title: Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2.
abstract: A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4 mg/kg) relative to diclofenac (ED50=114 mg/kg). Molecular modeling 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. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95 Å), Phe(518)(2.82 Å) and Arg(513)(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Al-Suwaidan
authors.forename: Amer M
authors.initials: AM
authors.lastname: Alanazi
authors.forename: Adel S
authors.initials: AS
authors.lastname: El-Azab
authors.forename: Abdulrahman M
authors.initials: AM
authors.lastname: Al-Obaid
authors.forename: Kamal E H
authors.initials: KE
authors.lastname: ElTahir
authors.forename: Azza R
authors.initials: AR
authors.lastname: Maarouf
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abu El-Enin
authors.forename: Alaa A-M
authors.initials: AA
authors.lastname: Abdel-Aziz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D003500:Cyclization; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006860:Hydrogen Bonding; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D000096926:Benzenesulfonamides
chemical_list: D000893:Anti-Inflammatory Agents; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D007094:Imides; D013449:Sulfonamides; D000096926:Benzenesulfonamides