title: Aspirin analogues as dual cyclooxygenase-2/5-lipoxygenase inhibitors: synthesis, nitric oxide release, molecular modeling, and biological evaluation as anti-inflammatory agents.
abstract: Analogues of aspirin were synthesized through an efficient one-step reaction in which the carboxyl group was replaced by an ethyl ester, and/or the acetoxy group was replaced by an N-substituted sulfonamide (SO(2)NHOR(2):R(2) =H, Me, CH(2)Ph) pharmacophore. These analogues were designed for evaluation as dual cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors. In vitro COX-1/COX-2 isozyme inhibition studies identified compounds 11 (CO(2) H, SO(2)NHOH), 12 (CO(2)H, SO(2)NHOCH(2)Ph), and 16 (CO(2)Et, SO(2)NHOH) as highly potent and selective COX-2 inhibitors (IC(50) range: 0.07-0.7 μM), which exhibited appreciable in vivo anti-inflammatory activity (ED(50) range: 23.1-31.4 mg kg(-1)). Moreover, compounds 11 (IC(50) =0.2 μM) and 16 (IC(50) =0.3 μM), with a sulfohydroxamic acid (SO(2)NHOH) moiety showed potent 5-LOX inhibitory activity. Furthermore, the SO(2)NHOH moiety present in compounds 11 and 16 was found to be a good nitric oxide (NO) donor upon incubation in phosphate buffer at pH 7.4. Molecular docking studies in the active binding site of COX-2 and 5-LOX provided complementary theoretical support for the experimental biological structure-activity data acquired.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D009569:Nitric Oxide; D001241:Aspirin