新型双胆碱酯酶抑制剂的设计和合成：分子对接支持的体外抑制研究,Chemistry & Biodiversity

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新型双胆碱酯酶抑制剂的设计和合成：分子对接支持的体外抑制研究
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-04-26 , DOI: 10.1002/cbdv.202200015
Mehmet Koca ₁ , Uğur Güller ₂ , Pınar Güller ₃ , Ziya Dağalan ₃ , Bilal Nişancı ₃

Affiliation

根据胆碱能假说，主要的胆碱酯酶、乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 在阿尔茨海默病 (AD) 的治疗中很重要。因此，近年来，双重胆碱酯酶抑制方法的研究已成为科学家们的重点。在这项研究中，合成了新型 N-(4-chlorobenzyl)-3,4-dimethoxy-N-(m-取代) 苯甲酰胺衍生物。然后，这些衍生物的抑制特性在体外在人 AChE 和 BuChE 中进行了检查，并通过分子对接研究确定了可能的相互作用。所有苯甲酰胺衍生物都表现出双重抑制特性和高 BBB 渗透性。发现对 AChE 和 BuChE最有效的抑制剂是N7 ，IC_{为 50}值分别为 1.57 和 2.85 μM。此外，就结合能而言，最有效的抑制剂被预测为N7 ，分别为 -12.18 kcal/mol 和 -9.92 kcal/mol。这些结果的原因是溴 ( N7 ) 是其他取代基团中体积最大的分子。这些衍生物可用于开发新的药物，通过充当 AChE 和 BChE 的双重抑制剂来治疗 AD 等中枢神经系统相关疾病。

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Design and Synthesis of Novel Dual Cholinesterase Inhibitors: In Vitro Inhibition Studies Supported with Molecular Docking

The major cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are important in the therapy of Alzheimer's disease (AD) based on the cholinergic hypothesis. As a result, in recent years, the investigation of dual cholinesterase inhibition methods has become important among scientists. In this study, novel N-(4-chlorobenzyl)-3,4-dimethoxy-N-(m-substituted)benzamide derivatives were synthesized. Then, inhibitory properties of these derivatives were examined in human AChE and BuChE in vitro and possible interactions were determined by molecular docking studies. All benzamide derivatives were exhibited dual inhibitory character and high BBB permeability. The most effective inhibitor was found as N7 for both AChE and BuChE with IC₅₀ values of 1.57 and 2.85 μM, respectively. Besides the most potent inhibitor was predicted as N7 in terms of binding energies with −12.18 kcal/mol and −9.92 kcal/mol, respectively. The reason for these results is that bromine (N7) is the bulkiest molecule among the other substituted groups. These derivatives could be exploited to develop new medications for the treatment of central nervous system-related diseases as AD by acting as dual inhibitors of AChE and BChE.

更新日期：2022-04-26

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