Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs.
Fiche publication
Date publication
août 2015
Journal
The FEBS journal
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
Tous les auteurs :
Johann L, Belorgey D, Huang HH, Day L, Chessé M, Becker K, Williams DL, Davioud-Charvet E
Lien Pubmed
Résumé
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 α-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 ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR 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.
Mots clés
Animals, Cell Line, Drug Evaluation, Preclinical, Electrochemistry, Enzyme Inhibitors, chemical synthesis, Glutathione, chemistry, Glutathione Reductase, antagonists & inhibitors, Humans, In Vitro Techniques, Mice, Multienzyme Complexes, antagonists & inhibitors, NADH, NADPH Oxidoreductases, antagonists & inhibitors, Naphthoquinones, chemical synthesis, Schistosoma mansoni, drug effects, Schistosomiasis mansoni, drug therapy, Schistosomicides, chemical synthesis, Structure-Activity Relationship, Thioredoxin-Disulfide Reductase, antagonists & inhibitors
Référence
FEBS J.. 2015 Aug;282(16):3199-217