Design, Synthesis and Evaluation of Aryl-Tailored Oxadiazole-Thiones as New Urease Inhibitors

Abstract

The ubiquitous chronic gastric infections that cause major human health disorders like gastritis and ulcers can be treated using drugs targeting the Helicobacter pylori (H. pylori) urease. Targeted eradication therapy is essential given the growing ineffectiveness of current treatment regimens due to broad-spectrum antibiotic resistance, significant side effects, and low compliance. Therefore, we here report the development of a new series of 1,3,4-oxadiazole-2-thiones with various aryl tail groups (compounds 20-27) as effective urease inhibitors. The most promising analog 5-[(4-methoxyphenoxy)methyl]-2,3-dihydro-1,3,4-oxadiazole-2-thione (21) inhibited the urease activity with an IC50 value of 26.6 mu M. In addition, kinetic studies revealed the competitive inhibition pattern for 21 with a K-i value of 8.72 mu M indicating the potent and specific binding interactions with the urease active site. Molecular docking analysis of 21 inside the active pocket of the urease highlighted several important interactions with amino acid residues such as H492, H519 and R439, which pave the way for further development of improved urease inhibitors with potential application as anti-infective agents.