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.
ABSTRACT Euphorbia members (Euphorbiaceae) are valuable sources of lead compounds for potential drug discovery. This study was conducted to evaluate, for the first time, the phytoconstituents, antioxidant capacity, enzyme inhibitory, and cytotoxic properties of E. peplis . Extracts were prepared from the aerial parts using ethyl acetate (EtOAc), ethanol (EtOH), 70% EtOH, and water. Results showed that the 70% EtOH and EtOH extracts contained the highest levels of total phenolics (68.12 mg GAE/g) and flavonoids (45.49 mg RE/g). UPLC‐ESI‐MSn analysis revealed a variety of phytochemicals, including flavonoids, cinnamic acid derivatives, tannins, triterpenoids, and saponins, with 24 metabolites tentatively identified. PCA grouped these metabolites into three clusters, and their distribution was visualized with a heatmap. Polar extracts demonstrated strong antioxidant activity, with the 70% EtOH extract showing the highest values in most assays (DPPH = 385.50 mg TE/g; ABTS = 466.31 mg TE/g; CUPRAC = 439.95 mg TE/g; FRAP = 305.07 mg TE/g; PBD = 2.45 mmol TE/g). The EtOH and EtOAc extracts exhibited the strongest anti‐acetylcholinesterase (2.83 mg GALAE/mg) and anti‐butyrylcholinesterase (2.18 mg GALAE/mg) activities, respectively. Both the 70% EtOH and EtOH extracts showed the best anti‐tyrosinase effects (54.40 and 53.39 mg KAE/g; p ≥ 0.05). The EtOAc extract was more toxic toward SHSY5Y cells, with a viability of 4.31%, compared to 8.18% in normal KEK293 cells. Network pharmacology identified 11 common targets for E. peplis metabolites, with AKT1, EGFR, GSK3B, ESR1/ESR2, and CCND1 serving as key hubs. Pathway enrichment analysis highlighted PI3K‐Akt, EGFR, and hormone‐related pathways. Docking and molecular dynamics simulations confirmed stable multi‐target binding. These findings suggest that E. peplis could be a promising source of antioxidants and compounds with potential anticancer and enzyme‐inhibitory activities relevant to human diseases.
Sakina Yagi, Esraa A. Elhawary, Omayma A. Eldahshna et al.· Food Science & Nutrition· 0 citations
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