Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
| Autor: | Lihong Yu, Wei-xiong Liu, Wei Yi, Hong Ji, Xuehua Zheng, Wenhao Wu, Lang-di Chen, Peiquan Zhang, Chao Zhang, Guolin Luo, Guoquan Xie, Xintong Liang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
self-induced Aβ aggregation Aché Pharmaceutical Science Pharmacology Inhibitory postsynaptic potential Protein Aggregation Pathological Antioxidants Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship lcsh:Organic chemistry Alzheimer Disease Catalytic Domain Drug Discovery Humans Physical and Theoretical Chemistry Cytotoxicity IC50 ligustrazine Amyloid beta-Peptides Binding Sites biology Drug discovery Chemistry Organic Chemistry Active site acetylcholinesterase Acetylcholinesterase language.human_language multi-targeted inhibitors Molecular Docking Simulation Kinetics 030104 developmental biology Chemistry (miscellaneous) Drug Design Pyrazines biology.protein language Molecular Medicine Cholinesterase Inhibitors Selectivity Alzheimer’s disease |
| Zdroj: | Molecules Volume 23 Issue 10 Molecules, Vol 23, Iss 10, p 2540 (2018) Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules23102540 |
| Popis: | A series of novel ligustrazine derivatives 8a&ndash r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer&rsquo s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106 for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against A&beta aggregation, with IC50 values of 17.36 µ M and 49.14 µ M, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 &mu M. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. |
| Databáze: | OpenAIRE |
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