title: Structural exploration, synthesis and pharmacological evaluation of novel 5-benzylidenethiazolidine-2,4-dione derivatives as iNOS inhibitors against inflammatory diseases.
abstract: In our previous work, 3I inhibited the LPS-induced iNOS activity and NO production in RAW 264.7 cells and improved joint inflammation and cartilage destruction in inflammatory model. In this study, we synthesized 59 derivatives and bioisosteres on the basis of 3I by Knoevenagel condensation and biologically evaluated for the study of structure-activity relationship (SAR). We found that 7-44 suppressed the iNOS activity (IC50 25.2 μM) and LPS-induced NO production (IC50 45.6 μM) in RAW 264.7 cells. As for the SAR study, the dimethoxylphenyl group of 7-44 was potential for a further modification. At a dose of 10 mg/kg, oral administration of 7-44 possessed protective properties in both carrageenan-induced paw edema of male ICR mice and adjuvant-induced arthritis of Lewis female rats. Although the activity of 7-44 was slightly inferior, the PK profiles of 7-44 were superior to those of 3I.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Heying
authors.initials: H
authors.lastname: Pei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Linhong
authors.initials: L
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: chenlijuan125@163.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C584486:5-benzylidene thiazolidine-2,4-dione; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D045162:Thiazolidinediones; D009569:Nitric Oxide; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II
keywords: 5-Benzylidenethiazolidine-2,4-dione; Inducible nitric oxide synthase; Inflammation; Nitric oxide; Paw edema