title: Design, synthesis and biological evaluation of Trypanosoma brucei trypanothione synthetase inhibitors.
abstract: Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62,000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.forename: Justin R
authors.initials: JR
authors.lastname: Harrison
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002463:Cell Membrane Permeability; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D019732:Amide Synthases; C064407:trypanothione synthetase