Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane 2c, 3c and quinoline 2d, 3d-substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H2O2. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative 2c due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.

中文翻译：

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新型基于1,4-二氮杂环庚烷的Sigma配体的合成，细胞毒性评估和计算见解。

在几种潜在的应用中，sigma受体配体可以用作抗精神病药，抗遗忘药，并用于对抗其他神经退行性疾病以及神经保护剂。我们在此介绍了一系列新的含二氮杂环戊烷的衍生物，作为σR配体，通过我们先前合成的哌啶类化合物的构象扩展方法获得。苯并呋喃2c，3c和喹啉2d，3d取代的二氮杂环庚烷衍生物达到了最佳结果，它们具有最高的σR亲和力。评估了合成化合物对两种癌细胞系的细胞毒活性，结果表明这些化合物均未在这些细胞中诱导出明显的毒性。我们还通过自由基清除剂对ABTS和H2O2的自由基清除能力评估了其抗氧化活性。获得的结果表明，我们的新衍生物具有出色的抗氧化特性，可以保护细胞。总体而言，苯并呋喃衍生物2c由于其与受体的活性位点之间的强相互作用而被分子动力学模拟所证实，因而成为具有高σ1R亲和力，低细胞毒性和有效抗氧化活性的最佳化合物。