Arylamino containing hydroxamic acids as potent urease inhibitors for the treatment of Helicobacter pylori infection
| Autor: | Qi Liu, Wei-Wei Ni, Shen-Zhen Ren, Hai-Liang Zhu, Peng Cao, He Xiao-Su, Wei-Yi Li, Chen Hui-Min, Jing Yuan, Jia-Jia Liu, Liu Pei, Wei-Kang Shi, Zhu-Ping Xiao, Pu-Zhen Yang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Helicobacter pylori infection Urease Hydroxamic Acids 01 natural sciences Helicobacter Infections Microbiology Mice Structure-Activity Relationship 03 medical and health sciences Urease Inhibitors Drug Discovery medicine Animals Humans Stomach Ulcer Amination Pharmacology chemistry.chemical_classification Helicobacter pylori biology Safety studies 010405 organic chemistry Chemistry Organic Chemistry General Medicine biology.organism_classification Acute toxicity Anti-Bacterial Agents 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Enzyme Gastritis biology.protein Female medicine.symptom |
| Zdroj: | European Journal of Medicinal Chemistry. 156:126-136 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.06.065 |
| Popis: | A novel series of aniline-containing hydroxamic acids were designed, synthesized and evaluated as anti-virulence agents for the treatment of gastritis and gastric ulcer caused by Helicobacter pylori. In vitro enzyme-based screen together with in vivo assays and structure−activity relationship (SAR) studies led to the discovery of three potent urease inhibitors 3-(3,5-dichlorophenylamino) N-hydroxypropanamide (3a), 3-(2-chlorophenylamino) N-hydroxypropanamide (3d) and 3-(2,4-dichlorophenylamino) N-hydroxypropanamide (3n). Compounds 3a, 3d and 3n showed excellent urease inhibition with IC50 values 0.043 ± 0.005, 0.055 ± 0.008 and 0.018 ± 0.002 μM, and significantly depressed gastritis developing at the dose of 32 mg/kg b. i.d with eradication rates of H. pylori reaching 92.3, 84.6 and 100%, respectively. Preliminary safety studies (acute toxicity in mice) disclosed that 3a, 3d and 3n was well-tolerated in KM mice with LD50s of 2982.8, 3349.4 and 3126.9 mg/kg, respectively. Collectively, the data obtained in this study indicate that 3a, 3d and 3n, in particular 3n, could considered as promising candidates for the potential treatment of H. pylori caused gastritis and gastric ulcer, and hence merit further studies. |
| Databáze: | OpenAIRE |
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