Discovery of N-(2,6-Dimethylphenyl)-Substituted Semicarbazones as Anticonvulsants: Hybrid Pharmacophore-Based Design

Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N 4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N -(2,6-dimethylphenyl)-N 4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.