Design, synthesis and biological evaluation of (E)-3-(3,4,5-trimethoxyphenyl) acrylic acid (TMCA) amide derivatives as anticonvulsant and sedative agents
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.
KeywordsSynthesis 3,4,5-Trimethoxycinnamic acid Amide derivatives Anticonvulsant Sedative Docking
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.
- 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
- 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
- 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
- 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