Antioxidant, Anti-Inflammatory, and Oral Bioavailability of Novel Sulfonamide Derivatives of Gallic Acid
Dania Hussein Alhyari, Nidal A. Qinna, Helen M. Sheldrake, Sriharsha Kantamneni, Bayan Y. Ghanem, Krzysztof J. Paluch
Abstract
Gallic acid (GA) is known for its antioxidant and anti-inflammatory properties, yet its clinical potential is hindered due to poor oral bioavailability. This study investigates novel GA sulfonamide derivatives, 3,4,5-trimethoxybenzenesulfonamide (3,4,5-TMBS) and 3,4,5-trihydroxybenzenesulfonamide (3,4,5-THBS), and determines their antioxidant and anti-inflammatory activities and bioavailability. Antioxidant activity was evaluated using DPPH, FRAP, and ROS assays in human intestinal epithelial cells (HIEC-6). Protein denaturation and COX-2 inhibition were assayed to measure anti-inflammatory effects. 3,4,5-TMBS metabolism was assessed via CYP2D6, and pharmacokinetics were profiled in Sprague Dawley rats. GA and 3,4,5-THBS showed a three-fold increase in ROS scavenging activity at 1000 µM (96% for GA, 93% for 3,4,5-THBS). 3,4,5-TMBS and 3,4,5-THBS demonstrated significant anti-inflammatory activity when compared to ibuprofen at concentrations ≥100 nM (p < 0.05). 3,4,5-TMBS (50 µM) exhibited high COX-2 inhibition (p < 0.001) unlike GA (50 µM) which had a low COX-2 inhibition effect (p > 0.05), compared to ibuprofen. The percentage of 3,4,5-TMBS metabolism increased from 65% to 81% at 1500 µM (p < 0.05) when metabolized by CYP2D6. Pharmacokinetic studies revealed that 3,4,5-TMBS and 3,4,5-THBS had significantly higher Cmax and longer half-lives than GA, with 3,4,5-TMBS showing a half-life of 7.17 ± 1.62 h, compared to 3.60 ± 0.94 h for GA (p < 0.05). 3,4,5-TMBS and 3,4,5-THBS demonstrated superior antioxidant and anti-inflammatory effects in HIEC-6 compared to GA, with enhanced bioavailability. These findings support the potential of 3,4,5-TMBS and 3,4,5-THBS as effective alternatives to GA for clinical applications.