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

• Published in: European journal of medicinal chemistry 2011-05, Vol.46 (5), p.1648-1655
• Main Authors: Abdel-Aziz, Alaa A.-M., ElTahir, Kamal E.H., Asiri, Yousif A.
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory activities; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan; COX-2 inhibitors; Crystallography, X-Ray; Cyclic imides; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Disease Models, Animal; Edema - chemically induced; Edema - drug therapy; Hydrogen Bonding; Imides - chemical synthesis; Imides - chemistry; Imides - pharmacology; Male; Medical sciences; Models, Molecular; Molecular docking; Molecular Structure; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sheep; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.02.013

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 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 5b as a highly potent (IC 50 = 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 (ED 50 = 104 mg/kg) relative to diclofenac (ED 50 = 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 3O 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 His 90 (2.43, 2.83 Å), Arg 513 (2.89 Å) and Tyr 355 (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. [Display omitted] ► Cyclic imide derivatives were synthesized and screened for COX-1/COX-2 inhibition. ► Compounds with COX-2 inhibition were subjected to anti-inflammatory studies. ► Compound 5b exhibit optimal COX-2 inhibitory potency (IC 50 = 0.1mM). ► This compound presents the pharmacophoric requisites for COX-2 inhibition. ► Molecular docking studies further supported the strong inhibitory activity of 5b.