title: Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents.
abstract: The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a-f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125microM.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.
authors.forename: Radim
authors.initials: R
authors.lastname: Vicik
authors.forename: Verena
authors.initials: V
authors.lastname: Hoerr
authors.forename: Melanie
authors.initials: M
authors.lastname: Glaser
authors.forename: Martina
authors.initials: M
authors.lastname: Schultheis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
authors.forename: August
authors.initials: A
authors.lastname: Stich
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D002264:Carboxylic Acids; D015853:Cysteine Proteinase Inhibitors