title: Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors.
abstract: In this study, we aimed to investigate the effect of some coumarin and benzoxazinone derivatives on the activity of human PON1. Human serum paraoxonase 1 was purified from fresh human serum blood by two-step procedures that are ammonium sulfate precipitation (60-80%) and then hydrophobic interaction chromatography (Sepharose 4B, L-tyrosine and 1-napthylamine). The enzyme was purified 232-fold with a final specific activity of 27.1 U/mg. In vitro effects of some previously synthesized ionic coumarin or benzoxazinone derivatives (1-21) on purified PON1 activity were investigated. Compound 14 (1-(2,3,4,5,6)-pentamethylbenzyl-3-(6,8-dimethyl-2H-chromen-2-one-4-yl))benzimidazolium chloride was found out as the strongest inhibitor (IC50 = 7.84 μM) for PON1 among the compounds. Kinetic investigation and molecular docking study were evaluated for one of the most active compounds (compound 12) and obtained data showed that this compound is competitive inhibitor of PON1 and interact with Leu262 and Ser263 in the active site of PON1. Moreover, coumarin derivatives were found out as the more potent inhibitors for PON1 than benzoxazinone derivatives.
authors.affiliation: a Department of Chemistry , Faculty of Arts and Science, Inonu University , Malatya , Turkey .
authors.forename: Mert Olgun
authors.initials: MO
authors.lastname: Karataş
authors.affiliation: b Department of Pharmaceutical Chemistry , Faculty of Pharmacy, Inonu University , Malatya , Turkey .
authors.forename: Harun
authors.initials: H
authors.lastname: Uslu
authors.affiliation: a Department of Chemistry , Faculty of Arts and Science, Inonu University , Malatya , Turkey .
authors.forename: Bülent
authors.initials: B
authors.lastname: Alıcı
authors.affiliation: c Department of Biochemistry , Faculty of Pharmacy, Suleyman Demirel University , Isparta , Turkey , and.
authors.forename: Başak
authors.initials: B
authors.lastname: Gökçe
authors.affiliation: d Department of Chemistry , Faculty of Art and Sciences, Balikesir University , Balikesir , Turkey.
authors.forename: Nahit
authors.initials: N
authors.lastname: Gencer
authors.affiliation: d Department of Chemistry , Faculty of Art and Sciences, Balikesir University , Balikesir , Turkey.
authors.forename: Oktay
authors.initials: O
authors.lastname: Arslan
mesh_terms: D043303:Aryldialkylphosphatase / Q000037:antagonists & inhibitors* / Q000097:blood; D048588:Benzoxazines / Q000494:pharmacology*; D002853:Chromatography, Liquid; D003374:Coumarins / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D003374:Coumarins; D004791:Enzyme Inhibitors; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
keywords: Benzoxazinone; coumarin; docking; inhibition; paraoxonase