Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.
Bioorg Chem. 2021 May;110:104792. doi: 10.1016/j.bioorg.2021.104792. Epub 2021 Mar 6.
Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b, IC= 0.451μM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC= 0.625μM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC= 0.466μM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC= 0.500μM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC= 0.590μM) exhibited promising AChE inhibitory activity even better than donepezil (IC= 0.711μM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and other physicochemical parameters. A correlation between the docking results and IC of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil.
二十种新型 7-苄氧基香豆素类化合物被合成，它们具有多种生物活性化学片段。合成的化合物表现出显著的乙酰胆碱酯酶（AChE）抑制活性。体外试验表明，化合物 7-苄氧基-4-[(4-苯基噻唑-2(3H)-亚基)腙基甲基]-2H-色烯-2-酮（5b，IC=0.451μM）、7-苄氧基-4-({[4-(4-甲氧基苯基)噻唑-2(3H)-亚基]腙基甲基}-2H-色烯-2-酮（5d，IC=0.625μM）、5-氨基-1-[2-(7-苄氧基-2-氧代-2H-色烯-4-基)乙酰基]-1H-吡唑-4-甲腈（13c，IC=0.466μM）、2-(7-苄氧基-2-氧代-2H-色烯-4-基)-N-(2-亚氨基-4-苯基噻唑-3(2H)-基)乙酰胺（16a，IC=0.500μM）和 2-(7-苄氧基-2-氧代-2H-色烯-4-基)-N-[4-(4-甲氧基苯基)-2-亚氨基噻唑-3(2H)-基]乙酰胺（16b，IC=0.590μM）表现出有前景的 AChE 抑制活性，甚至优于多奈哌齐（IC=0.711μM）。化合物 5b 的动力学研究表明，它是一种混合抑制剂，能够结合乙酰胆碱酯酶（AChE）酶的外周阴离子结合位点（PAS）和催化活性位点（CAS）。此外，在体内试验中，化合物 5b、13c 和 16a 在东莨菪碱诱导的损伤模型中对测试小鼠的记忆改善得到了证实。此外，对合成的化合物进行了计算化学研究，包括在重组人乙酰胆碱酯酶酶（rhAChE）的活性部位进行分子对接研究，以及对 ADMET 和其他物理化学参数的预测。通常观察到对接结果与测试化合物 IC 之间的相关性，并与共晶配体多奈哌齐具有相似的结合模式。
