title: Investigation of trypanothione reductase as a drug target in Trypanosoma brucei.
abstract: There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62,000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Shanks
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Stuart
authors.initials: S
authors.lastname: McElroy
authors.forename: Deuan
authors.initials: D
authors.lastname: Jones
authors.forename: Daniel
authors.initials: D
authors.lastname: James
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D011724:Pyridazines; D011804:Quinolines; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase