title: Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis.
abstract: Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (K(i)=330 nM) with an improved potency against T. brucei (EC(50)=775 nM).
authors: Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors: John L
authors: JL
authors: Richardson
authors: Isabelle R E
authors: IR
authors: Nett
authors: Deuan C
authors: DC
authors: Jones
authors: Mohamed H
authors: MH
authors: Abdille
authors: Ian H
authors: IH
authors: Gilbert
authors: Alan H
authors: AH
authors: Fairlamb
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase