Synthesis, Biological Properties, In Silico ADME, Molecular Docking Studies, and FMO Analysis of Chalcone Derivatives...

A series of chalcone derivatives were synthesized and characterized using UV-vis, FT-IR, ¹H NMR, and mass spectrometry, followed by the evaluation of their antimicrobial and antioxidant properties. In vitro screening against six bacterial strains (Staphylococcus aureus, Bacillus subtilis, Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginosa, and Citrobacter freundii) and two fungal strains (Aspergillus niger and Trichoderma harzianum) revealed outstanding antibacterial activities, particularly with compound 5b, 5d, and 5e against S. aureus, and compounds 5c and 5h against B. subtilis. Notably, compounds 5f and 5g exhibited significant effects against P. aeruginosa, while compound 5b showed the highest antifungal activity against T. harzianum. All compounds demonstrated remarkable antioxidant activities, with 5h (IC₅₀ values of 0.005 μM) and 5c (IC₅₀ values of 0.006 μM) being the most potent, comparable to ascorbic acid (IC₅₀ values of 0.007 μM). In silico evaluations confirmed favorable drug-likeness and pharmacokinetic properties for all analogues, adhering to both Lipinski's rule of Five and Veber's rule. Molecular docking studies of potent antibacterial compounds (5e and 5h) indicated strong binding affinities to the PBP-1b receptor in S. aureus, while DFT calculations provided valuable insights into their molecular reactivity and biological properties. Ligand-based enzymatic target predictions indicate that chalcone analogues (5a-m) show potential as inhibitors of oxidoreductases, kinases, enzymes, proteases, or ligands for family A GPCR. These findings position chalcone derivatives as promising candidates for therapeutic applications in combating bacterial infections and oxidative stress.