Coumarin Derivatives as Potent Urease Inhibitors: In Vitro Evaluation, and Molecular Docking Studies

ABSTRACT Urease, an enzyme responsible for the hydrolysis of urea, plays a significant role in agriculture, medicine, and microbial pathogenesis, including Helicobacter pylori and Proteus‐related infections. This study focuses on the evaluation of coumarin‐based N ‐arylacetamides as potential urease inhibitors. Synthetic derivatives of coumarin were prepared and the resulting compounds ( 5a‐n ) were analyzed using spectroscopic techniques. The biological evaluation of these compounds revealed that they exhibited varying degrees of urease inhibition, with IC 50 values ranging from 0.92 to 11.9 µM. Compound 5c , with an IC 50 of 0.92 ± 0.07 µM, was identified as the most potent inhibitor, better than the standard urease inhibitor thiourea (IC 50 = 23.00 ± 0.03 µM). Structure‐activity relationship (SAR) analysis indicated that the potency of these compounds was influenced by the presence and position of electron‐withdrawing or donating groups on the N ‐phenylacetamide rings. Mechanistic studies using the Lineweaver‐Burk plot suggested that compound 5c acts as a mixed‐type inhibitor and molecular docking analysis further confirmed strong binding interactions between 5c and the urease enzyme, supported by hydrogen bonds, π‐cation interactions, and van der Waals forces. The ADME analysis indicated favorable drug‐like properties for compound 5c , including good oral bioavailability, permeability, and compliance with Lipinski's Rule of Five. However, its coumarin moiety flagged a potential toxicity concern. These findings highlight the promise of coumarin derivatives as urease inhibitors and provide a strong foundation for further research into their clinical applications.