Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study
Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study
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DOI：
10.3390/ijms20071524
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发表时间：
2019-03-27
影响因子：
5.6
通讯作者：
Jampilek, Josef
中科院分区：
文献类型：
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作者：
Bak, Andrzej;Kozik, Violetta;Jampilek, Josef
设计、合成了一系列新型苯衍生物，并对其进行了全面表征。评价所有测试化合物在体外潜在抑制乙酰胆碱酯酶和丁酰胆碱酯酶的能力。还测定了单个分子对胆碱酯酶的选择性指数。一般来说，对丁酰-乙酰胆碱酯酶相比，抑制效力更强，然而，一些化合物显示出有希望的抑制两种酶。事实上，两种化合物（23，苄基乙基（1-氧代-1-苯基丙-2-基）氨基甲酸酯和28，苄基（1-（3-氯苯基）-1-氧代丙-2-基）（甲基）氨基甲酸酯）具有非常高的选择性指数，而第二种化合物（28）达到最低抑制浓度IC 50值，其与加兰他敏相当一致。此外，进行了比较性受体非依赖性和受体依赖性结构-活性研究，以解释所观察到的抑制所研究的氨基甲酸酯系列潜力的变化。基于配体的研究的主要目的是比较分析分子表面，以深入了解控制抑制酶活性的能力的电子和/或空间因素。潜在的重要的空间和静电因素的空间分布，确定使用概率引导的药效团映射程序，这是基于迭代变量消除法。此外，所有的活性化合物的主机-目标相互作用的平面和空间地图创建，并使用对接方法与药物分子进行比较。
A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure-activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host-target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.