Rational design and synthesis of sulfonamide-substituted coumarinyl-imidazolone hybrids against multidrug-resistant microbial strains: computational and biological evaluation studies.

AIM: The longstanding use of sulfonamides has contributed to the emergence of multidrug-resistant (MDR) pathogens, posing a major challenge to antimicrobial therapy worldwide. In response, a series of sulfonamide-linked coumarinyl-imidazolone derivatives (6a-t) were rationally designed and synthesized to identify potential antimicrobial candidates. MATERIALS AND METHODS: Structures were confirmed by spectroscopic techniques. In silico studies, including molecular docking, molecular dynamics (MD) simulations, and ADMET analysis, correlated with the observed biological activity. RESULTS: Compounds 6a (-11.97 kcal/mol) and 6m (-9.91 kcal/mol) demonstrated excellent binding toward C. albicans sterol 14α-demethylase (CYP51) and PBP2a of methicillin-resistant S. aureus (MRSA), respectively, while MD simulations support stable complexes. In vitro findings identified compounds 6a, 6m, and 6n as potent leads, exhibiting significant antimicrobial activity with minimum inhibitory concentration (MIC) values ranging from 15 to 500 µg/mL and antioxidant activity with DPPH IC50 values of 6.05 ± 0.57, 7.57 ± 0.36, and 6.35 ± 0.51 μM, respectively. Frontier Molecular Orbital (FMO) analysis further substantiated the reactivity and stability of the lead candidates, with compound 6n displaying the lowest energy gap (2.66 eV), indicating enhanced reactivity. CONCLUSIONS: Compounds 6a, 6m, and 6n exhibited potent antimicrobial and antioxidant activities, highlighting their promise as multifunctional antimicrobial scaffolds against MDR pathogens.