Synthesis and evaluation of 1, 4–naphthoquinone ether derivatives as SmTGR inhibitors and new anti‐schistosomal drugs. (3rd August 2015)

• Record Type: Journal Article
• Authors: Johann, Laure; Belorgey, Didier; Huang, Hsin‐Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L.; Davioud‐Charvet, Elisabeth
• Is Part Of: FEBS journal. Volume 282:Number 16(2015)
• Page Start: 3199
• Page End: 3217
• Publication Date: 2015-08-03
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13359
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs13359-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<bold>1</bold>–<bold>7</bold>) and their difluoromethylmenadione counterparts (<bold>8</bold>, <bold> 9</bold>) were found to be potent and specific inhibitors of <italic>Schistosoma mansoni</italic> thioredoxin‐glutathione reductase (<italic>Sm</italic>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 (<italic>h</italic>GR) and selenium‐dependent human thioredoxin reductase (<italic>h</italic>TrxR), 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 <italic>Sm</italic>TGR selectively compared to <italic>h</italic>GR and <italic>h</italic>TrxR enzymes, in particular those bearing an α‐fluorophenol methyl ether moiety, which improves anti‐schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (<bold>7</bold>) displayed time‐dependent <italic>Sm</italic>TGR inactivation, correlating with unproductive NADPH‐dependent redox cycling of <italic>Sm</italic>TGR, and potent anti‐schistosomal action in worms cultured <italic>ex vivo</italic>. In contrast, the difluoromethylmenadione analog <bold>9</bold>, which inactivates <italic>Sm</italic>TGR through an irreversible non‐consuming NADPH‐dependent process, has little killing effect in worms cultured <italic>ex vivo</italic>. Despite <italic>ex vivo</italic> activity, none of the compounds tested was active <italic>in vivo</italic>, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.</p> </abstract>