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

摘要

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.