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 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.