title: Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.
abstract: A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.
authors.affiliation: Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Mingfang
authors.initials: M
authors.lastname: Zheng
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Deju
authors.initials: D
authors.lastname: Ye
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Deng
authors.forename: Shuifeng
authors.initials: S
authors.lastname: Qiu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000032:analysis / Q000302:isolation & purification* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011714:Pyrans / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; D001094:Arachidonate 5-Lipoxygenase