title: 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.
authors.affiliation: Department of Chemistry and Materials, Faculty of Science and Engineering, The Manchester Metropolitan University, UK.
authors.forename: S
authors.initials: S
authors.lastname: Daunes
authors.forename: C
authors.initials: C
authors.lastname: D'Silva
authors.forename: H
authors.initials: H
authors.lastname: Kendrick
authors.forename: V
authors.initials: V
authors.lastname: Yardley
authors.forename: S L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000818:Animals; D002460:Cell Line; D004952:Esters; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D004952:Esters; D014344:Trypanocidal Agents; D005978:Glutathione