Babaei Elaheh, Küçükkılınç Tuba Tüylü, Jalili-Baleh Leili, Nadri Hamid, Öz Esin, Forootanfar Hamid, Hosseinzadeh Elaheh, Akbari Tayebeh, Ardestani Mehdi Shafiee, Firoozpour Loghman, Foroumadi Alireza, Sharifzadeh Mohammad, Mirjalili Bi Bi Fatemeh, Khoobi Mehdi
Department of Chemistry, Faculty of Science, Yazd University, Yazd, Iran.
Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Front Chem. 2022 Jun 30;10:895483. doi: 10.3389/fchem.2022.895483. eCollection 2022.
In this research, a series of coumarin-based scaffolds linked to pyridine derivatives a flexible aliphatic linkage were synthesized and assessed as multifunctional anti-AD agents. All the compounds showed acceptable acetylcholinesterase (AChE) inhibition activity in the nanomolar range (IC = 2-144 nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC = 9-123 nM) compared to donepezil as the standard drug (IC = 14 and 275 nM, respectively). Compound as the best AChE inhibitor (IC = 2 nM) showed acceptable BuChE inhibition activity (IC = 24 nM), 100 times more active than the standard drug. Compound could also significantly protect PC12 and SH-SY5Y cells against HO-induced cell death and amyloid toxicity, respectively, superior to the standard drugs. It could interestingly reduce β-amyloid self and AChE-induced aggregation, more potent than the standard drug. All the results suggest that compound could be considered as a promising multi-target-directed ligand (MTDL) against AD.
在本研究中，合成了一系列通过柔性脂肪族连接基与吡啶衍生物相连的香豆素基支架，并将其评估为多功能抗阿尔茨海默病（AD）药物。与作为标准药物的多奈哌齐（分别为IC = 14和275 nM）相比，所有化合物在纳摩尔范围内均表现出可接受的乙酰胆碱酯酶（AChE）抑制活性（IC = 2 - 144 nM）和显著的丁酰胆碱酯酶（BuChE）抑制特性（IC = 9 - 123 nM）。化合物作为最佳的AChE抑制剂（IC = 2 nM）表现出可接受的BuChE抑制活性（IC = 24 nM），活性比标准药物高100倍。化合物还可以分别显著保护PC12和SH - SY5Y细胞免受HO诱导的细胞死亡和淀粉样毒性，优于标准药物。有趣的是，它可以减少β - 淀粉样蛋白自身和AChE诱导的聚集，比标准药物更有效。所有结果表明，化合物可被视为一种有前景的抗AD多靶点导向配体（MTDL）。
