title: α-ketoheterocycles as inhibitors of Leishmania mexicana cysteine protease CPB.
abstract: Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas disease, and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinylsulfone-based cysteine protease inhibitors, a series of α-ketoheterocycles were developed as reversible inhibitors of a recombinant L. mexicana cysteine protease, CPB2.8. Three isoxazoles and especially one oxadiazole compound are potent reversible inhibitors of CPB2.8; however, in vitro whole-organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.
authors.affiliation: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Steert
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Westrop
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D057056:Cysteine Proteases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018314:Leishmania infantum / Q000187:drug effects; D007894:Leishmania mexicana / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000187:drug effects; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D006571:Heterocyclic Compounds; D057056:Cysteine Proteases
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