QSAR study on the contribution of log P and E-s to the in vitro antiprotozoal activity of glutathione derivatives

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.