Design, synthesis and biological evaluation of novel coumarin- N -benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease
| Autor: | Xin-Yu Zhang, Yun Liu, Tong Zhang, Sai-Sai Xie, Jin-Shuai Lan, Yue Ding, Jian-Wei Hou, Ping Kang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Monoamine Oxidase Inhibitors Molecular model Aché Stereochemistry Pyridinium Compounds PC12 Cells 01 natural sciences Protein Aggregates Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Alzheimer Disease Coumarins Drug Discovery Animals Humans Moiety Molecule Monoamine Oxidase Pharmacology Amyloid beta-Peptides Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry Active site General Medicine Coumarin language.human_language Rats 0104 chemical sciences 030104 developmental biology chemistry Drug Design Toxicity Acetylcholinesterase language biology.protein Cholinesterase Inhibitors Pyridinium |
| Zdroj: | European Journal of Medicinal Chemistry. 139:48-59 |
| ISSN: | 0223-5234 |
| Popis: | Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aβ (1–42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 μM for eeAChE; 2.32 μM for eqBuChE; 1.57 μM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aβ (1–42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect