Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors
| Autor: | Zhu-Ping Xiao, Wan-Qing Song, Su-Ya Li, Hai-Lian Fang, Mei-Ling Liu, Hui Ouyang, Wei-Yi Li, Hai-Liang Zhu, Ya-Xi Ye |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Urease
Antineoplastic Agents Mixed inhibition Microbial Sensitivity Tests Biochemistry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Acetamides Drug Discovery medicine Humans Potency Sulfhydryl Compounds Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics IC50 Cell Proliferation Pharmacology Dose-Response Relationship Drug Helicobacter pylori Molecular Structure biology Acetohydroxamic acid Organic Chemistry In vitro Anti-Bacterial Agents chemistry biology.protein Molecular Medicine Drug Screening Assays Antitumor Acetamide Cysteine medicine.drug |
| Zdroj: | ChemMedChem. 17 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | Thirty-eight disulfides containing N-arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell-free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 µM. Of note, 2,2'-dithiobis(N-(2-fluorophenyl)acetamide) (d7), 2,2'-dithiobis(N-(3,5-difluorophenyl)acetamide) (d24), and 2,2'-dithiobis(N-(3-fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 µM, showing 32- to 355-fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti-Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections. |
| Databáze: | OpenAIRE |
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