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Design, synthesis and biological evaluation of (E)-3-(3,4,5-trimethoxyphenyl) acrylic acid (TMCA) amide derivatives as anticonvulsant and sedative agents

  • Zefeng Zhao
  • Yajun Bai
  • Xufei Chen
  • Shaoping Wu
  • Xirui He
  • Yujun Bai
  • Ying Sun
  • Xiaohui Zheng
Original Research
  • 7 Downloads

Abstract

In this article, a novel series of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (TMCA) amide derivatives 1-18 were designed and synthesized by a facile and one-pot step, which were achieved with good yields using 1-hydroxybenzotriazole (HOBT) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as activation system. All the synthesized derivatives were biologically evaluated for their anticonvulsant, sedative activity and neurotoxicity using the maximal electroshock (MES) model, sc-pentylenetetrazol (PTZ) model, pentobarbital sodium-induced sleeping model, and locomotor activity tests, respectively. Among them, compounds 4, 9 and 16 exhibited good anticonvulsant activity in primary evaluation. Furthermore, compound 4 is the most effective anticonvulsant and sedative agent in subsequent tests, while the low threshold of toxicity of compound 4 is vigilant. Compounds 9 and 16 also performed significantly anticonvulsant activity in subsequent tests with weak toxicity. The molecular modeling experiments also predicted good binding interactions of the obtained active molecules with the GABA transferas. Therefore, it could be concluded that the synthesized derivatives 4, 9 and 16 would represent useful lead compounds for further investigation in the development of anticonvulsant and sedative agents.

Keywords

Synthesis 3,4,5-Trimethoxycinnamic acid Amide derivatives Anticonvulsant Sedative Docking 

Notes

Acknowledgements

This work was supported by the Changjiang Scholars and Innovative Research Team in Universities, Ministry of Education of China (IRT_15R55), the 7th Group of Hundred-Talent Program of Shaanxi Province (2015), and Natural Science Foundation of Shaanxi Province, China (Grant No. 2017JM8054).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2228_MOESM1_ESM.docx (35.2 mb)
Supplementary Information

