Design, synthesis and evaluation of NBP/borneol hybrids as neuroprotective agents for the treatment of ischemic stroke

The pathogenesis of cerebral ischemia is a highly complex biochemical process, mainly caused by cerebral vascular occlusion or rupture, which results in the interruption of blood flow and ischemic injury to brain tissue. Based on 3-n-Butylphthalide (NBP), a listed drug with approved neuroprotective properties, a series of NBP/Borneol hybrids were designed, synthesized and evaluated for their biological activities in vitro. Most of these compounds exhibited potent neuroprotection with low cytotoxicity, among all derivatives, L-NRB and S6b exhibited significantly improved cell viabilities compared to NBP in OGD/R model and glutamate induced model using HT22 cells. Further biological activity studies revealed that compounds L-NRB, S6b inhibit LDH release and may exert anti-cerebral ischemia activities by resisting oxidative stress and reducing Apoptosis. In addition, L-NRB, S6b could regulate the levels of Apoptosis pathway-related proteins Caspase 3, Bcl-2 and Bax. Notably, S6b reduced cerebral thrombosis in the ponatinib-induced zebrafish model. In conclusion, this work designed, synthesized and evaluated a novel series of NBP derivatives with neuroprotective activity and provides a reference for the design of Other potential compounds for the treatment of ischemic stroke.

3-N-butylphthalide; Borneol; Derivatives; Ischemic stroke; Neuroprotective agents.