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Inflammation is a complex phenomenon that results as a healing response of organisms to different factors, exerting immune signaling, excessive free radical activity and tissue destruction. Lipoxygenases and their metabolites e.g., LTB₄, are associated with allergy, cell differentiation and carcinogenesis. Lipoxygenase 12/15 has been characterized as a mucosal-specific inhibitor of IgA and a contributor to the development of allergic sensitization and airway inflammation. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. In this study we extended our previous research synthesizing a series of multi-target cinnamic acids from the corresponding aldehydes with suitable 4-OH/Br substituted phenyl acetic acid by Knoevenagel condensation. The final products 1i , 3i , 3ii , 4i , 6i , 6ii , and 7i were obtained in high yields (52⁻98%) Their structures were verified spectrometrically, while their experimentally lipophilicity was determined as R M values. The novel derivatives were evaluated for their antioxidant activity using DPPH, hydroxyl radical, superoxide anion and ABTS +• , anti-lipid peroxidation and soybean lipoxygenase inhibition assays. The compounds presented medium interaction with DPPH (30⁻48% at 100 µM). In contrast all the synthesized derivatives strongly scavenge OH radicals (72⁻100% at 100 µM), ABTS +• (24⁻83% at 100 µM) and presented remarkable inhibition (87⁻100% at 100 µM) in linoleic acid peroxidation (AAPH). The topological polar surface of the compounds seems to govern the superoxide anion scavenging activity. Molecular docking studies were carried out on cinnamic acid derivative 3i and found to be in accordance with experimental biological results. All acids presented interesting lipoxygenase inhibition (IC 50 = 7.4⁻100 µM) with compound 3i being the most potent LOX inhibitor with IC 50 = 7.4 µM combining antioxidant activities. The antioxidant results support the LOX inhibitory activities. The recorded in vitro results highlight compound 3i as a lead compound for the design of new potent lipoxygenase inhibitors for the treatment of asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders.

Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies