Design, synthesis, and biological evaluation of novel imidazole–morpholinone hybrids as broad-spectrum antimicrobial agents: molecular docking, DFT, and ADMET studies

Abstract

A novel series of five imidazole–morpholinone hybrid compounds (10a–e) was designed, synthesised, and evaluated as broad-spectrum antimicrobial agents. The target molecules integrate a 5-formyl-1-butylimidazole core, a (3-oxomorpholin-4-yl)phenyl pharmacophore, and variable C5-aryl groups introduced via late-stage Suzuki–Miyaura cross-coupling, assembled through a concise five-step convergent route. All compounds were characterised by ¹H/¹³C NMR, IR, and HR-ESI-MS. In vitro antimicrobial evaluation against four bacterial (S. aureus, S. pyogenes, E. coli, P. aeruginosa) and two fungal (C. albicans, A. niger) strains revealed compound 10c as the most potent analogue, matching chloramphenicol (MIC 7.81 µg mL⁻¹) and griseofulvin (MIC 15.62 µg mL⁻¹) reference standards. Molecular docking against S. aureus DNA gyrase (2XCT) and E. coli GyrB24 (7P2M), corroborated by DFT analysis (B3LYP/6-311++G(d,p)) and ADMET profiling, confirmed DNA gyrase inhibition as the primary mechanism and established 10c as a promising drug-like lead for further development.