期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 92, 期 -, 页码 115-123出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.12.039
关键词
Phthalimides; COX-2 inhibitors; Anti-inflammatory activity; Analgesic activity; Molecular docking
资金
- Deanship of Scientific Research at King Saud University [RGP-VPP-163]
A group of 30 cyclic imides (1-10a-c) was designed for evaluation as a selective COX-2 inhibitor and investigated in vivo for anti-inflammatory and analgesic activities. Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency (IC50 = 0.18, 0.24, 0.28 and 036 AM; respectively) and selectivity index (SI) range of 363-668. In vitro COX-1/COX-2 inhibition structure activity studies identified compound 6a as a highly potent (IC50 = 0.18 AM), and an extremely selective [COX-2 (SI) = 668] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 54.0 mg/kg) relative to didofenac (ED50 = 114 mg/kg). Molecular Docking study of the synthesized compound 6a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Docking study showed that the methoxy moeities of 6a inserted deep inside the 2 degrees-pocket of the COX-2 active site, where the O-atoms of such groups underwent an H-bonding interaction with His(90) (3.02 angstrom), Arg(513) (1.94, 2.83 angstrom), and Gln(192) (3.25 angstrom). (C) 2014 Elsevier Masson SAS. All rights reserved.
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