Novel menthone derivatives with anticonvulsant effect

Abstract

Nowadays, a significant number of antiepileptic drugs aimed at influencing the main inhibitory transmitter – gamma-aminobutyric acid (GABA). Compounds with various chemical structures, binding to different GABAA sites, potentiate the action of amino acid. Recent studies have reported that terpenoids such as l-menthone and its derivatives were found to act as modulators of GABAA receptors, thereby demonstrating anticonvulsant activity. On the other hand, neuroprotective and anticonvulsant potentialities were revealed in phenoxyacetic acid derivatives. Based on the foregoing, the combination of l-menthone and phenoxyacetic acid residues into one molecule is feasible for obtaining the pharmacological agents with antiseizure action. In order to achieve the above-mentioned goal, l-menthone hydrazones were synthesized via condensation of terpenoid with 4-R-phenoxyacetic acid hydrazides in the presence of a catalytic amount of glacial acetic acid. The structure of the target compounds has been established by FTIR-ATR, Raman, 1H-NMR and 13C-NMR spectral analysis and EI/FAB/ESI mass spectrometry. Thermal properties of hydrazones were elucidated by DSC and their purity ‒ by HPLC coupled to mass spectrometry. Synthesized compounds were found to exist as Z/E geometrical isomers about C=N bond and cis/trans amide conformers. At the present study, the influence of obtained derivatives on the central nervous system was reliably confirmed by evaluating their anticonvulsant activity. The present findings indicate that all aforementioned compounds possess antiseizure action after oral administration on PTZ-induced convulsion and maximal electroshock-induced (MES) seizures.