Rn. Puthucode et al., ANTICONVULSANT ACTIVITY OF VARIOUS ARYL, ARYLIDENE AND ARYLOXYARYL SEMICARBAZONES, European journal of medicinal chemistry, 33(7-8), 1998, pp. 595-607
A number of aryl, arylidene and aryloxyaryl semicarbazones were evalua
ted as candidate anticonvulsants. In particular, insertion of an olefi
nic 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 d
oses 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 maxima
l electroshock (MES) screen suggested that the binding site of the sec
ond aryl ring was capable of accommodating groups with molecular refra
ctivity values of over 40. The greatest activity was displayed by a se
ries of aryloxyaryl semicarbazones 8 which had oral activity in the ME
S screen substantially greater than phenytoin and with protection indi
ces of over 100. A binding site hypothesis formulated as a result of t
he biodata generated was in accord with the information obtained by X-
ray crystallography. (C) Elsevier, Paris.