Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease

被引：23

作者：

Abdpour, Shahin ^{[1
]}

Jalili-Baleh, Leili ^{[2
]}

Nadri, Hamid ^{[3
]}

Forootanfar, Hamid ^{[4
]}

Bukhari, Syed Nasir Abbas ^{[5
]}

Ramazani, Ali ^{[1
]}

Ebrahimi, Seyed Esmaeil Sadat ^{[6
]}

Foroumadi, Alireza ^{[6
]}

Khoobi, Mehdi ^{[6
,7
]}

机构：

[1] Univ Zanjan, Dept Chem, Zanjan, Iran

[2] Univ Tehran Med Sci, Inst Pharmaceut Sci TIPS, Tehran 1417614411, Iran

[3] Shahid Sadoughi Univ Med Sci, Fac Pharm & Pharmaceut Sci Res Ctr, Yazd, Iran

[4] Kerman Univ Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol, Kerman, Iran

[5] Jouf Univ, Coll Pharm, Dept Pharmaceut Chem, Aljouf 2014, Sakaka, Saudi Arabia

[6] Univ Tehran Med Sci, Fac Pharm, Dept Med Chem, Tehran 14176, Iran

[7] Univ Tehran Med Sci, Pharmaceut Sci Res Ctr, Inst Pharmaceut Sci TIPS, Biomat Grp, Tehran 1417614411, Iran

来源：

BIOORGANIC CHEMISTRY | 2021年 / 110卷

关键词：

Alzheimer?s disease; Cholinesterase inhibitors; Neuroprotective activity; Anti-amyloid aggregation; Chromone; Pyridinium salts; AMYLOID-BETA; OXIDATIVE STRESS; FIBRIL FORMATION; ACETYLCHOLINESTERASE INHIBITORS; HYDROGEN-PEROXIDE; BUTYRYLCHOLINESTERASE; DESIGN; AGGREGATION; ANTIOXIDANT; DISCOVERY;

D O I：

10.1016/j.bioorg.2021.104750

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer?s disease (AD). Most of the compounds were good AChE inhibitors (IC50 = 9.8?0.71 ?M) and showed remarkable BuChE inhibition activity (IC50 = 1.9?0.006 ?M) compared with donepezil as the standard drug (IC50 = 0.023 and 3.4 ?M). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50 = 0.71 ?M) and BuChE (IC50 = 0.006 ?M), respectively. The ligand?protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on H2O2- and A?-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced A? aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.

引用

页数：12

共 66 条

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