title: Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase.
abstract: Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K(i) = 2 µM.
authors.affiliation: Department of Chemistry, Carleton College, Northfield, MN 55057, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Duyzend
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Clark
authors.forename: Shayna L
authors.initials: SL
authors.lastname: Simmons
authors.forename: Wade B
authors.initials: WB
authors.lastname: Johnson
authors.forename: Anna M
authors.initials: AM
authors.lastname: Larson
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Leconte
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Wills
authors.forename: Matthew
authors.initials: M
authors.lastname: Ginder-Vogel
authors.forename: April K
authors.initials: AK
authors.lastname: Wilhelm
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Czechowicz
authors.forename: David G
authors.initials: DG
authors.lastname: Alberg
mesh_terms: D015195:Drug Design; D057075:Enzyme Assays; D004926:Escherichia coli / Q000235:genetics; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009249:NADP / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D017550:Spectroscopy, Fourier Transform Infrared; D013095:Spermidine / Q000031:analogs & derivatives* / Q000737:chemistry; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D014349:Trypanosoma cruzi / Q000737:chemistry* / Q000201:enzymology
chemical_list: D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D009249:NADP; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine