TY - JOUR
T1 - Trypanosoma cruzi
T2 - Inhibition of α-hydroxyacid dehydrogenase isozyme II by N-allyl and N-propyl oxamates and their effects on intact epimastigotes
AU - Chena, Miguel A.
AU - Elizondo-Jiménez, Silvia
AU - Rodríguez-Páez, Lorena
AU - Nogueda-Torres, Benjamín
AU - Baeza-Ramírez, Isabel
AU - Wong-Ramírez, Carlos
PY - 2004/12
Y1 - 2004/12
N2 - 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 (K i = 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.
AB - 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 (K i = 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.
KW - Ethyl N-allyl oxamate
KW - Ethyl N-propyl oxamate
KW - N-allyl oxamate
KW - N-propyl oxamate
KW - Trypanosoma cruzi
KW - Trypanosoma cruzi α-hydroxyacid dehydrogenase-isozyme II inhibition
KW - α-hydroxyacid dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=13844254062&partnerID=8YFLogxK
U2 - 10.1590/S0074-02762004000800009
DO - 10.1590/S0074-02762004000800009
M3 - Artículo
SN - 0074-0276
VL - 99
SP - 831
EP - 837
JO - Memorias do Instituto Oswaldo Cruz
JF - Memorias do Instituto Oswaldo Cruz
IS - 8
ER -