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 IC₅₀ range of 0.1-1.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 5b as a highly potent (IC₅₀ = 0.1 μM), 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 (ED₅₀ = 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 CH₃O substituents of 5b inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such group underwent a H-bonding interaction with His⁹⁰ (2.43, 2.83 Å), Arg⁵¹³ (2.89 Å) and Tyr³⁵⁵ (3.34 Å). 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.