Design, Synthesis And Activity Evaluation Of4-(2-Acetoxybenzoylamino) Butyrate As Antiepileptic Agents

Seizures are the clinical syndrome complex characterized by the dysfunction of central nervous system due to the spontaneous and synchronous electrical discharge in the brain, y-aminobutyric acid (GABA) as the most important inhibitory neurotransmitter is able to inhibit the overexcitement of epilepsy focus of glial cells. However, GABA lacks the drug-like characteristics due to the easy ionization in the physiological pH condition, higher hydrophility, and lower penetrability through blood-brain barrier. Seizures can cause central nervous system injury and increased the sequela of epilepsy. Aspirin with the nerve protection can reduce the formation of free radicals in the brain in case of seizures, prevent reverse transcription factor NF-κB activation, reduce the expression of iNOS, and reduce the consumption of ATP.In this paper, seven4-(2-hydroxyl-benzoylamino) butyrate compounds (dl-d7) with ASA as the carrier were designed and synthesized, and their structures were fully identified by1HNMR,13CNMR, HRMS and IR spectra. Additionally, we study the influence of reaction conditions on the yield to optimize the technics of the target compounds synthesis.In the epilepsy model induced by ignition method of4-aminopyridine in mice, the systematic evaluation of antiepileptic action of the seven target compounds in shake of determination by modified Cole’s method of ED50and LD50resulted in the potency of compound d3-d70.5to2.2folds higher than the one of sodium valproate as the positive control drug. Particularly, compound d6with163.15mg·kg-1of ED50and514.52mg·kg-1of LD50is worthy to be further developed.