Abstract
BackgroundLigustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system. Previous study in our laboratory reported that ligustrazine-benzoic acid derivatives have been shown to exhibit beneficial effect against CoCl2-induced neurotoxicity in differentiated PC12 cells. To further improve ligustrazine’s neuroprotection, we integrated the ligustrazine and phenolic acid fragments into one molecule via an amide bond based on structural combination.ResultsIn this study, 12 novel ligustrazine-phenolic acid derivatives were synthesized and nine others were prepared by improved methods. Furthermore, these compounds were evaluated for their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells. The amides conjunctional derivatives exhibited promising neuroprotective activities in comparison with ligustrazine. In addition, the most active congener (E)-3-(2,3,4-trimethoxyphenyl)-N-((3,5,6-trimethylpyrazin-2-yl)methyl)acrylamide (L10, EC50 = 25 μM), which is 2 times higher than that of ligustrazine, may be a potential candidate for intervention in neurological diseases. Structure-activity relationship was discussed briefly.ConclusionsResults of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects. Our completed work supports that the attempt to apply structure combination to discover more efficient neuroprotection lead compounds is viable.Graphical Ligustrazinyl Amides L1-L21 with Neuroprotective Effects.
Highlights
Recent studies have indicated that ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system [14,15,16,17,18,19,20,21]
A recent study has reported that part of ligustrazinyl amides congener structures exhibited good proliferative activities on human umbilical vascular endothelial cells (HUVECs) [25]
Their protective effects against neurotoxicity were evaluated in differentiated PC12 cells
Summary
12 novel ligustrazine-phenolic acid derivatives were synthesized and nine others were prepared by improved methods. These compounds were evaluated for their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells. The amides conjunctional derivatives exhibited promising neuroprotective activities in comparison with ligustrazine. The most active congener (E)-3-(2,3,4-trimethoxyphenyl)-N-((3,5,6-trimethylpyrazin-2-yl)methyl)acrylamide (L10, EC50 = 25 μM), which is 2 times higher than that of ligustrazine, may be a potential candidate for intervention in neurological diseases.
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