title: Anticonvulsants containing the N-(3-aryl-2-propenoyl) amido pharmacophore.
abstract: A series of 1-(3-aryl-2-propenoyl)-4-oxopiperidines (1) as well as some related semicarbazones (2) and thiosemicarbazones (3) were prepared in order to determine whether the relative locations of aryl rings and amidic groups would lead to novel anticonvulsant agents. Initially the compounds were administered intraperitoneally to mice and examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. The biodata revealed that anticonvulsant properties were displayed by most of the compounds in series (1), in half of the semicarbazones (2) while protection was absent by members of series (3). Molecular modeling was utilized in order to compare the positions of a phenyl ring in relation to amidic groups in representative compounds in series (1-3) with previously reported anticonvulsant agents. Molecular simplification of 4-oxo-1-(3-phenyl-2-propenoyl)piperidine (la) led to 1-(3-phenyl-2-propenoyl)piperidine (7) and N,N-diethylcinnamamide (8) with retention of anticonvulsant properties. Both (la) and (8) afforded protection in the hippocampal kindling screen in rats. When administered orally to rats, (la) and (8) demonstrated activity in the MES screen and in the case of (8), a huge protection index was observed revealing it to be an important lead compound. The IC50 values of all of the compounds towards murine P388 cells were in excess of 50 microM while several compounds displayed cytotoxicity towards Mycobacterium tuberculosis.
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. dimmock@skyway.usask.ca
authors.forename: J R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: S G R
authors.initials: SG
authors.lastname: Gunda
authors.forename: S C
authors.initials: SC
authors.lastname: Vashishtha
authors.forename: G A
authors.initials: GA
authors.lastname: Zello
authors.forename: U
authors.initials: U
authors.lastname: Das
authors.forename: K H
authors.initials: KH
authors.lastname: Nienaber
authors.forename: J P
authors.initials: JP
authors.lastname: Stables
authors.forename: T M
authors.initials: TM
authors.lastname: Allen
authors.forename: C L
authors.initials: CL
authors.lastname: Santos
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D000927:Anticonvulsants; D012664:Semicarbazones