Abstract In the present study, we have synthesized a series of fifteen nipecotic acid 1,3,4-oxadiazole based hybrids with significant (60–78%) yields. All the compounds were characterized by using different spectroanalytical techniques such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. This design strategy was validated by using in vivo anti-epileptic and anti-depressant bioassay models. Anti-convulsant activity was evaluated using subcutaneous pentylenetetrazol (scPTZ) in mice and MES induced seizure. Among a spectrum of activities, three compounds (4i, 4m, and 4n) displayed significant activity against pentylenetetrazole (scPTZ) induced seizures. No disruptions in motor co-ordination were observed in mice pretreated with the test compounds in the rotarod test. Their influence on the safety profile of elevated serum levels of biochemical markers such as hepatic and renal toxicity has been found to be safe. The derivatives also show marked anti-depressant activity, devoid of serotonergic augmentation as assessed using the despair swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test and learned helplessness test. In silico docking studies targeted on homology modelled GABA transporter 1 (GAT1) protein shows the critical enzyme-ligand interactions leading to the inhibition of the GAT1 transporter. The compound 4m was found to be the most active compound among all the synthesized compounds.

中文翻译：

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作为抗惊厥药和抗抑郁药的 3-[5-(芳基-[1,3,4]恶二唑-2-基]-哌啶衍生物的合成和药理学评价

摘要 在本研究中，我们合成了一系列 15 种基于 1,3,4-恶二唑的尼泊松酸杂种，产率显着（60-78%）。通过使用不同的光谱分析技术，如 FT-IR、1H NMR、13C NMR 和元素分析，对所有化合物进行了表征。通过使用体内抗癫痫和抗抑郁生物测定模型验证了这种设计策略。在小鼠和 MES 诱导的癫痫发作中使用皮下戊四唑 (scPTZ) 评估抗惊厥活性。在一系列活动中，三种化合物（4i、4m 和 4n）对戊四唑 (scPTZ) 诱发的癫痫发作表现出显着的活性。在旋转棒试验中用测试化合物预处理的小鼠中没有观察到运动协调的中断。已发现它们对升高的血清生化标志物（如肝和肾毒性）水平的安全性的影响是安全的。这些衍生物还显示出显着的抗抑郁活性，没有使用绝望游泳测试、5-羟色氨酸 (5-HTP) 诱导的头部抽搐测试和习得性无助测试评估的血清素能增强。针对同源建模的 GABA 转运蛋白 1 (GAT1) 蛋白的计算机对接研究显示了导致 GAT1 转运蛋白抑制的关键酶-配体相互作用。发现化合物4m是所有合成化合物中活性最强的化合物。5-羟色氨酸 (5-HTP) 诱发的头部抽搐测试和习得性无助测试。针对同源建模的 GABA 转运蛋白 1 (GAT1) 蛋白的计算机对接研究显示了导致 GAT1 转运蛋白抑制的关键酶-配体相互作用。发现化合物4m是所有合成化合物中活性最强的化合物。5-羟色氨酸 (5-HTP) 诱发的头部抽搐测试和习得性无助测试。针对同源建模的 GABA 转运蛋白 1 (GAT1) 蛋白的计算机对接研究显示了导致 GAT1 转运蛋白抑制的关键酶-配体相互作用。发现化合物4m是所有合成化合物中活性最强的化合物。