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 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.
Yogeeswari
Perumal
P
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India. pyogee@bits-pilani.ac.in
Sriram
Dharmarajan
D
Thirumurugan
Rathinasabapathy
R
Raghavendran
Jegadeesan Vaigunda
JV
Sudhan
Kannan
K
Pavana
Roheeth Kumar
RK
Stables
James
J
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
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