References

  1. Al-Baghdadi OB, Prater NI, Van der Schyf CJ, Geldenhuys WJ (2012) Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson’s disease. Bioorg Med Chem Lett 22:7183–7188CrossRefGoogle Scholar
  2. Carreiro EP, Louro P, Adriano G, Guedes RA, Vannuchi N, Costa AR, Antunes CM, Guedes RC, Burke AJ (2014) 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal alpha-glucosidase. Bioorg Chem 54:81–88CrossRefGoogle Scholar
  3. Chen CY, Wei XD, Chen CR (2016) 3,4,5-Trimethoxycinnamic acid, one of the constituents of Polygalae Radix exerts anti-seizure effects by modulating GABAAergic systems in mice. J Pharmacol Sci 131:1–5CrossRefGoogle Scholar
  4. Chen CY, Li W, Qu KP, Chen CR (2013) Piperine exerts anti-seizure effects via the TRPV1 receptor in mice. Eur J Pharmacol 714:288–294CrossRefGoogle Scholar
  5. Chen H, Chen H, Bai X, Li Y, Yin S (2011) Synthesis and calm activity of helicid-pyrazoline derivatives. Chin J Org Chem 31:231–234Google Scholar
  6. da Cruz GM, Felipe CF, Scorza FA, da Costa MA, Tavares AF, Menezes ML, de Andrade GM, Leal LK, Brito GA, da Graca Naffah-Mazzacoratti M, Cavalheiro EA, de Barros Viana GS (2013) Piperine decreases pilocarpine-induced convulsions by GABAergic mechanisms. Pharmacol Biochem Behav 104:144–153CrossRefGoogle Scholar
  7. Dunham NW, Miya TS, Edwards LD (1957) The pharmacological activity of a series of basic esters of mono- and dialkylmalonic acids. J Am Pharm Assoc Am Pharm Assoc 46:64–66CrossRefGoogle Scholar
  8. Gunia-Krzyzak A, Panczyk K, Waszkielewicz AM, Marona H (2015) Cinnamamide derivatives for central and peripheral nervous system disorders--a review of structure-activity relationships. ChemMedChem 10:1302–1325CrossRefGoogle Scholar
  9. Gunia-Krzyzak A, Zelaszczyk D, Rapacz A, Zeslawska E, Waszkielewicz AM, Panczyk K, Sloczynska K, Pekala E, Nitek W, Filipek B, Marona H (2017) Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3. Bioorg Med Chem 25:471–482CrossRefGoogle Scholar
  10. Gupta G, Kazmi I, Afzal M, Rahman M, Saleem S, Ashraf MS, Khusroo MJ, Nazeer K, Ahmed S, Mujeeb M, Ahmed Z, Anwar F (2012) Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. J Ethnopharmacol 141:810–816CrossRefGoogle Scholar
  11. Jung JC, Moon S, Min D, Park WK, Jung M, Oh S (2013) Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents. Chem Biol Drug Des 81:389–398CrossRefGoogle Scholar
  12. Kamal A, Bajee S, Lakshma Nayak V, Venkata Subba Rao A, Nagaraju B, Ratna Reddy C, Jeevak Sopanrao K, Alarifi A (2016) Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents. Bioorg Med Chem Lett 26:2957–2964CrossRefGoogle Scholar
  13. Klein Jr LC, de Andrade SF, Cechinel Filho V (2012) A pharmacognostic approach to the Polygala genus: phytochemical and pharmacological aspects. Chem Biodivers 9:181–209CrossRefGoogle Scholar
  14. Lee CI, Han JY, Hong JT, Oh KW (2013) 3,4,5-Trimethoxycinnamic acid (TMCA), one of the constituents of Polygalae Radix enhances pentobarbital-induced sleeping behaviors via GABA(A)ergic systems in mice. Arch Pharm Res 36:1244–1251CrossRefGoogle Scholar
  15. May BH, Lu C, Lu Y, Zhang AL, Xue CC (2013) Chinese herbs for memory disorders: a review and systematic analysis of classical herbal literature. J Acupunct Meridian Stud 6:2–11CrossRefGoogle Scholar
  16. Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL, Naik SR (1990) Effect of piperine on pentobarbitone induced hypnosis in rats. Indian J Exp Biol 28:486–487PubMedGoogle Scholar
  17. Sahu M, Siddiqui N, Iqbal R, Sharma V, Wakode S (2017) Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential. Bioorg Chem 74:166–178CrossRefGoogle Scholar
  18. Seo YH, Kim JK, Jun JG (2014) Synthesis and biological evaluation of piperlongumine derivatives as potent anti-inflammatory agents. Bioorg Med Chem Lett 24:5727–5730CrossRefGoogle Scholar
  19. Swinyard EA (1969) Laboratory evaluation of antiepileptic drugs. Review of laboratory methods. Epilepsia 10:107–119CrossRefGoogle Scholar
  20. Ucar H, Van dK, Cacciaguerra S, Spampinato S, Stables JP, Depovere P, Isa M, Masereel B, Delarge J, Poupaert JH (1998) Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives. J Med Chem 41:3102CrossRefGoogle Scholar
  21. Vamecq J, Lambert D, Poupaert JH, Masereel B, Stables JP (1998) Anticonvulsant activity and interactions with neuronal voltage-dependent sodium channel of analogues of ameltolide. J Med Chem 41:3307–3313CrossRefGoogle Scholar
  22. Wang L, Vieth R, Landes RC, Suzuki Y, Walson PD (1993) Antiepileptic effect of antiepilepsirine in pentylenetetrazol and amygdala kindled rats. Epilepsy Res 15(1):1–5CrossRefGoogle Scholar
  23. Wang L, Zhao D, Zhang Z, Zuo C, Zhang Y, Pei YQ, Lo YQ (1999) Trial of antiepilepsirine (AES) in children with epilepsy. Brain Dev 21:36–40CrossRefGoogle Scholar
  24. Yang T, Kong B, Gu JW, Kuang YQ, Cheng L, Yang WT, Cheng JM, Ma Y, Yang XK (2013) Anticonvulsant and sedative effects of paederosidic acid isolated from Paederia scandens (Lour.) Merrill. in mice and rats. Pharmacol Biochem Behav 111:97–101CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Zefeng Zhao
    • 1
  • Yajun Bai
    • 1
    • 2
  • Xufei Chen
    • 1
  • Shaoping Wu
    • 1
    • 2
  • Xirui He
    • 3
  • Yujun Bai
    • 1
  • Ying Sun
    • 1
  • Xiaohui Zheng
    • 1
  1. 1.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of EducationNorthwest UniversityXi’anChina
  2. 2.College of Chemistry and Materials ScienceNorthwest UniversityXi’anChina
  3. 3.Honghui HospitalXi’an Jiaotong UniversityXi’anChina

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