Design,Synthesis And Biological Activities Of Novel Caspase-3inhibitors Against Ischemic Stroke

Stroke,also known as cerebral stroke,is one of the three major diseases that cause human death.It is particularly common among middle-aged and elderly people.About 4.6 million people die of cerebral stroke every year,and about two-thirds of them are ischemic stroke.The incidence,disability,relapse rate,and death rate of the disease are all very high,which seriously threatens human health.At present,ischemic stroke still lacks effective curative drugs.Therefore,it is of great significance to explore the search for new anti-stroke neuroprotectants.The active compounds 3# and 34# were lead compounds.Combined with the structural analysis of the reported Caspase-3 inhibitors,the principle of splitting was used to design and synthesize Caspase-3 inhibitor against ischemic stroke.two classes of total 20 compounds were designed.All the compounds were confirmed by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy.None of them were reported in the literature.Some of the compounds were tested for cell biological activity and animal pharmacodynamic evaluation.The results showed that the compound showed protective activity against glutamate-induced PC12 cell injury in each dose group.In the experiment of ligating both bilateral common carotid arteries and vagus nerve ligation mice,the compounds can prolong the survival time of mice significantly and exhibit better in vivo activity.Further animal pharmacodynamic evaluation,mechanism of action and structure-activity relationship studies are ongoing.