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

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, NC and 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

The lipid composition of a cell membrane modulates the interaction of an antiparasitic peptide at the air-water interface

The antiparasitic property of peptides is believed to be associated with their interactions with the protozoan membrane, which calls for research on the identification of membrane sites capable of peptide binding. in this study we investigated the interaction of a lipophilicglutathioine peptide known to be effective against the African Sleeping Sickness (ASS - African Trypanosomiasis) and cell membrane models represented by Langmuir monolayers. It is shown that even small amounts of the peptide affect the monolayers of some phospholipids and other lipids, which points to a significant interaction. the latter did not depend on the electrical charge of the monolayer-forming molecules but the peptide action was particularly distinctive for cholesterol + sphingomyelin monolayers that roughly resemble rafts on a cell membrane. Using in situ polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), we found that the orientation of the peptide is affected by the phospholipids and dioctadecyldimethylammonium bromide (DODAB), but not in monolayers comprising cholesterol + sphingomyelin. in this mixed monolayer resembling rafts, the peptide still interacts and has some induced order, probably because the peptide molecules are fitted together into a compact monolayer. Therefore, the lipid composition of the monolayer modulates the interaction with the lipophilic glutathioine peptide, and this may have important implications in understanding how the peptide acts on specific sites of the protozoan membrane. (C) 2011 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)rede nBioNet (Brazil)Univ Estadual Paulista, Fac Ciencias & Letras Assis, Assis, SP, BrazilUniv São Paulo, Inst Fis Sao Carlos, Sao Carlos, SP, BrazilUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Diadema, SP, BrazilManchester Metropolitan Univ, Sch Biol Chem & Hlth Sci, Manchester M15 6BH, Lancs, EnglandUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Diadema, SP, BrazilWeb of Scienc

Reinvestigation of the roles of the carboxyl groups of glutathione with yeast glyoxalase I : Implications as to the mechanism and coenzymic role of glutathione

A number of carboxyl-substituted s-blocked glutathiones have been shown to be competitive inhibitors of yeast glyoxalase I at 25[deg]C, pH 6.6. Amidation of the glycyl carboxyl group of S-(p-bromobenzyl)glutathione has no appreciable effect on binding whilst methylation reduces binding by 8.9-fold, indicating a steric constraint and the possible presence of a hydrogen bond in this region of the enzyme. Amidation of both carboxyl groups of S-(p-bromobenzyl)glutathione reduces binding significantly by 237-fold; this result agrees with electrostatic interaction of the Glu COO- group with a group located within the enzyme surface as opposed to the Gly COO- group, previously proposed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26104/1/0000180.pd

Glutathione Derivatives Active against Trypanosoma brucei rhodesiense and T. brucei brucei In Vitro

Diesters based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl) GSH (CBzGSDNP) containing linear alcohols 3 to 9, branched alcohols 10 to 20, or heteroatom linear alcohols 21 to 25, were investigated as in vitro inhibitors of pathogenic parasites. Diesters 3 to 25 were better inhibitors of Trypanosoma brucei rhodesiense than of T. brucei brucei and had low cytotoxicities. The most active compound had a 50% effective dose (ED(50)) of 0.2 μM. A quantitative structure activity regression equation relating the log (1/ED(50)) versus the hydrophobicity parameter (log P), Taft's steric parameter (E(s)), molecular weight (MW), and the WienI descriptor (W) was determined, and the species difference was found to be related to membrane penetration and steric effects

The interaction of an antiparasitic peptide active against African Sleeping Sickness with cell membrane models

Zwitterionic peptides with trypanocidal activity are promising lead compounds for the treatment of African Sleeping Sickness, and have motivated research into the design of compounds capable of disrupting the protozoan membrane. In this study, we use the Langmuir monolayer technique to investigate the surface properties of an antiparasitic peptide, namely S-(2,4-dinitrophenyl)glutathione di-2-propyl ester, and its interaction with a model membrane comprising a phospholipid monolayer. The drug formed stable Langmuir monolayers, whose main feature was a phase transition accompanied by a negative surface elasticity. This was attributed to aggregation upon compression due to intermolecular bond associations of the molecules, inferred from surface pressure and surface potential isotherms, Brewster angle microscopy (BAM) images, infrared spectroscopy and dynamic elasticity measurements. When co-spread with dipalmitoyl phosphatidyl choline (DPPC), the drug affected both the surface pressure and the monolayer morphology, even at high surface pressures and with low amounts of the drug. The results were interpreted by assuming a repulsive, cooperative interaction between the drug and DPPC molecules. Such repulsive interaction and the large changes in fluidity arising from drug aggregation may be related to the disruption of the membrane, which is key for the parasite killing property