A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a-4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS^•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC₅₀ 36.9 and 37.1 μM). In the DCF-DA assay, the 4'-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3'-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC₅₀ 11.4, 4.1, and 8.7 μM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. In silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 μΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60-97%) values.

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