Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.
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.
Zheng
Mingfang
M
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Zheng
Mingyue
M
Ye
Deju
D
Deng
Yangmei
Y
Qiu
Shuifeng
S
Luo
Xiaomin
X
Chen
Kaixian
K
Liu
Hong
H
Jiang
Hualiang
H
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
D004791:Enzyme Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; D001094:Arachidonate 5-Lipoxygenase