Coumarin–Amino Acid Hybrids Used as Possible Multifactorial Anti-Inflammatory Agents

A series of coumarin–amino acid hybrids of glycine, γ-aminobutyric acid, and L-glutamic acid was developed. These compounds were evaluated for their antioxidant and anti-inflammatory activities in vitro and for their drug-likeness in silico. Antioxidant activity was assessed in vitro using the AAPH-induced linoleic acid peroxidation assay. Soybean lipoxygenase and ovine cyclooxygenase 2 were used in vitro to test the inhibitory activity of the adducts. An in silico evaluation was performed using the open-access platforms Molinspiration, SwissADME, PreADMET, Molsoft, GLORYx, CypRules, and LiverTox Workspace. The synthesis of the compounds proceeded via a facile procedure through the corresponding acid in very good yields. The antioxidant activity of the compounds is shown to be highly dependent on the linkage used, with compound 15 presenting the highest activity (93% inhibition). The most active LOX inhibitor is compound 4 (IC50 = 58 μM), while compounds 4 and 5 are the most potent COX-2 inhibitors (IC50 = 55 μM for both). Compounds 4, 9, and 15 are depicted as pleiotropic molecules (compound 4: IC50 for SLOX-1 = 58 μM and IC50 for COX-2 = 55 μM; compound 9: IC50 for COX-2 = 60 μM, and 59% antilipid peroxidation; compound 15: IC50 for COX-2 = 70.5 μM, 93% antilipid peroxidation). An in silico evaluation showed favorable properties of the designed agents, which were quantified, with all the compounds showing a QED score higher than 0.5. The overall results highlight that compound 4 can be used as a lead molecule for the design of more potent agents with a pleiotropic profile.