Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors

• Published in: Bioorganic & medicinal chemistry 2024-03, Vol.102, p.117656-117656, Article 117656
• Main Authors: Wang, Yi-Ning, Li, Su-Ya, Yuan, Liang-Chao, Bu, Shu-Fang, Zeng, Yao, Xiao, Zhu-Ping, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - pharmacology; Helicobacter pylori; Kinetic study; Mammals - metabolism; Molecular docking; Molecular Docking Simulation; Oxadiazolone; Stomach Ulcer; Triazolone; Urea; Urease; Urease inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2024.117656

[Display omitted] •A novel triazolone/oxadiazolone was determined as a urease inhibitor.•These inhibitors inhibit urease with a mixed competitive mechanism.•Triadimefon/oxadiazolone as a urea-like fragment specifically binds to urease.•The most active compound showed over 20-fold higher potency than the clinical used drug.•The hit compounds with high safety and favorable solubility are promising inhibitors for further developing. Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC50 value of 1.2 μM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.