title: Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase.
abstract: Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP (1, 1-(1-benzo[b]thiophen-2-yl-cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (K(i)=1 microM) and biologically active against bloodstream T. brucei (EC(50)=10 microM), but with poor selectivity against mammalian MRC5 cells (EC(50)=29 microM). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.
authors: Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Stephen
authors: S
authors: Patterson
authors: Deuan C
authors: DC
authors: Jones
authors: Emma J
authors: EJ
authors: Shanks
authors: Julie A
authors: JA
authors: Frearson
authors: Ian H
authors: IH
authors: Gilbert
authors: Paul G
authors: PG
authors: Wyatt
authors: Alan H
authors: AH
authors: Fairlamb
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: C544433:1-(1-(benzo(b)thiophen-2-yl)cyclohexyl)piperidine; D004791:Enzyme Inhibitors; D010880:Piperidines; D013876:Thiophenes; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D010622:Phencyclidine