Robust therapeutic potential of carbazole-triazine hybrids as a new class of urease inhibitors: A distinctive combination of nitrogen-containing heterocycles
| Autor: | Aamer Saeed, Sobia Ahsan Halim, Aliya Ibrar, Ajmal Khan, Saifullah Mehsud, Madiha Kazmi, Ahmed Al-Harrasi, Imtiaz Khan |
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| Rok vydání: | 2019 |
| Předmět: |
Urease
Nitrogen Carbazoles Biochemistry chemistry.chemical_compound Structure-Activity Relationship Heterocyclic Compounds Drug Discovery Enzyme Inhibitors Molecular Biology Triazine chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure Carbazole Triazines Aryl Organic Chemistry Active site Combinatorial chemistry Canavalia Enzyme chemistry biology.protein Amine gas treating Pharmacophore |
| Zdroj: | Bioorganic chemistry. 95 |
| ISSN: | 1090-2120 |
| Popis: | The inhibition of urease enzyme is very important as it plays a key role in the treatment of several urinary and gastrointestinal tract infections. This enzyme provides a suitable environment for Helicobacter pylori at the low pH of the stomach, a causative agent of gastric and peptic ulcer that may lead to cancer. In agriculture, the high urease content causes environmental and economic problems. In this pursuit, given the well-established importance of integrated pharmacophores in medicinal chemistry and to explore new inhibitors of urease featuring two distinct heterocyclic functionalities, we herein report a facile synthesis of carbazole-triazine hybrids (3a-j). These new propeller-shaped chemical scaffolds were evaluated for their urease inhibitory potential in order to identify suitable leads. The initial structure-activity survey work guided through in vitro bioactivity results recognized 3e and 3f as new starting point hits incorporating bulky iodo (3e) and strong electron-withdrawing nitro (3f) groups at the para-position of aryl amine component. The potent compounds (3e & 3f) exhibited the highest activity with IC50 values of 5.6 and 6.7 µM, respectively. In the molecular docking analysis, these compounds depicted excellent binding interactions with the active site residues. The key interactions observed include hydrogen bonding, π–π interactions, π–cation and nickel atom coordination to the triazine nitrogen of both inhibitors. |
| Databáze: | OpenAIRE |
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