2. Academic Validation
  3. Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors

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

  • Bioorg Med Chem. 2024 Mar 15:102:117656. doi: 10.1016/j.bmc.2024.117656.
Yi-Ning Wang 1,  Su-Ya Li 1,  Liang-Chao Yuan 2,  Shu-Fang Bu 1,  Yao Zeng 1,  Zhu-Ping Xiao 3,  Hai-Liang Zhu 4
Affiliations

Affiliations

  • 1 Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
  • 3 Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xiaozhuping2005@163.com.
  • 4 Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.
PMID: 38422567 DOI: 10.1016/j.bmc.2024.117656
Abstract

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.

Keywords

Kinetic study; Molecular docking; Oxadiazolone; Triazolone; Urease inhibitor.

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