To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

中文翻译：

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发现3-正丁基-2,3-二氢-1H-异吲哚-1-酮作为潜在的抗缺血性中风剂。

为了开发具有更好疗效和生物利用度的新型抗缺血性中风药物，我们设计并合成了一系列3-烷基-2,3-二氢-1H-异吲哚-1-酮化合物（3a-i）衍生物，其中之一（3d）对二磷酸腺苷和花生四烯酸诱导的血小板聚集表现出最强的抑制活性。该活性优于3-正丁基邻苯二甲醚，并与阿司匹林和依达拉奉相当。同时，3d不仅在清除自由基和提高HT22细胞抵抗活性氧介导的体外细胞毒性方面表现出强大的活性，而且还显着减轻了缺血/再灌注诱导的缺血大鼠脑的氧化应激。短暂性大脑中动脉阻塞和永久性大脑中动脉阻塞模型的结果表明，3d可以显着减小梗塞面积，改善神经行为缺陷，并显着降低脑损伤的衰减。最重要的是，3d具有很高的绝对生物利用度，并迅速分布在脑组织中，以保持较高的血浆药物浓度以治疗缺血性中风。总之，我们的发现表明，一系列新型化合物3-烷基-2,3-二氢-1H-异吲哚-1-酮可能是治疗急性缺血性中风的候选药物，而3d可能是有前途的治疗方法药物用于缺血性中风的一级和二级预防。并显着降低脑损伤的衰减。最重要的是，3d具有很高的绝对生物利用度，并迅速分布在脑组织中，以保持较高的血浆药物浓度以治疗缺血性中风。总之，我们的发现表明，一系列新型化合物3-烷基-2,3-二氢-1H-异吲哚-1-酮可能是治疗急性缺血性中风的候选药物，而3d可能是有前途的治疗方法药物用于缺血性中风的一级和二级预防。并显着降低脑损伤的衰减。最重要的是，3d具有很高的绝对生物利用度，并迅速分布在脑组织中，以保持较高的血浆药物浓度以治疗缺血性中风。总之，我们的发现表明，一系列新型化合物3-烷基-2,3-二氢-1H-异吲哚-1-酮可能是治疗急性缺血性中风的候选药物，而3d可能是有前途的治疗方法药物用于缺血性中风的一级和二级预防。