Coumarin derivatives protect against ischemic brain injury in rats

• 36 new 3-piperazinyl coumarins have been designed and synthesized.
• All of the compounds have been evaluated for neuroprotective activity in vitro.
• Compound 20 showed significant neuroprotection in vitro and in MCAO rats.
• Mechanistic studies indicated that 20 exhibited antiapoptosis of neurons.
• Pharmacokinetic evaluation indicated that 20 could cross the BBB of rats.

Neuroprotection strategies are of great importance in the treatment of ischemic brain injury. Screening of our in-stock coumarin derivatives identified compound 1 as exhibiting neuroprotective activity. Subsequently, a structural optimization was carried out, which led to the discovery of the potent compound 20. This compound significantly attenuated the damage in a cell line derived from a pheochromocytoma of the rat adrenal medulla induced by oxygen–glucose deprivation in vitro. Furthermore, compound 20 exhibited clear neuroprotection in middle cerebral artery occlusion rats by reducing infarct size and brain-water content, improving neurological function, and suppressing neuronal loss and neuropathological changes in the cortex and hippocampus. Pharmacokinetic evaluation indicated that compound 20 could penetrate the blood–brain barrier of rats.

A series of novel coumarin derivatives were designed and synthesized. The most effective compound 20 showed significant neuroprotection in MCAO rats.Figure optionsDownload as PowerPoint slide