Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ± 0.28 µM - 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.

中文翻译：

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对某些天然和半合成的O-烷基香豆素衍生物进行分子建模和胆碱酯酶抑制的组合研究。

合成或天然来源的香豆素是发挥多种药理活性的重要化学类别。在本研究中，合成了26种新颖的O-烷基香豆素衍生物，并已在100 µM的条件下测试了它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）靶标的体外抑制潜力，而乙酰胆碱酯酶（BChE）靶标是在阿尔茨海默氏病发病机理中发挥关键作用。在测试的香豆素中，没有一种能够抑制AChE，而与参考文献（加兰他敏，IC50 = 46.58±0.91 µM）相比，它们中的12种对BChE表现出显着的选择性抑制作用。实际上，有10种活性香豆素具有比加兰他敏更高的抑制作用（IC50 = 7.01±0.28 µM-43.31±3.63 µM）。发现最活跃的是7-苯乙烯基香豆素（IC50 = 7.01±0。28 µM）和7-异戊烯氧基-4-甲基香豆素（IC50 = 8.18±0.74 µM）。除体外测试外，MetaCore / MetaDrug二元QSAR模型和对接模拟还用于通过基于配体和靶标驱动的方法评估活性化合物。该化合物的预测药代动力学特征表明，该化合物具有亲脂性并渗透血脑屏障（BBB），而ADME模型则预测该化合物具有更高的人血清蛋白结合率（> 50％）。计算的对接分数表明，显示出显着的BChE抑制作用的香豆素在与靶标的配体结合域相互作用时具有良好的自由结合能。因此，我们的研究结果表明，O-烷基香豆素是胆碱酯酶的有希望的选择性抑制剂，在我们的案例中，尤其是BChE，