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Synthesis and evaluation of 1,4–naphthoquinone ether derivatives as Sm TGR inhibitors and new anti‐schistosomal drugs
Author(s) -
Johann Laure,
Belorgey Didier,
Huang HsinHung,
Day Latasha,
Chessé Matthieu,
Becker Katja,
Williams David L.,
DavioudCharvet Elisabeth
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13359
Subject(s) - menadione , ex vivo , chemistry , in vivo , bioavailability , thioredoxin reductase , glutathione , biochemistry , mechanism of action , ether , enzyme , antioxidant , reductase , pharmacology , in vitro , stereochemistry , biology , organic chemistry , microbiology and biotechnology
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 ( Sm TGR ), 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 ( h GR ) and selenium‐dependent human thioredoxin reductase ( h T rxR), 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 Sm TGR selectively compared to h GR and h T rxR enzymes, in particular those bearing an α‐fluorophenol methyl ether moiety, which improves anti‐schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative ( 7 ) displayed time‐dependent Sm TGR inactivation, correlating with unproductive NADPH ‐dependent redox cycling of Sm TGR , and potent anti‐schistosomal action in worms cultured ex vivo . In contrast, the difluoromethylmenadione analog 9 , which inactivates Sm TGR through an irreversible non‐consuming NADPH ‐dependent process, has little killing effect in worms cultured ex vivo . Despite ex vivo activity, none of the compounds tested was active in vivo , suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.