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Aspirin Analogues as Dual Cyclooxygenase‐2/5‐Lipoxygenase Inhibitors: Synthesis, Nitric Oxide Release, Molecular Modeling, and Biological Evaluation as Anti‐Inflammatory Agents
Author(s) -
Kaur Jatinder,
Bhardwaj Atul,
Huang Zhangjian,
Knaus Edward E.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100460
Subject(s) - chemistry , pharmacophore , moiety , cyclooxygenase , arachidonate 5 lipoxygenase , stereochemistry , lipoxygenase , enzyme inhibitor , enzyme , aspirin , biological activity , nitric oxide synthase , pharmacology , nitric oxide , in vitro , biochemistry , arachidonic acid , organic chemistry , medicine
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 μ M ), 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 μ M ) and 16 (IC 50 =0.3 μ M ), 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.