Structure-Dependent Modulation of Antioxidant Activity and Multi-Target Enzyme Inhibition by Resveratrol Derivatives

The antioxidant activity of polyphenolic scaffolds and the selectivity of enzyme inhibition can be significantly modified through structural modification. The antioxidant properties and the multi-target enzyme inhibitory properties of resveratrol and three structurally different analogs (oxyresveratrol, 3′,5′-dimethoxyresveratrol and triacetylresveratrol) were comparatively assessed to clarify the structure-activity relationships. The antioxidant activity was measured using complementary electron-transfer assay, radical-scavenging assay, and metal chelating assay, whereas the enzyme inhibition was evaluated against hCA I and hCA II, GST, AChE, BChE, and α-glycosidase, as well as α-amylase enzymes. Oxyresveratrol showed the best antioxidant behavior in most of the assays, which is in line with the occurrence of the extra additional hydroxyl groups, which increases the ability to donate electrons. Conversely, acetylation significantly minimized radical scavenging action and enhanced enzyme inhibition abilities. The strongest inhibitory activity of triacetylresveratrol was exhibited against hCA I (IC50: 49.50 nM), hCA II (IC50: 46.50 nM), BChE (IC50: 46.20 nM), and against α-glycosidase, whereas, 3′,5′-dimethoxyresveratrol showed the strongest inhibition ability against AChE (IC50: 13.86 nM). Comparatively, resveratrol exhibited a relatively high GST inhibition (IC50: 463.54 nM), which showed the role of the free phenolic groups in the enzyme interaction. These results reveal that hydroxylation positively impacts the antioxidant activity, but acetylation and methoxylation regulate selectivity and the enzymes inhibition potency. The observed differences in biological profiles between the derivatives provide mechanistic insight of activity changes based on functional groups and the selection of resveratrol multi-target therapeutic derivatives in oxidative stress-linked and metabolic diseases.