State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 561113, P. R. China.
Department of Pharmacy, the, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, P. R. China.
Chem Biodivers. 2024 May;21(5):e202400110. doi: 10.1002/cbdv.202400110. Epub 2024 Apr 17.
Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.
具有抗血小板聚集和神经保护作用的药物对缺血性脑卒中的治疗具有重要意义。设计并合成了一系列依达拉奉和 6-苯基-4,5-二氢哒嗪-3(2H)-酮的杂合体。其中，化合物 6g 对氧葡萄糖剥夺/复氧诱导的 BV2 细胞损伤表现出最有效的细胞保护作用，对二磷酸腺苷和花生四烯酸诱导的血小板聚集具有优异的抑制作用。此外，6g 可以预防氯化铁引起的大鼠血栓形成，与阿司匹林相比，出血风险较低。与依达拉奉相比，6g 能更好地保护大鼠免受缺血/再灌注损伤，并通过增加 GSH 和 SOD 水平、降低 MDA 浓度来减轻与脑缺血/再灌注相关的氧化应激。最后，分子对接结果表明，6g 可能作用于 PDE3A 并发挥抗血小板聚集作用。总的来说，6g 可能是治疗缺血性脑卒中的潜在候选化合物。
