Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
Department of Chemistry, Britannia House, King's College London, SE1 1DB, London, UK.
Chem Biodivers. 2022 Dec;19(12):e202200315. doi: 10.1002/cbdv.202200315. Epub 2022 Nov 14.
Series of synthetic coumarin derivatives (1-16) were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes linked to the pathology of Alzheimer's disease (AD). Compound 16 was the most active AChE inhibitor with IC 32.23±2.91 μM, while the reference (galantamine) had IC =1.85±0.12 μM. Compounds 9 (IC 75.14±1.82 μM), 13 (IC =16.14±0.43 μM), were determined to be stronger BChE inhibitors than the reference galantamine (IC =93.53±2.23 μM). The IC value of compound 16 for BChE inhibition (IC =126.56±11.96 μM) was slightly higher than galantamine. The atomic interactions between the ligands and the key amino acids inside the binding cavities were simulated to determine their ligand-binding positions and free energies. The three inhibitory coumarins (9, 13, 16) were next tested for their effects on the genes associated with AD using human neuroblastoma (SH-SY5Y) cell lines. Our data indicate that they could be considered for further evaluation as new anti-Alzheimer drug candidates.
一系列合成香豆素衍生物（1-16）被测试对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制作用，这两种酶与阿尔茨海默病（AD）的病理学有关。化合物 16 是最活跃的 AChE 抑制剂，IC 32.23±2.91 μM，而参考物（加兰他敏）的 IC =1.85±0.12 μM。化合物 9（IC 75.14±1.82 μM）、13（IC =16.14±0.43 μM）被确定为比参考物加兰他敏（IC =93.53±2.23 μM）更强的 BChE 抑制剂。化合物 16 对 BChE 抑制的 IC 值（IC =126.56±11.96 μM）略高于加兰他敏。模拟配体与结合腔内部关键氨基酸之间的原子相互作用，以确定它们的配体结合位置和自由能。接下来，用人类神经母细胞瘤（SH-SY5Y）细胞系测试了三种抑制香豆素（9、13、16）对与 AD 相关的基因的影响。我们的数据表明，它们可以被考虑作为新的抗阿尔茨海默病药物候选物进一步评估。
