title: Synthesis and bioevaluation of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acids as potent xanthine oxidase inhibitors.
abstract: A series of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid derivatives (8a-f, 9a-m) were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro. Structure-activity relationship analyses have also been presented. Most of the target compounds exhibited potency levels in the nanomolar range. Compound 9e emerged as the most potent xanthine oxidase inhibitor (IC50 = 5.5 nM) in comparison to febuxostat (IC50 = 18.6 nM). Steady-state kinetics measurements with the bovine milk enzyme indicated a mixed type inhibition with Ki and Ki' values of 0.9 and 2.3 nM, respectively. A molecular modeling study on compounds 9e was performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors related with 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid scaffold.
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guan
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Zengjin
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Geratology, The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Geratology, The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Dongjie
authors.initials: D
authors.lastname: Feng
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Bao
authors.affiliation: Department of Geratology, The First Affiliated Hospital, China Medical University, Shenyang 110001, China. Electronic address: wulan_2000@sina.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhangweige2000@sina.com.
authors.forename: Weige
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D014969:Xanthine Oxidase
keywords: 2-Phenyl-4-methyl-1,3-selenazole-5-carboxylic acid; Molecular modeling; Structure–activity relationship; Synthesis; Xanthine oxidase inhibitors