Acetylcholinesterase Inhibition (Potential Anti‐Alzheimer Effects) by Aminobenzoic Acid Derivatives: Synthesis, in Vitro and in Silico Evaluation,ChemistrySelect

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Acetylcholinesterase Inhibition (Potential Anti‐Alzheimer Effects) by Aminobenzoic Acid Derivatives: Synthesis, in Vitro and in Silico Evaluation
ChemistrySelect ( IF 1.9 ) Pub Date : 2020-11-27 , DOI: 10.1002/slct.202003471
José A. Altamirano‐Espino ₁ , Luis A. Sánchez‐Labastida ₁ , Marlet Martínez‐Archundia ₂ , Erik Andrade‐Jorge _{1,

3} , José G. Trujillo‐Ferrara ₁

Affiliation

Alzheimer's disease is a neurodegenerative condition that decreases cognitive function. Thus, intense research efforts have focused on developing acetylcholinesterase (AChE) inhibitors with less side effects. The aim of this study was to synthesize aminobenzoic acid derivatives and test their AChE inhibitory capacity in silico and in vitro. Ten electron‐poor aminobenzoic acid derivatives were synthesized in good‐high yields. Their interaction with EeAChE, according to docking simulations, is mainly mediated by the aromatic ring of the ligands and the catalytic triad of the receptor (π‐π interactions). The in vitro evaluation revealed mixed inhibition (mostly competitive) in all cases. The structural analysis showed better Ki values for heterocyclic than linear compounds and with the presence of two carboxylic groups attached. 5‐Aminoisophthalic acid (AIPA_3, K_I=73 μM) showed the lowest K_I of all compounds. The electron‐poor aromatic ring of the test compounds is recognized by the electron‐rich peripheric and catalytic binding sites of AChE. AIPA_3, with the best properties, is a promising lead compound for developing new AChE inhibitors.

中文翻译：

氨基苯甲酸衍生物对乙酰胆碱酯酶的抑制作用（潜在的抗阿尔茨海默氏效应）：合成，体外和计算机评估

阿尔茨海默氏病是一种神经退行性疾病，会降低认知功能。因此，大量的研究工作集中在开发副作用较小的乙酰胆碱酯酶（AChE）抑制剂上。这项研究的目的是合成氨基苯甲酸衍生物，并在计算机和体外测试其对AChE的抑制能力。以高高收率合成了十种贫电子氨基苯甲酸衍生物。根据对接模拟，它们与EeAChE的相互作用主要由配体的芳环和受体的催化三联体介导（π-π相互作用）。在体外评估显示在所有情况下混合抑制（主要是竞争性）。结构分析表明，杂环化合物的Ki值比线性化合物好，并且存在两个羧基。5-氨基间苯二甲酸（AIPA_3，K _I = 73μM ）显示所有化合物中最低的K _I.AChE的富电子外围和催化结合位点可识别测试化合物的贫电子芳环。具有最佳性能的AIPA_3是开发新型AChE抑制剂的有前途的先导化合物。

更新日期：2020-11-27

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