title: Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors.
abstract: In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4',7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 μM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 μM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.
authors.affiliation: College of Chemistry and Chemical Engineering, and Key Laboratory of Hunan Forest Products and Chemical Industry Engineering, Jishou University, Jishou 416000, PR China. xiaozhuping2005@163.com
authors.forename: Zhu-Ping
authors.initials: ZP
authors.lastname: Xiao
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Peng
authors.forename: Jing-Jun
authors.initials: JJ
authors.lastname: Dong
authors.forename: Juan
authors.initials: J
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Ouyang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Feng
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Lu
authors.forename: Wan-Qiang
authors.initials: WQ
authors.lastname: Lin
authors.forename: Jin-Xiang
authors.initials: JX
authors.lastname: Wang
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Xiang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000201:enzymology*; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C584488:4',7,8-trihydroxyl-2-isoflavene; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D014510:Urease