Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood–brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 μM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

中文翻译：

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取代茚满酮/苯并呋喃酮和哌啶杂化物的合成和神经保护评价


基于丁苯酞和多奈哌齐的神经保护作用，设计并合成了一系列茚满酮/苯并呋喃酮和哌啶杂化物，用于评估其神经保护活性，旨在提高天然苯酞类似物的生物利用度和治疗效果。在这项研究中，观察到与苯并呋喃酮化合物相比，大多数尾部带有 1-甲基哌啶的茚满酮衍生物对体外氧糖剥夺/再灌注 (OGD/R) 诱导的大鼠原代神经元细胞损伤模型表现出优异的神经保护作用。在合成的化合物中，11 种（4、14、15、22、26、35、36、37、48、49 和 52）在 OGD/R 模型中表现出强大的细胞活力，以及良好的血脑屏障渗透性：通过平行人工膜渗透性测定证实。值得注意的是，化合物 4 在 3.125 至 100 μM 的浓度范围内表现出显着的神经元细胞活力，且不诱导细胞毒性。体内大脑中动脉闭塞/R实验的进一步结果表明，4可有效改善缺血再灌注损伤，在40 mg/kg的剂量下将梗塞体积减少至18.45%。这一结果表明，与 20 mg/kg 的依达拉奉相比，其具有更优异的神经保护作用，进一步凸显了化合物 4 在解决神经系统疾病方面的潜在治疗功效。