Synthesis, anti-inflammatory activity and COX-1/COX-2 inhibition of novel substituted cyclic imides. Part 1: Molecular docking study

A group of cyclic imides (1-13) was designed for evaluation as selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model. Compounds 5b, 6b, 11b, 11c, 12b and 12c were proved to be potent COX-2 inhibitors with IC(50) range of 0.1 -1.0 mu M. In vitro COX-1/COX-2 inhibition structure activity studies identified compound 5b as a highly potent (IC(50) = 0.1 mu M), and an extremely selective [COX-2 (SI) = 400] comparable to celecoxib [COX-2 (SI) > 333.3], COX-2 inhibitor that showed superior anti-inflammatory activity (ED(50) = 104 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). A Virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Molecular modeling (docking) study showed that the CH(3)O substituents of 5b inserted deep inside the 2 degrees-pocket of the COX-2 active site, where the O-atoms of such group underwent a H-bonding interaction with His(90) (2.43, 2.83 angstrom), Arg(513) (2.89 angstrom) and Tyr(355) (3.34 angstrom). Docking study of the synthesized compound 5b into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. (C) 2011 Elsevier Masson SAS. All rights reserved.