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New edaravone derivatives containing a benzylpiperazine moiety are designed and synthesized. The structures are characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry. The potential neuroprotective activities of the target compounds are evaluated in differentiated rat pheochromocytoma cells (PC12 cells) and in mice subjected to acute cerebral ischemia. Most of the target compounds showed neuroprotective activities both in vivo and in vitro, especially 1-(4-(4-fluorobenzyl) piperazin-1-yl)-2-(4-(5-hydroxy-3-methyl-1 H-pyrazol-1-yl)phenoxy)ethanone and 1-(4-(4-nitrobenzyl)piperazin-1-yl)-2-(4-(5-hydroxy-3-methyl-1 H-pyrazol-1-yl)phenoxy)ethanone, which displayed significant protective effects on cell viability against damage caused by H2O2, and remarkably prolonged the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all doses. These compounds represent lead compounds for the further discovery of neuroprotective agents for treating cerebral ischemic stroke. Molecular docking studies and basic structure–activity relationships are also presented.

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