Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles

Abstract

Starting from the corresponding acetophenone and glycine derivatives, a series of new 3-aminopyrroles was synthesized in few steps. Using this procedure with hydrazine and hydroxylamine instead of the glycinates provides access to 3-aminopyrazoles and 5-amino 1,2-oxazoles. The various derivatives were tested for anticonvulsant activity in a variety of test models. Several compounds exhibit considerable activity with a remarkable lack of neurotoxicity. 4-(4-Bromophenyl)-3-morpholinopyrrole-2-carboxylic acid methyl ester, 3, proved to be the most active compound. It was protective in the maximal electroshock seizure (MES) test in rats with an oral ED50 of 2.5 mg/kg with no neurotoxicity noted at doses up to 500 mg/kg. Compound 3 blocks sodium channels in a frequency-dependent manner. The essential structural features which could be responsible for an interaction with an active site of the voltage-dependent sodium channel are established within a suggested pharmacophore model.

Molecular Model of Anticonvulsant Drug Binding to the Voltage-Gated Sodium Channel Inner Pore

“…Methyl (or alkyl) substitutions of the amide nitrogens of the hydantoin ring reduced binding significantly (Brown et al, 1997), which underlines the importance of these hydrogens for binding. It has been proposed that one aromatic ring and one amide group of the hydantoin form the pharmacophore core of phenytoin (Unverferth et al, 1998;Brown et al, 1999).…”

Synthesis and anticonvulsant activity of clubbed thiazolidinone–barbituric acid and thiazolidinone–triazole derivatives

“…This requirement was further evidenced by compounds 4k-4y and 5k-5y where the -OH function was replaced by a -Cl, CH 3 or -NO 2 moiety. The complete loss of activity due to the disappearance of this function could be explained in terms of interaction at the binding site by the pharmacophoric models which were previously proposed [30][31][32][33] (Scheme 2). In these models, it has been reported that the existence of a hydrophobic unit (Ar), an electron donor group (D) and hydrogen-bonding domain (HBD) was essential for anticonvulsant activity, as evidenced by the active drugs, such as carbamazepine or phenytoin, fulfilling these demands.…”

Design and Synthesis of Pyrazolyl Thiosemicarbazones as New Anticonvulsants

“…Several pyrazole derivatives have been reported possessing important pharmacological activities which now are useful materials in drug research. In 1998, Unverferth et al 15 described a series of 3-aminopyrroles as anticonvulsants, in which an interaction between pyrrole and voltage-dependent sodium channel were established. As a backup, 3-amino-and 5-aminopyrazoles were also prepared.…”