National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Chinese Medicine, Nanchang 330006, China.
College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
ACS Chem Neurosci. 2024 May 15;15(10):2042-2057. doi: 10.1021/acschemneuro.4c00054. Epub 2024 Apr 24.
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 (, , , , , , , , , , and ) 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 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 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 in addressing neurological disorders.
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/苯并呋喃酮和哌啶类杂合体，以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。在本研究中，观察到大多数带有 1-甲基哌啶尾部片段的茚满酮衍生物在体外氧葡萄糖剥夺/再灌注（OGD/R）诱导的大鼠原代神经元细胞损伤模型中表现出比苯并呋喃酮化合物更优异的神经保护作用。在所合成的化合物中，化合物 11（、、、、、、、、、和）在 OGD/R 模型中具有良好的细胞活力，并且平行人工膜透过性测定证实其具有良好的血脑屏障透过性。值得注意的是，化合物在 3.125 至 100 μM 的浓度范围内表现出显著的神经元细胞活力，而没有诱导细胞毒性。体内大脑中动脉闭塞/再灌注实验的进一步结果表明，化合物在 40 mg/kg 剂量下有效改善了缺血再灌注损伤，将梗死体积减少到 18.45%。这一结果表明与 20 mg/kg 的依达拉奉相比，具有更好的神经保护作用，进一步强调了化合物在治疗神经障碍方面的潜在治疗效果。
