In search of novel neuroprotective agents with higher potency and lower h ERG liability, a series of novel Fenazinel derivatives were designed and synthesized, among which compounds 8m–o containing amide moiety exhibited good neuroprotective effects in vitro and in vivo. Especially, the representative compound 8o showed lower activity in a patch clamp h ERG K+ion channel screen and could be considered as a lead compound for further development. These findings provided an alternative approach to the development of drugs more potent than Fenazinel for the intervention of ischemic stroke. In a search of novel neuroprotective agents with higher potency and lower h ERG liability, a series of novel Fenazinel derivatives were designed and synthesized, among which compounds 8m-o containing the amide moiety exhibiting good neuroprotective effects in vitro and in vivo. 8o showed lower activity in a patch clamp h ERG K + ion channel screen and could be be considered as a lead compound for further development. These findings provided an alternative approach to the development of drugs more potent than Fenazinel for the intervention of ischemic stroke.