Comparative Antioxidant Profiling of Phenolic Acids and Flavonoids: Assay-Resolved Structure–Activity Relationships Under Harmonized In Vitro Conditions

Phenolic acids and flavonoids remain attractive redox-active scaffolds in medicinal chemistry, where they are widely used for early-stage prioritization and intrinsic reactivity ranking. However, direct comparisons under harmonized conditions remain scarce, limiting structure-based assessment. Here, a structurally diverse panel of hydroxybenzoic acids, hydroxycinnamic acids, flavonoids, a flavanone, and synthetic comparators was profiled using Folin–Ciocalteu response, ABTS radical cation scavenging, DPPH radical scavenging, and reducing power assays. The data reveal pronounced assay dependence alongside clear structure–activity trends. Gallic acid showed the strongest DPPH scavenging (half-maximal inhibitory concentration, IC50 = 4.45 µmol/L) and reducing power (17.26 µmol TE/mg), while quercetin was consistently active across all four endpoints. Eriocitrin (IC50 = 2.47 µmol/L) and rutin (IC50 = 2.66 µmol/L) were particularly effective in the ABTS assay, showing that glycosylation does not abolish cation-radical scavenging. Lipinski’s Rule of Five and Veber oral-bioavailability criteria place these findings within a drug-likeness context. The results also highlight the limitations of the Folin–Ciocalteu assay as a standalone measure of total phenolic content, since its response depends strongly on hydroxylation density. Rather than asserting therapeutic efficacy, this work provides a harmonized comparative dataset identifying phenolic substructures with the strongest and most consistent redox activity, together with the structural drivers underlying these patterns.