Novel 5-aminosalicylic derivatives as anti-inflammatories and myeloperoxidase inhibitors evaluated in silico, in vitro and ex vivo

Abstract

During the inflammation process, myeloperoxidase (MPO) contributes to the production of reactive species mainly for the destruction of pathogens. When inflammation is dysregulated, the overproduction of reactive species generates cellular damage via the oxidation of biomolecules (proteins, lipids and nucleic acids) that are associated with many acute or chronic inflammatory diseases, including cardiovascular and neurodegenerative disorders, dermatitis, ulcerative colitis, and cancer. Therefore, MPO plays a crucial role in inflammation and oxidative stress, representing an interesting target for drug design. Hence, in this work, four 5-aminosalicylic acid derivatives (C1–C4) were synthesized and evaluated. The results showed that C1 has anti-inflammatory activity (ear model) comparable to indomethacin, while C2, C3 and C4 showed better MPO inhibitory effects when evaluated in vitro using the O-dianisidine method; however, in the in silico analyses, C3 and C4 were coupled on MPO under the better geometric and free energy values than the other tested compounds. In addition, compounds C3 and C4 showed good antioxidant properties according to the in vitro assays using the 2,2′-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid methods. Taken together, these findings suggest that C1–C4 may be useful for the treatment of several inflammatory diseases in the future. Keywords: Oxidative stress, Antioxidants, Ear edema, 5-Aminosalicylic derivatives