Synthesis, Molecular Docking, and ADMET Evaluation of Novel Quinazolinone-Coumarin Hybrid Derivatives as Dual Inhibitors of Urease and Acetylcholinesterase

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Objective: In this study, new amide-bridged quinazolinone and coumarin hybrid compounds were synthesized. The characterization of these compounds was carried out using spectral data such as FT-IR, ¹H NMR, ¹³C NMR, and elemental analysis. Enzyme inhibition properties of the compounds were investigated against both urease and acetylcholinesterase enzymes. Methods: Compounds 2a–2g were dissolved in benzene, and coumarin derivatives were added. The reaction mixture was heated under reflux for the synthesis of compounds 4a–4n. Enzyme inhibition studies were carried out using the Weatherburn method for urease and the Ellman method for acetylcholinesterase. The structures were further elucidated through molecular docking studies. Results and Discussion: While all synthesized compounds exhibited acetylcholinesterase inhibition, urease inhibition was observed only in some of the compounds. Molecular docking studies were performed to evaluate the binding affinities of the compounds against AChE and urease enzymes. The docking results were evaluated based on the scoring function of AutoDock Vina. The reported values represent relative binding affinity scores rather than absolute binding free energies. All tested compounds exhibited favorable binding affinities toward both enzymes, with compound 4a showing a significant docking score against AChE (11.4) and compound 4d against urease (11.0). Interaction analyses revealed that these ligands maintain high conformational fit and stability through hydrogen bonds and various π-interactions, suggesting the potential of specific derivatives as potent dual inhibitors. ADMET predictions showed that most compounds exhibited good gastrointestinal absorption, low blood-brain barrier permeability (which is desirable for peripheral targets), and an acceptable toxicity profile. Conclusions: In particular, compound N-(4-oxo-2-(3-bromobenzyl)-6-methyl-2-oxo-quinazolin-3(4H)-yl)-2H-chromene-3-carboxamide (4d) showed an IC50 value of 11.50 ± 0.15 µg/mL for urease inhibition, whereas this value was 14.50 ± 0.10 µg/mL for acetylcholinesterase. These findings demonstrate that this compound exhibits inhibitory activity against both enzymes.