QSAR Study on the Contribution of Log P and E_s to the in Vitro Antiprotozoal Activity of Glutathione Derivatives

Abstract

A series of N-S-blocked glutathione monoester and diester derivatives based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione were evaluated for activity against the pathogenic parasites Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania donovani in vitro.Only monoesters 7-9 with a log P value of >2.7 were active inhibitors of T.b. brucei bloodstream form trypomastigotes. Diester compounds 10-15 and 17-27 in most cases were better inhibitors of T.b. 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 T.b. brucei having ED(50) values of <0.4 microM. Analysis of the inhibition data (ED(50)) vs calculated 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, respectively. A QSAR equation relating log(1/ED(50)) vs log P and E(s) was determined and interpreted within the proposed mechanism of activity for these compounds.

Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

“…In that study a model was proposed in which these compounds inserted into the membrane of T. b. brucei cells via weak lipophilic forces, compromising structural and membrane fluidity. 26 The studies reported here further support that view, with the N-substituents of glutathione contributing to a small increase in lipophilic binding energy of 1.2-5. ).…”

“…As previously observed glutathione compounds with a log P of 4.0-7.0 showed the highest in vitro activity against Trypanosoma. 26,27 Compound 8 containing the N-myristoyl group(log P: 8.73) proved no exception and showed significantly reduced activity versus 2. Compound 20, although similar to the substrates of the P2 receptor showed no enhanced activity in the inhibition of trypanosome growth.…”

“…26 However in the absence of a simple graphical relationship between the experimental and calculated parameters and the large size of the data set used this led us to use the CODESSA Pro program for statistical analysis. This program uses diverse statistical structure property/activity correlation techniques for the analysis of experimental data in combination with independently calculated molecular descriptors.…”

“…This inference was dismissed, based on an absence of any inhibitory effects of these compounds on enzymes of the trypanothione cycle 25 (trypanothione reductase, tryparedoxin (TXN1 and TXN2) and glutathione peroxidase). A study of the inhibitory properties of lipophilic benzyloxycarbonyl-S-(2,4-dinitrophenyl) glutathione diesters derivatives against T.b.brucei and T.b.rhodesiense, found a parabolic dependence between log(1/ED 50 ) and log P (lipophilicity) with both species showing an optimium value in the range between 5.0-6.0, which indicated membrane penetration, played a key role in the antiparasitic activity of these compounds 26,27 . A QSAR analysis of the inhibition data determined a, linear relationship between log P and the Taft's steric parameter ( s ) 26,27 the latter related to lipophilic chain branching.…”

Synthesis and biological evaluation of glutathione-like tripeptides against Trypanosoma cruzi

“…33 The chemical structure of 10 and 11 is presented in Figure 3. These results presented above together with the biological activity of glutathione derivatives reported by D'Silva et al 34,35 targeting trypanothione metabolism encouraged us to prepare analogues assuming that the optimum glutathione tripeptide derivative should be L-γ-Glu-L-LeuGly. Compound 12, a protected tripeptide derivative of glutathione, was moderately potent against T. brucei (ED 50 = 1.9 µM) but exhibited vanishing biological activity against T. cruzi ( Figure 4).…”