Ligustrazine-benzoic acid derivatives which exhibited promising neuroprotective activities have previously been reported. To further improve the neuroprotective effect of ligustrazine, a series of new ligustrazine derivatives was synthesized and evaluated for their protective effect against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. Most compounds exhibited higher activity than ligustrazine, of which, we found compound (E)-(3,5,6-trimethylpyrazin-2-yl)methyl 3-(2,3,4-trimethoxyphenyl)acrylate (9) displayed the highest protective effect on the PC12 cells damaged by CoCl₂ (EC₅₀ = 0.719 μM). Structure–activity relationships are briefly discussed.