Synthesis and molecular docking of sulphonamide-imidazole derivatives as potential antibacterial agents

Abstract

A novel series of sulphonamide–imidazole hybrid derivatives (12a–12l) was rationally designed, synthesized, and evaluated for antibacterial activity against Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus. The antibacterial potential was assessed using the broth microdilution method, with streptomycin serving as the reference drug. Among the synthesized compounds, 12a, 12c, 12d, 12f, and 12h demonstrated notable antibacterial activity, exhibiting inhibition zones of 16–19 mm (B. subtilis) and 15–20 mm (S. aureus), with MIC values ranging from 4.58 to 9.56 µg/mL, comparable to that of streptomycin (6.14–6.25 µg/mL). To further understand their mechanism of action, molecular docking studies were conducted against the FimH lectin domain of Escherichia coli K12 (PDB ID: 4XO8). Compounds 12a and 12b displayed strong binding affinities (−7.92 and −7.18 kcal/mol, respectively), forming key hydrogen bonds with active site residues, validating the design rationale. Structure–activity relationship (SAR) analysis indicated that electron-withdrawing and sterically favorable substituents on the sulphonamide ring enhance antibacterial potency. Additionally, in silico ADME and toxicity predictions revealed that most compounds exhibited favorable drug-likeness, with the exception of 12l, which showed potential reproductive toxicity. These findings highlight the sulphonamide–imidazole hybrids—particularly 12a, 12c, 12d, 12f, and 12h—as promising leads for further optimization as antibacterial agents targeting resistant Gram-positive pathogens.