Design,Synthesis And Biological Activities Of Novel Neuroprotective Agents Against Ischemic Stroke

Stroke is the second leading cause of death worldwide and the leading cause of disability.In China,there are 2.5 million new stroke cases each year,of which 1.6million die from ischemic stroke.Among stroke survivors,three-quarters of patients have physical diseases,two-thirds of patients have cognitive impairments,which lead to a significant decline in the quality of life of the patients and bring a heavy economic burden to the patients’families and society.Stroke is divided into ischemic stroke and hemorrhagic stroke.Ischemic strokes are caused by clogged arteries,while hemorrhagic strokes are caused by rupture of arteries in or around the brain.In China,more than 80%of stroke cases are ischemic,which are characterized by obstruction of blood supply leading to cerebral infarction.Although intravenous thrombolysis is the basic and most effective treatment method for ischemic stroke,there are many limiting factors for this method,especially the narrow time window requirements（3-6 h）.Neuroprotective therapy is a promising alternative to thrombolytic therapy,this topic is mainly engaged in the research of neuroprotective agents.The pathogenesis of ischemic stroke involves oxidative stress,the production of a large number of reactive oxygen species（ROS）is the main cause of oxidative stress damage.A large number of studies have shown that exogenous supplementation of antioxidants has the activity of removing ROS,which may be a potential method for the treatment of nerve damage in stroke.Through literature research,our research group found that melatonin（MLT）and its analogues with indole nucleus exhibit excellent antioxidant activity and significant neuroprotective activity.In previous studies,a large number of MLT analogues were synthesized,some of compounds show good antioxidant activity.In the above studies,the structural modification mainly focused on the 3-substituted side chain and 5-position substituent of the indole ring.In this project,5-methoxyindole-2-carboxylic acid was selected as the lead compound.the structure of the 2-position substituted side chain and 5-position substituent of the indole ring were planed to modify and reform in order to explore and study new drugs for the treatment of cerebral ischemia with antioxidant activity.In this work,28 target compounds have been synthesized,which have been confirmed by high-resolution mass spectrometry,¹H-NMR and ¹³C-NMR,none of the compounds have been reported in the literature.Preliminary pharmacodynamic evaluation studies have shown that the compounds CLY-T15 and CLY-T17 in the 200mg/kg and 100 mg/kg dose groups can significantly prolong the survival time of mice with acute cerebral ischemia.In the 100 mg/kg,50 mg/kg and 25 mg/kg dose groups,CLY-T2 and CLY-T7 can significantly prolong the survival time of mice with acute cerebral ischemia,showing good neuroprotective activity in a dose-dependent manner.In vitro pharmacological activity screening results have displayed that the target compounds CLY-T1,CLY-T2,CLY-T3,CLY-T4,CLY-T5,CLY-T7,CLY-T8,CLY-T9,CLY-T10 show good protective activity against PC12 cell injury induced by H₂O₂in three dose groups of 0.1μM,1μM and 10μM,which was better than the positive control drug MLT.Based on the results of in vivo and in vitro activity tests,CLY-T2 and CLY-T7both show outstanding neuroprotective activity.In the follow-up work,we will conduct in-depth research on these two compounds.At the same time,in vitro pharmacological activity screening,mechanism research,toxicology and detailed pharmacodynamic evaluation will be carried out in the following studies.