Discovery of <i>bis</i>-chalcones and <i>bis</i>-pyrimidines as potential urease inhibitors: from synthesis to computational insights

This study focuses on the design and evaluation of <i>bis</i>-chalcones and <i>bis</i>-pyrimidines as potential urease inhibitors. A series of <i>bis</i>-chalcone and <i>bis</i>-pyrimidine derivatives were synthesized and assessed for their <i>in vitro</i> urease inhibitory activity. Kinetic studies were conducted using Lineweaver–Burk plots to determine the inhibition mechanism of the most potent compound. Molecular docking was employed to investigate the binding interactions with the urease active site, followed by MD simulations to validate complex stability. Computational ADMET analysis was performed to assess the drug-like properties of the most active inhibitor. Several synthesized compounds exhibited potent urease inhibitory activity, significantly surpassing the standard inhibitor thiourea. The most active compound, 8P, displayed noncompetitive inhibition, as confirmed by kinetic studies. SAR analysis revealed that electron-withdrawing substituents enhanced inhibitory potency. Molecular docking studies demonstrated favorable interactions between inhibitors and key urease residues, while MD simulations confirmed complex stability. ADMET analysis supported the drug-like potential of 8P. This study provides valuable insights into the development of target compounds as promising urease inhibitors. These findings suggest their potential therapeutic applications for urease-related disorders.