Synthesis, Characterization and in vitro, in vivo and in silico Anti-Inflammatory Studies of the Novel Hybrid Based on Ibuprofen and 3-Hydroxy-Copalic Acid Isolated from Copaiba Oil (Copaifera multijuga)

A novel anti-inflammatory hybrid 3-ibuprofenyl-copalic acid (3-IbuCA) was synthesized from 3-hydroxy-copalic acid isolated from Amazonian copaiba oil (Copaifera multijuga Hayne), and the anti-inflammatory ibuprofen. After full characterization, several assays to verify its anti-inflammatory effects were performed in vitro, in vivo and in silico (molecular docking). Induced fit docking was performed to observe the interactions with the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). In vitro tests of cytotoxicity and tumor necrosis factor (TNF)- α inhibition, and in vivo tests of pleurisy, protein expression and gastrocytotoxicity were performed. Molecular docking studies with COX-1 and 2 showed binding free energies ( Δ G) of -2.2 and -7.8 kcal mol-1, respectively, while for mofezolac and indomethacin, the binding free energies Δ G presented values of -8.5 and -10.1 kcal mol-1, which makes 3-IbuCA selective for COX-2 inhibition. This hybrid showed no toxicity against human macrophage at concentrations up to 2 µM, and inhibited TNF- α production in lipopolysaccharide (LPS)-stimulated macrophages. In the pleurisy assays, 3-IbuCA reduced the total leukocytes and mononuclear cells, which was followed by reduction of p-IKB α (phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) protein expression. Compared with ibuprofen alone, the hybrid caused less gastric damage. Thus, the docking, together with in vitro and...
Source: Journal of the Brazilian Chemical Society - Category: Chemistry Source Type: research