title: Design and comparative anticonvulsant activity assessment of CNS-active alkyl-carbamoyl imidazole derivatives.
abstract: A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6Hz psychomotor (6Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties. In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED50 values ranging from 12 to 20mg/kg coupled with high protective index (PI=TD50/ED50) values of 4.1-7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED50 values of 14-26mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6Hz model with ED50 values of 32 and 44mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy-safety profile and consequently, might be promising candidates for development as new antiepileptics.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO 12065, Jerusalem 91120, Israel.
authors.forename: Hafiz
authors.initials: H
authors.lastname: Mawasi
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO 12065, Jerusalem 91120, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Bibi
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO 12065, Jerusalem 91120, Israel; David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Israel. Electronic address: bialer@md.huji.ac.il.
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D004597:Electroshock; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D013329:Structure-Activity Relationship
chemical_list: C000621438:2-propylpentyl (3-(1H-imidazol-1-yl)propyl)carbamate; C000621439:3-methyl-2-propylpentyl (3-(1H-imidazol-1-yl)propyl)carbamate; D000927:Anticonvulsants; D002219:Carbamates; D007093:Imidazoles
keywords: Alkyl-carbamoyl imidazole derivatives; Anticonvulsant activity; New antiepileptic drugs