title: Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense.
abstract: A new series of N-substituted S-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The results obtained indicate that N-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against KB cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. We suggest that the interaction of N-substituted S-(2,4-dinitrophenyl) glutathione dibutyl diesters with T. b. brucei occurs mainly by weak hydrophobic interactions such as London and van der Waals forces. A QSAR study indicated that the inhibitory activity of the peptide is associated negatively with the average number of C atoms, NCand positively to SZX,the ZX shadow a geometric descriptor related to molecular size and orientation of the compound. HPLC-UV studies in conjunction with optical microscopy indicate that the observed selectivity of inhibition of these compounds against bloodstream form T. b. brucei parasites in comparison to L. donovani under the same conditions is due to intracellular uptake via endocytosis in the flagellar pocket.
authors.affiliation: School of Chemistry and Environmental Sciences, The Manchester Metropolitan University, Faculty of Science and Engineering, John Dalton Building, Chester Street, Manchester M1 5GD, UK.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Daunes
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.affiliation: School of Chemistry and Environmental Sciences, The Manchester Metropolitan University, Faculty of Science and Engineering, John Dalton Building, Chester Street, Manchester M1 5GD, UK; School of Chemistry, Central University of Rajasthan, Bandar Sindari, Jaipur-Ajmer Highway (Rajasthan), India. Electronic address: c.dsilva@ymail.com.
authors.forename: Claudius
authors.initials: C
authors.lastname: D'Silva
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005407:Flagella / Q000378:metabolism*; D005978:Glutathione / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D007893:Leishmania donovani / Q000187:drug effects; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D005978:Glutathione
keywords: Antiprotozoal peptides; Endocytosis; Flagellar pocket; Glutathione derivatives; Leishmania donovani; MPRA receptor; Membrane rafts; Trypanosoma brucei rhodesiense; Trypanosoma cruzi