Several studies underscore that the 5-hydroxytryptamine subtype 6 (5-HT6) receptor is intrinsically related to the onset of Alzheimer’s disease and its blocking significantly improve the learning and memory processes. In this manuscript, we apply quantitative structure-activity relationship (QSAR) techniques to a series of potential arylsulfonamide-derived 5-HT6 receptor antagonists aiming to design new anti-AD ligands. In order to describe physicochemical properties of the compounds, a plethora of descriptor types was calculated, and then selected by statistical techniques to build models that relate the chemical structure to antagonist activity of these studied ligands. Thereafter, structural variations were performed on the C15, C25, and C47 compounds by analyzing the steric and electrostatic fields as well as 2D maps. At last, the new compounds were submitted to the constructed QSAR models which presented promising results. It is noteworthy that the C4704 compound exhibited the highest biological activity value, surpassing even the values of the compounds used in the construction of the model. In conclusion, the robustness of the model allowed to confidently predict the biological activity values of the designed compounds. Graphical abstract Graphical abstract

中文翻译：

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新型 5-HT6 拮抗剂的药物设计：芳基磺酰胺衍生物的 QSAR 研究

几项研究强调，5-羟色胺 6 亚型 (5-HT6) 受体与阿尔茨海默病的发病有着内在的关系，其阻断可显着改善学习和记忆过程。在这份手稿中，我们将定量构效关系 (QSAR) 技术应用于一系列潜在的芳基磺酰胺衍生的 5-HT6 受体拮抗剂，旨在设计新的抗 AD 配体。为了描述化合物的物理化学性质，计算了大量的描述符类型，然后通过统计技术进行选择，以建立将化学结构与这些研究配体的拮抗剂活性相关联的模型。此后，通过分析空间和静电场以及二维图，对 C15、C25 和 C47 化合物进行了结构变化。最后，将新化合物提交给构建的 QSAR 模型，该模型呈现出有希望的结果。值得注意的是，C4704 化合物表现出最高的生物活性值，甚至超过了用于构建模型的化合物的值。总之，模型的稳健性允许自信地预测设计化合物的生物活性值。图形摘要图形摘要