Anticonvulsant activity of various aryl, arylidene and aryloxyaryl semicarbazones

Abstract

A number of aryl, arylidene and aryloxyaryl semicarbazones were evaluated as candidate anticonvulsants. In particular, insertion of an olefinic group between the carbimino carbon atom and an aryl ring (referred to as the proximal ring) led to series 6 in which there was retention in activity and 6b,c were shown to be useful lead molecules. At the doses utilized, neurotoxicity was absent in these compounds when given orally to rats. Attachment of a 2-naphthyloxy group at the 4 position of the proximal ring gave 7 whose high activity in the rat oral maximal electroshock (MES) screen suggested that the binding site of the second aryl ring was capable of accommodating groups with molecular refractivity values of over 40. The greatest activity was displayed by a series of aryloxyaryl semicarbazones 8 which had oral activity in the MES screen substantially greater than phenytoin and with protection indices of over 100. A binding site hypothesis formulated as a result of the biodata generated was in accord with the information obtained by X-ray crystallography.