In silico DFT, ADMET and molecular docking studies of novel coumarin-linked pyrazole and quinoline derivatives as...

Ten novel coumarin-based hybrids comprising coumarin-pyrazole (7a-e) and coumarin-quinoline (11a-e) derivatives were synthesized via multistep reactions and characterized spectroscopically. Solvent optimization identified DMF: Ethanol (1:1) with H₂SO₄ as optimal conditions, achieving 88% yield in 2-3 h. Antimicrobial evaluation against four bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii) and one fungal strain (Aspergillus niger) revealed compound 7a as the most potent (MIC: 25 μg/mL), superior to standard drugs. Antioxidant screening showed that 7a exhibited excellent activity (IC₅₀: 20.23 ± 0.29 mg/mL), comparable to that of ascorbic acid. Molecular docking against three target proteins (4WMZ, 5FNR, 4LOL) demonstrated strong binding affinity, with 7b showing the highest docking score (- 9.71186 kcal/mol) against 4WMZ. Notably, compound 7b showed the highest predicted binding affinity in silico, whereas compound 7a demonstrated the superior experimental antimicrobial activity; this discrepancy underscores that docking scores offer predictive, not confirmatory, evidence of biological potency. DFT calculations (B3LYP/6-311++ G(d,p)) elucidated electronic properties, including HOMO-LUMO gap (3.8640 eV), Mulliken charge distribution, RDG, ELF, LOL, thermodynamic parameters, and global reactivity descriptors. In silico ADMET profiling revealed favorable physicochemical and drug-like properties for most derivatives; however, uniformly high predicted genotoxicity scores (> 0.99) and moderate hERG cardiotoxicity liability were identified, highlighting the need for rigorous experimental safety validation prior to further development. This integrated approach establishes coumarin-pyrazole and coumarin-quinoline hybrids as promising multifunctional therapeutic agents with antimicrobial and antioxidant potential.