title: Structure-activity study on the in vitro antiprotozoal activity of glutathione derivatives.
abstract: A series of N-, S-, and COOH-blocked glutathione derivatives were evaluated against the pathogenic parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani in vitro, to identify the determinants necessary for activity and for further development into an active lead structure. The results show that N,S-blocked glutathione diesters are the most effective inhibitors of T. brucei with structures 14-16 being the most active, 14 having an IC(50) approximately 1.9 microM. The toxicity effects observed for glutathione derivatives 12, 14, and 16 have been correlated to the K562 antileukemic activity of these compounds and their inhibitory effects on the glyoxalase system of the host. Diester compounds based on S-2,4-dinitrophenylglutathione (17-22) were found to be significantly better inhibitors of T. brucei with ED(50)'s in the range 16-0.19 microM. Compounds 19 and 20 were the two best inhibitors, with an ED(50) of approximately 1.07 and 0.19 microM, respectively; however 20 displayed toxicity in parasitic assays. Monoesters, monoamides, and diamides tested generally exhibited low in vitro activity. The compounds did not inhibit glutathionylspermidine synthetase and trypanothione reductase enzyme targets in the unique trypanothione pathway of these parasites. Diester compounds per se were considered to be ineffective inhibitors of trypanothione metabolism suggesting that these compounds might act as prodrugs, being hydrolyzed in situ into a variety of glutathione derivatives which include combinations of monoesters, free acids, and amines, some of which are inhibitors of trypanothione metabolism.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K. C.DSilva@mmu.ac.uk
authors.forename: C
authors.initials: C
authors.lastname: D'Silva
authors.forename: S
authors.initials: S
authors.lastname: Daunes
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004951:Esterification; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D013095:Spermidine / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000981:Antiprotozoal Agents; C044809:trypanothione; D005978:Glutathione; D013095:Spermidine