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 IC50 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 (IC50 = 29.89  µg/mL), while 12g and 12h showed superior anti-proteinase activity (IC50 = 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 (LD50 > 6000 mg/kg). The hybrids presented here represent promising multifunctional leads with antibacterial, antioxidant, anti-inflammatory, and drug-like properties.