QSAR Study on the Contribution of Log P and Es to the in Vitro Antiprotozoal Activity of Glutathione Derivatives
- 1 August 2001
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 44 (18) , 2976-2983
- https://doi.org/10.1021/jm000502n
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.donovani17, 19, 29. Compounds 14, 24, and 25 were the most active compounds identified against T.b. brucei having ED50 values of 50) vs calculated log P and Es 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 Es determined were 5.8 and −0.70, respectively. A QSAR equation relating log(1/ED50) vs log P and Es was determined and interpreted within the proposed mechanism of activity for these compounds.Keywords
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