Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents

• Published in: Bioorganic & medicinal chemistry letters 2006-04, Vol.16 (8), p.2283-2292
• Main Authors: Andricopulo, A.D., Akoachere, M.B., Krogh, R., Nickel, C., McLeish, M.J., Kenyon, G.L., Arscott, L.D., Williams, C.H., Davioud-Charvet, E., Becker, K.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Chloroquine - pharmacology; Dose-Response Relationship, Drug; Drug development; Drug Resistance; Enzyme inhibition; Humans; Inhibitory Concentration 50; Kinetics; Malaria; Medical sciences; Molecular Structure; Oxidation-Reduction; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Quinoxalines - chemistry; Thioredoxin reductase; Thioredoxin-Disulfide Reductase - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.01.027

Uncompetitive inhibition of Plasmodium falciparum thioredoxin reductase by nitrophenyl derivatives. Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH + Trx(S) 2 + H + ↔ NADP + + Trx(SH) 2) is a high M r 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 ( IC 50 PfTrxR = 2 μ M and IC 50 hTrxR = 50 μ M ) , 7 ( IC 50 PfTrxR = 2 μ M and IC 50 hTrxR = 140 μ M ) , and 11 ( IC 50 PfTrxR = 0.5 μ M and IC 50 hTrxR = 4 μ M ) 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.