Synthesis and biological evaluation of 1,2,4-oxadiazole core derivatives as potential neuroprotectants against acute ischemic stroke

Abstract

Here, we report the synthesis and neuroprotective capacity of 27 compounds with a bisphenol hydroxyl-substituted 1,2,4-triazole core or 1,2,4-oxadiazole core for stroke therapy. In vitro studies of the neuroprotective effects of compounds 1-27 on sodium nitroprusside (SNP)-induced apoptosis in PC12 cells indicate that compound 24 is the most effective compound conferring potent protection against oxidative injury. Compound 24 inhibits reactive oxygen species (ROS） accumulation and restores the mitochondrial membrane potential (MMP). Moreover, further analysis of the mechanism showed that compound 24 activates the antioxidant defence system by promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increasing the expression of haem oxygenase 1 (HO-1). An in vivo study was performed in a rat model of transient focal cerebral ischaemia generated by the intraluminal occlusion of the middle cerebral artery (MCAO). Compound 24 significantly reduced brain infarction and improved neurological function. Overall, compound 24 potentially represents a promising compound for the treatment of stroke.

Keywords: 1,2,4-oxadiazole; Fe(II) chelation; Ischemic stroke; Neuroprotection; Nrf2 signal pathway.