Synthesis of Chalcone‐Sulfonamide Hybrids as Antibacterial, Antioxidant, and Anti‐Inflammatory Agents With Comprehensive In Silico and ADMET Profiling

Chalcone‐sulfonamide hybrids ( 12a–h ) were synthesized via Claisen–Schmidt condensation in good yields (64%–83%) and confirmed by NMR spectroscopy. The compounds exhibited moderate to good antibacterial activity against Gram‐negative ( Escherichia coli , Pseudomonas aeruginosa ) and Gram‐positive ( Staphylococcus aureus , Streptococcus pyogenes ) bacteria, with inhibition zones of up to 14.7 mm at 10 mg/mL, lower than that of sulfamethoxazole but comparable to that of related hybrids. DPPH antioxidant evaluation revealed IC 50 values of 5.2–11.8 μg/mL, with compounds 12e and 12c exhibiting the highest activity. Additionally, compound 12e had the strongest protein denaturation inhibition (IC 50 = 29.89 µg/mL), while 12g and 12h showed superior anti‐proteinase activity (IC 50 = 115.6 and 112.2 µg/mL), outperforming diclofenac sodium. Molecular docking against DHPS (1AJ0, 1AD4), myeloperoxidase (1DNU), COX‐2 (5IKR), and topoisomerase IIα (4FM9) showed strong binding affinities (−8.3 to −10.3 kcal/mol), supported by key hydrogen–bonding and hydrophobic interactions. SwissADME and ProTox II analyses indicate favorable drug‐like properties, including Lipinski compliance, high GI absorption, no BBB penetration, and low predicted toxicity (LD 50 > 6000 mg/kg). The hybrids presented here represent promising multifunctional leads with antibacterial, antioxidant, anti‐inflammatory, and drug‐like properties.