title: Trypanosoma cruzi: inhibition of alpha-hydroxyacid dehydrogenase isozyme II by N-allyl and N-propyl oxamates and their effects on intact epimastigotes.
abstract: N-allyl (NAOx) and N-propyl (NPOx) oxamates were designed as inhibitors of alpha-hydroxyacid dehydrogenase (HADH) isozyme II from Trypanosoma cruzi. The kinetic studies showed that NAOx and NPOx were competitive inhibitors of HADH-isozyme II (Ki = 72 microM, IC50 = 0.33 mM and 70 microM, IC50 = 0.32 mM, respectively). The attachment of the allylic and propylic chains to nitrogen of the competitive inhibitor oxamate (Ki = 0.91 mM, IC50 = 4.25 mM), increased 12.6 and 13-folds respectively, the affinity for T. cruzi HADH-isozyme II. NAOx and NPOx were selective inhibitors of HADH-isozyme II, because other T. cruzi dehydrogenases were not inhibited by these substances. Since HADH-isozyme II participates in the energy metabolism of T. cruzi, a trypanocidal effect can be expected with these inhibitors. However, we were not able to detect any trypanocidal activity with these oxamates. When the corresponding ethyl esters of N-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested as a possible trypanocidal prodrugs, in comparison with nifurtimox and benznidazole, the expected trypanocidal effects were obtained.
authors.affiliation: Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Apartado Postal 4-129, Admon. 4, Mexico City, Mexico.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Chena
authors.forename: Silvia
authors.initials: S
authors.lastname: Elizondo-Jiménez
authors.forename: Lorena
authors.initials: L
authors.lastname: Rodríguez-Páez
authors.forename: Benjamín
authors.initials: B
authors.lastname: Nogueda-Torres
authors.forename: Isabel
authors.initials: I
authors.lastname: Baeza-Ramírez
authors.forename: Carlos
authors.initials: C
authors.lastname: Wong-Ramírez
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007302:Insect Repellents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D051379:Mice; D009930:Organic Chemicals; D010072:Oxamic Acid / Q000031:analogs & derivatives*; D011355:Prodrugs; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D007302:Insect Repellents; D007527:Isoenzymes; D009930:Organic Chemicals; D011355:Prodrugs; D014344:Trypanocidal Agents; C048603:oxamate (repellent); D000429:Alcohol Oxidoreductases; C021379:D-2-hydroxyacid dehydrogenase; D010072:Oxamic Acid