Synthesis of GABA‐Valproic Acid Derivatives and Evaluation of Their Anticonvulsant and Antioxidant Activity

Abstract

The synthesis and the anticonvulsant activity of a number of GABA and valproic acid derivatives are reported. The lipophilicity of these compounds and their inhibitory effect on lipid peroxidation were also investigated, in an effort to correlate the anticonvulsant activity with lipophilicity and inhibitory effect on lipid peroxidation. The synthesized compounds exhibited anticonvulsant effects which were stronger for the more lipophilic derivatives. One of the active anticonvulsants showed appreciable antioxidant properties. Finally, a good correlation was found between the experimentally derived (RM) and calculated (sigma f and log PSK) lipophilicity for this series of compounds.

Research on the pharmacochemistry of some GABA and valproic acid derivatives

“…The results for compounds 1d-e and 2d-e combine very well with the results for compounds 1a-c and 2a-c[Rekatas et al, 1996a]:…”

“…2e, being a valproate ester and significantly more lipophilic than the acid itself, is expected to act as an anticonvulsant. 1e is not a valproic acid derivative (it is a 2-propylpentyl ester) but also exhibits significant activity in this respect; it is noteworthy that two more 2-propylpentyl esters, 1c and 2c, also exhibited potent anticonvulsant activity [Rekatas et al, 1996a]. On the other hand, 2d, although a valproic acid derivative, exhibits very weak activity in vivo and 1d is inactive in this respect.…”

“…1). Considering the fact that the most potent anticonvulsants were 2-propyl-1-pentyl esters, we synthesized 2-propyl-1-pentyl nicotinate; also, as the nicotinoyl moiety exhibited a tendency to confer activity in our series of compounds [Rekatas et al, 1996a], we synthesized 3-pyridinyl-methyI valproate (1e and 2e, Fig. 2).…”

“…We have synthesized and tested several derivatives of GABA and valproic acid as candidate mutual prodrugs of these two anticonvulsants [Rekatas et al, 1996a] (1a-c and 2a-c, Fig. 1).…”

Synthesis and Investigation of 2-Propylpentanoyl Amino Acid and Dipeptide Conjugates as Novel Anticonvulsants

“…administration to mice. However, valproyl conjugates of amino acids, particularly their amides, appeared recently as attractive anticonvulsant candidates (6,7) .…”