yahoo.com.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Nogueda-Torres
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. qbpjmserna@yahoo.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serna
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. semeza@hotmail.com.
authors.forename: Sergio
authors.initials: S
authors.lastname: Meza-Toledo
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. isabelbaeza@yahoo.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Baeza
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico. carloswongr@yahoo.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Wong
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D004952:Esters / Q000138:chemical synthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D010072:Oxamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004952:Esters; D007527:Isoenzymes; C000608098:N-propyl oxamate benzyl ester; D009593:Nitroimidazoles; D011355:Prodrugs; D014344:Trypanocidal Agents; D000429:Alcohol Oxidoreductases; C021379:D-2-hydroxyacid dehydrogenase; D009547:Nifurtimox; D010072:Oxamic Acid; C009999:benzonidazole