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Ligustrazinyl amides: a novel class of ligustrazine-phenolic acid derivatives with neuroprotective effects.

Li G, Xu X, Xu K, Chu F, Song J, Zhou S, Xu B, Gong Y, Zhang H, Zhang Y, Wang P, Lei H - Chem Cent J (2015)

Bottom Line: Ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system.Results of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects.Graphical AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, No.6 Wangjing Middle Ring South Road, Beijing, Chaoyang District China.

ABSTRACT

Background: Ligustrazine 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.

Results: In 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.

Conclusions: Results 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 AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects.

No MeSH data available.


Related in: MedlinePlus

Synthetic routes to ligustrazine derivatives L1–L15, L17–L21. Reagents and Conditions: (i) anhydrous CH2Cl2, EDCI/(CH3CH2)3 N, r.t., 12 h; (ii) anhydrous DMF (L11 anhydrous CH2Cl2), EDCI/HOBt, r.t., 12 h; (iii) anhydrous DMF (L21 DMI), EDCI/HOBt, r.t., 12 h.
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Sch2: Synthetic routes to ligustrazine derivatives L1–L15, L17–L21. Reagents and Conditions: (i) anhydrous CH2Cl2, EDCI/(CH3CH2)3 N, r.t., 12 h; (ii) anhydrous DMF (L11 anhydrous CH2Cl2), EDCI/HOBt, r.t., 12 h; (iii) anhydrous DMF (L21 DMI), EDCI/HOBt, r.t., 12 h.

Mentions: All the target compounds were synthesized via the routes outlined in Scheme 1, Scheme 2 and Scheme 3. The key intermediate (3,5,6-trimethylpyrazin-2-yl)methanamine (L) was prepared according to our previous study with minor improvements. Compound B (TMP-Br) was synthesized from anhydrous ligustrazine and N-bromosuccinimide (NBS) in carbon tetrachloride via free radical reaction, the crude product was used directly in the next reaction without further purification. The mixture of TMP-Br and phthalimide potassium in CH3CN that was refluxing for 2 h gave compound C. Intermediate L was obtained by reaction of C and 80% hydrazine hydrate in absolute ethanol refluxing for 5 h.Scheme 1


Ligustrazinyl amides: a novel class of ligustrazine-phenolic acid derivatives with neuroprotective effects.

Li G, Xu X, Xu K, Chu F, Song J, Zhou S, Xu B, Gong Y, Zhang H, Zhang Y, Wang P, Lei H - Chem Cent J (2015)

Synthetic routes to ligustrazine derivatives L1–L15, L17–L21. Reagents and Conditions: (i) anhydrous CH2Cl2, EDCI/(CH3CH2)3 N, r.t., 12 h; (ii) anhydrous DMF (L11 anhydrous CH2Cl2), EDCI/HOBt, r.t., 12 h; (iii) anhydrous DMF (L21 DMI), EDCI/HOBt, r.t., 12 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4372684&req=5

Sch2: Synthetic routes to ligustrazine derivatives L1–L15, L17–L21. Reagents and Conditions: (i) anhydrous CH2Cl2, EDCI/(CH3CH2)3 N, r.t., 12 h; (ii) anhydrous DMF (L11 anhydrous CH2Cl2), EDCI/HOBt, r.t., 12 h; (iii) anhydrous DMF (L21 DMI), EDCI/HOBt, r.t., 12 h.
Mentions: All the target compounds were synthesized via the routes outlined in Scheme 1, Scheme 2 and Scheme 3. The key intermediate (3,5,6-trimethylpyrazin-2-yl)methanamine (L) was prepared according to our previous study with minor improvements. Compound B (TMP-Br) was synthesized from anhydrous ligustrazine and N-bromosuccinimide (NBS) in carbon tetrachloride via free radical reaction, the crude product was used directly in the next reaction without further purification. The mixture of TMP-Br and phthalimide potassium in CH3CN that was refluxing for 2 h gave compound C. Intermediate L was obtained by reaction of C and 80% hydrazine hydrate in absolute ethanol refluxing for 5 h.Scheme 1

Bottom Line: Ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system.Results of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects.Graphical AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, No.6 Wangjing Middle Ring South Road, Beijing, Chaoyang District China.

ABSTRACT

Background: Ligustrazine 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.

Results: In 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.

Conclusions: Results 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 AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects.

No MeSH data available.


Related in: MedlinePlus