title: Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents.
abstract: Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH+Trx(S)2+H+<-->NADP++Trx(SH)2) is a high Mr flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3(IC50(PfTrxR)=2 microM and IC50(hTrxR)=50 microM), 7(IC50(PfTrxR)=2 microM and IC50(hTrxR)=140 microM), and 11(IC50(PfTrxR)=0.5 microM and IC50(hTrxR)=4 microM) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based on a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro.
authors.affiliation: College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: M B
authors.initials: MB
authors.lastname: Akoachere
authors.forename: R
authors.initials: R
authors.lastname: Krogh
authors.forename: C
authors.initials: C
authors.lastname: Nickel
authors.forename: M J
authors.initials: MJ
authors.lastname: McLeish
authors.forename: G L
authors.initials: GL
authors.lastname: Kenyon
authors.forename: L D
authors.initials: LD
authors.lastname: Arscott
authors.forename: C H
authors.initials: CH
authors.lastname: Williams
authors.forename: E
authors.initials: E
authors.lastname: Davioud-Charvet
authors.forename: K
authors.initials: K
authors.lastname: Becker
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011810:Quinoxalines / Q000737:chemistry*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000962:Antimalarials; D011810:Quinoxalines; D002738:Chloroquine; D013880:Thioredoxin-Disulfide Reductase