靶向乙酰胆碱酯酶的新型1,2-恶嗪类小分子的合成与表征
Synthesis and characterization of novel 1,2-oxazine-based small molecules that targets acetylcholinesterase.
作者信息
Sukhorukov Alexey Yu, Nirvanappa Anilkumar C, Swamy Jagadish, Ioffe Sema L, Nanjunda Swamy Shivananju, Rangappa Kanchugarakoppal S
机构信息
N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia.
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India.
出版信息
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3618-21. doi: 10.1016/j.bmcl.2014.05.040. Epub 2014 May 21.
Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC50 values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of -1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (logP=2.66), suggesting a potential ability to penetrate the blood-brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer's agents.
合成了13种基于2-恶嗪的小分子，靶向5-脂氧合酶（LOX）和乙酰胆碱酯酶（AChE）。测试表明，新合成的化合物在较低的微摩尔浓度下对5-LOX和AChE均具有强效抑制作用。在测试的化合物中，活性最高的化合物2-[(2-乙酰基-6,6-二甲基-4-苯基-5,6-二氢-2H-1,2-恶嗪-3-基)甲基]-1H-异吲哚-1,3(2H)-二酮（2a）对5-LOX和AChE均表现出抑制活性，其IC50值分别为1.88和2.5 μM。此外，计算机模拟分子对接研究表明，与同系列的其他化合物相比，化合物2a与AChE的催化结构域紧密结合，最高CDOCKER评分为-1.18 kcal/mol。此外，2a表现出良好的亲脂性（logP=2.66），表明其具有穿透血脑屏障的潜在能力。这些初步的药理学数据表明，化合物2a可作为开发抗阿尔茨海默病药物的种子。
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