title: Design, synthesis, and biological testing of novel naphthoquinones as substrate-based inhibitors of the quinol/fumarate reductase from Wolinella succinogenes.
abstract: Novel naphthoquinones were designed, synthesized, and tested as substrate-based inhibitors against the membrane-embedded protein quinol/fumarate reductase (QFR) from Wolinella succinogenes, a target closely related to QFRs from the human pathogens Helicobacter pylori and Campylobacter jejuni. For a better understanding of the hitherto structurally unexplored substrate binding pocket, a structure-activity relationship (SAR) study was carried out. Analogues of lawsone (2-hydroxy-1,4-naphthoquinone 3a) were synthesized that vary in length and size of the alkyl side chains (3b-k). A combined study on the prototropic tautomerism of 2-hydroxy-1,4-naphthoquinones series indicated that the 1,4-tautomer is the more stable and biologically relevant isomer and that the presence of the hydroxyl group is crucial for inhibition. Furthermore, 2-bromine-1,4-naphthoquinone (4a-c) and 2-methoxy-1,4-naphthoquinone (5a-b) series were also discovered as novel and potent inhibitors. Compounds 4a and 4b showed IC50 values in low micromolar range in the primary assay and no activity in the counter DT-diaphorase assay.
authors.affiliation: Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt , Max-von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Nasiri
authors.forename: M Gregor
authors.initials: MG
authors.lastname: Madej
authors.forename: Robin
authors.initials: R
authors.lastname: Panisch
authors.forename: Michael
authors.initials: M
authors.lastname: Lafontaine
authors.forename: Jan W
authors.initials: JW
authors.lastname: Bats
authors.forename: C Roy D
authors.initials: CR
authors.lastname: Lancaster
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D016968:Wolinella / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D010088:Oxidoreductases; C424907:quinol fumarate reductase; C005090:lawsone