Novel hybrids of 6-amino-3-n-butylphthalide and neuroprotective groups against ischemic stroke

Abstract

Ischemic stroke (IS) is the leading cause of disability and the second most common cause of death in adults globally. Unfortunately, the recombinant tissue plasminogen activator (rt-PA), the only thrombolytic drug approved by the Food and Drug Administration (FDA), has numerous side effects such as hemorrhage risk and narrow therapeutic windows, which limits its clinical application. Butylphthalide (NBP) from celery seeds was approved against IS, and its derivative 6-amino-3-n-butylphthalide has been demonstrated to offer better neuroprotective effects against IS-induced injury. In this study, a series of 6-amino-3-n-butylphthalide (ABP) derivatives were designed and synthesized in order to obtain novel powerful compounds against IS. Permanent middle cerebral artery occlusion (pMCAO)-operated mice and oxygen and glucose deprivation (OGD)-treated primary cortical neurons and HT22 cell lines were used to evaluate the activity of these derivatives in protecting against ischemic injury. The results showed that the effect of compound ABP18 (ABP connecting with memantine) on alleviating OGD-induced cell death was better than that of NBP both in primary cortical neurons and HT22 cells, and the safety of ABP18 is comparable to that of NBP. In addition, ABP18 significantly reduced the brain infarct volume and improved neurological function in mice at 24 h after pMCAO. The acute toxicity test showed that ABP18 had high safety. Therefore, the present study identified that ABP18 is a potential candidate for the treatment of IS.