Journal article

Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new antischistosomal drugs


Authors listJohann, L; Belorgey, D; Huang, HH; Day, L; Chesse, M; Becker, K; Williams, DL; Davioud-Charvet, E

Publication year2015

Pages3199-3217

JournalThe FEBS Journal

Volume number282

Issue number16

ISSN1742-464X

eISSN1742-4658

Open access statusGreen

DOI Linkhttps://doi.org/10.1111/febs.13359

PublisherWiley


Abstract
Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an -fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured exvivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured exvivo. Despite exvivo activity, none of the compounds tested was active invivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.



Citation Styles

Harvard Citation styleJohann, L., Belorgey, D., Huang, H., Day, L., Chesse, M., Becker, K., et al. (2015) Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new antischistosomal drugs, The FEBS Journal, 282(16), pp. 3199-3217. https://doi.org/10.1111/febs.13359

APA Citation styleJohann, L., Belorgey, D., Huang, H., Day, L., Chesse, M., Becker, K., Williams, D., & Davioud-Charvet, E. (2015). Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new antischistosomal drugs. The FEBS Journal. 282(16), 3199-3217. https://doi.org/10.1111/febs.13359


Last updated on 2025-10-06 at 10:31