Discovery of novel danshensu derivatives bearing pyrazolone moiety as potential anti-ischemic stroke agents with antioxidant activity

• DOI: 10.1016/j.bioorg.2022.106283
• Publication Date: 2022-11-19T10:58:20Z
• Authors: Yi Li; Yunchun Luo; Jing Wang; Hao Shi; Jun Liao; Yan Wang; Zhesheng Chen; Liyan Xiong; Chuan Zhang; Tingfang Wang
• Keywords: 0301 basic medicine; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Hydrogen Peroxide; Antioxidants; Rats; 3. Good health; Molecular Docking Simulation; Stroke; Mice; Oxidative Stress; 03 medical and health sciences; Neuroprotective Agents; Animals; Reactive Oxygen Species

Neuroprotective agents with attenuation of oxidative stress by directly scavenging ROS and indirectly through Keap1-Nrf2 signal pathway activation may be a promising cerebral ischemic stroke therapeutic strategy. In this study, a series of novel danshensu derivatives bearing pyrazolone moieties with dual antioxidant effects were synthesized for the treatment of ischemic stroke. Most compounds exhibited considerable DPPH free radical scavenging ability and neuroprotective activity against H2O2-induced oxidative injury in PC12 neuronal cells, without cytotoxicity. Among these target compounds, Del03 displayed the strongest dose-dependent neuroprotective activity in vitro, directly downregulated intracellular ROS levels, and improved the oxidative stress parameters MDA, SOD, and LDH. Del03 also promoted Nrf2 translocation to the nucleus, subsequently increasing the expression of the Nrf2 downstream target HO-1. Molecular docking analysis revealed that Del03 could anchor to the key site of Keap1. Del03 possessed the ability to penetrate blood-brain barrier and displayed good ability on pharmacokinetic properties in rats Del03 possessed good BBB penetration efficiency, suitable pharmacokinetic properties in vivo. Del03 reduced cerebral infarction volume and promoted neurological function in a middle cerebral artery occlusion (MCAO) mouse model at a dose of 20 mg/kg by intravenous injection. The characteristics of Del03 detailed in this study demonstrate its potential as a therapeutic agent in the treatment of ischemic stroke.