Multi-Target Anti-Inflammatory and Antioxidant Potential of Phloracetophenone 4-O-β-d-Glucopyranoside: Experimental Validation and Computational Mechanistic Insights

This research explores the biological activities and the structure-activity relationship of phloracetophenone 4-O-β-d-glucopyranoside (1). The antioxidant activity was assessed using four different techniques. The structure-activity relationship was studied through three primary mechanisms, namely, hydrogen atom transfer (HAT), sequential proton loss electron transfer (SPLET), and SET-PT, using BDE(E0), energy decomposition scheme (ETS)-natural orbitals for chemical valence (NOCV), and BDE. Atoms in molecules (AIM) and key thermodynamic parameters were calculated using DFT. Moreover, the anti-inflammatory potential was evaluated by its ability to inhibit ovalbumin denaturation, along with molecular docking against tumor necrosis factor-alpha (TNF-α), MAP kinase, cyclooxygenase-1 (COX-1), and COX-2 targets. The molecule demonstrated high antioxidant activity in ferric thiocyanate test (FTC) (82.74%), reducing power (RP) (A_0.5 = 15.9 µg/mL), total antioxidant capacity (TAC) (25.88 µg EAA/mg), and cupric reducing antioxidant capacity (CUPRAC) assays (A_0.5 = 0.51 µg/mL). This correlation is consistent with theoretical predictions; the HAT mechanism was predominant in nonpolar environments, whereas SPLET was favored in polar solvents. Additionally, Compound (1) demonstrated a moderate anti-inflammatory effect (34.82% at 1 mg/mL) compared to diclofenac (99.42% at 1 mg/mL) and has a consistent ability to dock into the binding sites of all selected inflammatory targets, with high binding affinities (-7.2 to -8.6 kcal/mol). Furthermore, the predicted physicochemical and drug-like properties of Compound (1) showed a favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile with acceptable oral bioavailability. Thus, phloracetophenone 4-O-β-d-glucopyranoside could constitute a promising and safe therapeutic agent.