title: Synthesis and evaluation of indatraline-based inhibitors for trypanothione reductase.
abstract: The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition.
authors.affiliation: School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK.
authors.forename: Jeffrey G A
authors.initials: JG
authors.lastname: Walton
authors.forename: Deuan C
authors.initials: DC
authors.lastname: Jones
authors.forename: Paula
authors.initials: P
authors.lastname: Kiuru
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Durie
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Westwood
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008744:Methylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D007189:Indans; D008744:Methylamines; C418119:indatraline; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase