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

Abstract

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 N4-(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 N1-(2,6-dimethylphenyl)-N4-(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.

Design, synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant agent

“…The rotarod test was used to evaluate neurotoxicity (28). The level of GABA in brain tissues of rats was estimated enzymatically as previously described (29). Approximate lethal dose (ALD 50 ) of the selected compounds was determined according to the literature (30).…”

“…-Adult Wistar rats were divided into three groups of three animals each. After 2 h of clobazam (30 mg kg -1 body mass) or test compound (5c or 5i, 100 mg kg -1 body mass) administration, the animals were decapitated and the brain regions, mid brain, cerebellum and medulla oblongata were dropped into separate vessels containing 4~6 mL of ice cold 80 % ethanol and processed further as per the reported procedure (29).…”

Semicarbazone – a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design

“…In the series of N- (2,6-dimethylphenyl) substituted semicarbazones, a large number of compounds were found active at a dose of 30 mg kg -1 in ScSTY tests. Therefore, these compounds could be assumed to act through glycine receptors (55). A few compounds (50) with p-nitrophenyl substitution also showed activity in ScSTY tests.…”

Synthesis, anticonvulsant, antioxidant and binding interaction of novel N-substituted methylquinazoline-2,4(1H,3H)-dione derivatives to bovine serum albumin: A structure–activity relationship study

“…The MES test is associated with the electrical induction of the seizure. The neurotoxicity of the compounds was primarily determined in the rotorod method [30]. The characteristic feature of this series is the presence of the propionyl group at third position and the different substituents on phenyl ring.…”