Inhibition of Trypanosoma cruzi alpha-hydroxyacid dehydrogenase-isozyme II by N-isopropyl oxamate and its effect on intact epimastigotes.
The effect of N-isopropyl oxamate on the activity of alpha-hydroxyacid dehydrogenase-isozyme II (HADH-isozyme II) from Trypanosoma cruzi was investigated. The kinetic studies showed that this substance was a competitive inhibitor of this isozyme. The attachment of the nonpolar isopropylic branched chain to the nitrogen of oxamate increased 12-fold the affinity of N-isopropyl oxamate for the active site of T. cruzi HADH-isozyme II. N-isopropyl oxamate was a selective inhibitor of HADH-isozyme II, since other T. cruzi dehydrogenases were not inhibited by this substance. Since HADH-isozyme II participates in the energy metabolism of T. cruzi, a trypanocidal effect can be expected with inhibitors of this isozyme. However, although it was not possible to detect any trypanocidal activity with N-isopropyl oxamate when the ethyl ester was tested as a possible trypanocidal prodrug, the expected trypanocidal effect was obtained, comparable to that obtained with nifurtimox and benznidazole.
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008956:Models, Chemical; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D010072:Oxamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011355:Prodrugs; D020033:Protein Isoforms; D013997:Time Factors; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000201:enzymology*
C109929:N-isopropyloxamate; D009593:Nitroimidazoles; D011355:Prodrugs; D020033:Protein Isoforms; D014344:Trypanocidal Agents; D000429:Alcohol Oxidoreductases; C021379:D-2-hydroxyacid dehydrogenase; D009547:Nifurtimox; D010072:Oxamic Acid; C009999:benzonidazole