| en |
Trypanosoma cruzi: Inhibition of α-hydroxyacid Dehydrogenase Isozyme II by N-allyl and N-propyl Oxamates and their Effects on Intact Epimastigotes
Miguel A Chena; Silvia Elizondo-Jiménez; Lorena Rodríguez-Páez; Benjamín Nogueda-Torres; Isabel Baeza-Ramírez & Carlos Wong-Ramírez
Abstract
N-allyl (NAOx) and N-propyl (NPOx) oxamates were designed as inhibitors of α-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 μM, IC50 = 0.33 mM and 70 μM, 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.
Keywords
Trypanosoma cruzi - Trypanosoma cruzi α-hydroxyacid dehydrogenase-isozyme II inhibition - N-allyl oxamate - N-propyl oxamate - ethyl N-propyl oxamate - ethyl N-allyl oxamate - α-hydroxyacid dehydrogenase
|
