S. Daunes et al., QSAR study on the contribution of log P and E-s to the in vitro antiprotozoal activity of glutathione derivatives, J MED CHEM, 44(18), 2001, pp. 2976-2983
A series of N-S-blocked glutathione monoester and diester derivatives based
on N-benzyloxy-carbonyl-S-(2,4-dinitrophenyl)glutathione were evaluated fo
r activity against the pathogenic parasites Trypanosoma brucei brucei, Tryp
anosoma cruzi, and Leishmania donovani in vitro. Only monoesters 7-9 with a
log P value of >2.7 were active inhibitors of Tb. brucei bloodstream form
trypomastigotes. Diester compounds 10-15 and 17-27 in most cases were bette
r inhibitors of TA brucei than monoester compounds, and some displayed high
activity against T. cruzi 14 and L. donovani 17, 19, 29. Compounds 14, 24,
and 25 were the most active compounds identified against Tb. brucei having
ED50 values of <0.4 muM. Analysis of the inhibition data (ED50) vs calcula
ted log P and E-s values provided evidence to support membrane penetration
and steric factors as the key component in the activity of these compounds.
The optimum values for log P and E-s determined were 5.8 and -0.70, respec
tively. A QSAR equation relating log(1/ED50) vs log P and E-s was determine
d and interpreted within the proposed mechanism of activity for these compo
unds.