TY - JOUR
T1 - Inhibition of Trypanosoma cruzi α-hydroxyacid dehydrogenase-isozyme II by N-isopropyl oxamate and its effect on intact epimastigotes
AU - Elizondo, Silvia
AU - Chena, Miguel A.
AU - Rodríguez-Páez, Lorena
AU - Nogueda, Benjamín
AU - Baeza, Isabel
AU - Wong, Carlos
N1 - Funding Information:
This work was partially supported by research grants from the Coordinación General de Posgrado e Investigación del Instituto Politécnico Nacional (CGEPI-IPN), México. C.W., L.R.P., B.N. and I.B. are fellows of the COFAA-IPN, M.A.C. and S.E. are fellows of the CONACYT and PIFI-IPN.
PY - 2003/6
Y1 - 2003/6
N2 - The effect of N-isopropyl oxamate on the activity of α-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.
AB - The effect of N-isopropyl oxamate on the activity of α-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.
KW - Ethyl N-isopropyl oxamate
KW - N-isopropyl oxamate
KW - T. cruzi α-hydroxyacid dehydrogenase inhibition
KW - T. cruzi α-hydroxyacid dehydrogenase-isozyme II inhibition
KW - Trypanocidal activity
UR - http://www.scopus.com/inward/record.url?scp=0038351812&partnerID=8YFLogxK
U2 - 10.1080/1475636031000071826
DO - 10.1080/1475636031000071826
M3 - Artículo
SN - 1475-6366
VL - 18
SP - 265
EP - 271
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 3
ER -