PDF(Pubmed)
Abstract：
The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest for new neurotropic drugs among derivatives of these heterocycles with pharmacophore groups remains a significant research challenge. The aim of this research work was to develop a synthesis method for new heterocyclic compounds, evaluate their neurotropic and neuroprotective activities, study histological changes, and perform docking analysis. Classical organic synthesis methods were used in the creation of novel heterocyclic systems containing pharmacophore rings. To evaluate the neurotropic activity of these synthesized compounds, a range of biological assays were employed. Docking analysis was conducted using various software packages and methodologies. The neuroprotective activity of compound 13 was tested in seizures with and without pentylenetetrazole (PTZ) administration. Histopathological examinations were performed in different experimental groups in the hippocampus and the entorhinal cortex. As a result of chemical reactions, 16 new, tetra- and pentacyclic heterocyclic compounds were obtained. The biologically studied compounds exhibited protection against PTZ seizures as well as some psychotropic effects. The biological assays evidenced that 13 of the 16 studied compounds showed a high anticonvulsant activity by antagonism with PTZ. The toxicity of the compounds was low. According to the results of the study of psychotropic activity, it was found that the selected compounds have a sedative effect, except compound 13, which exhibited activating behavior and antianxiety effects (especially compound 13). The studied compounds exhibited antidepressant effects, especially compound 13, which is similar to diazepam. Histopathological examination showed that compound 13 produced moderate changes in the brain and exhibited neuroprotective effects in the entorhinal cortex against PTZ-induced damage, reducing gliosis and neuronal loss. Docking studies revealed that out of 16 compounds, 3 compounds bound to the γ-aminobutyric acid type A (GABAA) receptor. Thus, the selected compounds demonstrated anticonvulsant, sedative, and activating behavior, and at the same time exhibited antianxiety and antidepressant effects. Compound 13 bound to the GABAA receptor and exhibited antianxiety, antidepressant, and neuroprotective effects in the entorhinal cortex against PTZ-induced changes.
摘要：
杂环化合物及其稠合类似物的探索，以吡啶等关键药效团片段为特征，噻吩,嘧啶,和三嗪环，是药物化学的关键.这些化合物具有广泛的生物活性，使它们成为一个有趣的研究领域。在这些具有药效基团的杂环的衍生物中寻求新的神经营养药物仍然是一个重大的研究挑战。这项研究工作的目的是开发一种新的杂环化合物的合成方法，评估他们的神经营养和神经保护活动，研究组织学变化，并进行对接分析。经典的有机合成方法用于创建包含药效团环的新型杂环系统。为了评估这些合成化合物的神经活性，采用了一系列生物测定法。使用各种软件包和方法进行对接分析。在给予和不给予戊四唑(PTZ)的癫痫发作中测试化合物13的神经保护活性。在海马和内嗅皮层的不同实验组进行组织病理学检查。由于化学反应，16个新的,得到四环和五环杂环化合物。生物学研究的化合物表现出对PTZ癫痫发作的保护作用以及一些精神作用。生物学测定证明,16种研究的化合物中的13种通过与PTZ的拮抗作用显示出高抗惊厥活性。化合物的毒性低。根据精神活动的研究结果，发现所选化合物具有镇静作用，除了化合物13,其表现出激活行为和抗焦虑作用(尤其是化合物13)。研究的化合物表现出抗抑郁作用，尤其是化合物13，与地西泮相似。组织病理学检查表明，化合物13在大脑中产生中度变化，并在内嗅皮层中表现出针对PTZ引起的损伤的神经保护作用，减少神经胶质增生和神经元丢失。对接研究显示，在16种化合物中，3个化合物与γ-氨基丁酸A型(GABAA)受体结合。因此，选定的化合物证明了抗惊厥药，镇静剂,和激活行为，同时表现出抗焦虑和抗抑郁作用。化合物13与GABAA受体结合并表现出抗焦虑，抗抑郁药,以及内嗅皮层对PTZ诱导的变化的神经保护作用。
