ABSTRACT Xanthones from natural and synthetic origins have shown interesting diverse pharmacological activities. This study aims to assess the in silico and in vitro activities of new synthetic xanthones as inhibitors of acetylcholinesterase enzyme (AChE). A series of eight new xanthones were designed and synthesised, using an in house strategy, from a readily available starting material. Their inhibitory activities against AChE were assessed in vitro and presented as IC50 values. The binding mode of these compounds inside AChE was investigated using Auto-Dock 4.2.2. Additionally, molecular dynamics simulation was performed, using GROMACS 5.0.2, to explore the dynamics of the inhibitory mechanism and stability of xanthone 5a within the active site of AChE enzyme. All xanthones showed promising activities when tested in vitro and in silico with xanthone 5a being the most potent in terms of both binding energy (−12.32 kcal/mol) and IC50 (0.20 ± 0.04 µM). Molecular dynamics simulation revealed several interesting features responsible for the potency of xanthone 5a as an AChE inhibitor. Furthermore, the calculated Log P of xanthone (5a) was found to be 6.56 suggesting it to be a potential drug candidate for the management of AChE associated diseases such as Alzheimer’s disease and myasthenia gravis.

中文翻译：

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深入了解氧杂蒽酮抑制乙酰胆碱酯酶的分子基础：计算机和体外方法的整合

摘要来自天然和合成来源的氧杂蒽酮已显示出有趣的多种药理活性。本研究旨在评估新型合成氧杂蒽酮作为乙酰胆碱酯酶 (AChE) 抑制剂的计算机模拟和体外活性。使用内部策略，从现成的起始材料中设计和合成了一系列八种新的氧杂蒽酮。它们对 AChE 的抑制活性在体外评估并表示为 IC50 值。使用 Auto-Dock 4.2.2 研究了这些化合物在 AChE 内的结合模式。此外，使用 GROMACS 5.0.2 进行分子动力学模拟，以探索抑制机制的动力学和呫吨酮 5a 在 AChE 酶活性位点内的稳定性。所有呫吨酮在体外和计算机测试中都显示出有希望的活性，在结合能 (-12.32 kcal/mol) 和 IC50 (0.20 ± 0.04 µM) 方面，呫吨酮 5a 是最有效的。分子动力学模拟揭示了几个有趣的特征，这些特征决定了氧杂蒽酮 5a 作为 AChE 抑制剂的效力。此外，计算出的氧杂蒽酮 (5a) 的 Log P 为 6.56，表明它是治疗 AChE 相关疾病（如阿尔茨海默病和重症肌无力）的潜在候选药物。