Cyclopentyl-linked N-Acylthioureas as Promising Urease Inhibitors: Insights from in vitro Bioassay, Structure-activity Relationships and Computational Analysis

Helicobacter pylori is a Gram-negative bacteria responsible for gastrointestinal disorders, including chronic gastritis and potentially life-threatening conditions like gastric cancer. To manage these adverse outcomes, inhibiting the urease enzyme emerges as a promising strategy. A concise set of cyclopentyl-bearing N-acylthioureas 4a-j was synthesized, characterized and assessed for their ability to inhibit urease enzyme. All the tested compounds exhibited urease inhibitory activities, displaying superior enzyme inhibition when compared to the standard, thiourea (IC50 values 23.00 ± 0.03 μM). 4a and 4b exhibited the highest inhibitory efficacy with IC50 values of 2.21 ± 0.62 and 3.92 ± 0.59 μM, respectively. Both compounds demonstrated ≈10- and ≈6-folds superior inhibition than standard inhibitor, respectively. Moreover, molecular docking investigations revealed crucial interactions between potent ligands and active site residues. Molecular dynamics simulations and ADME properties revealed ligand-protein stability and druglikeness behavior of potent leads paving the way for treatment for gastritis.