title: 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.
authors.affiliation: Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India. pyogee@bits-pilani.ac.in
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Rathinasabapathy
authors.initials: R
authors.lastname: Thirumurugan
authors.forename: Jegadeesan Vaigunda
authors.initials: JV
authors.lastname: Raghavendran
authors.forename: Kannan
authors.initials: K
authors.lastname: Sudhan
authors.forename: Roheeth Kumar
authors.initials: RK
authors.lastname: Pavana
authors.forename: James
authors.initials: J
authors.lastname: Stables
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015195:Drug Design; D005260:Female; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000097:blood
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; C505553:N(1)-(2,6-dimethylphenyl)-N(4)-(2-hydroxybenzaldehyde) semicarbazone; D012664:Semicarbazones; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; C055323:ameltolide