Novel (‒)-carvone derivatives as potential anticonvulsant and analgesic agents

Abstract

Novel hydrazones based on (-)-carvone were synthesized via condensation of terpenoid with 4-R-phenoxyacetic acid hydrazides. The structure of target compounds was established by FT-IR, Raman, 1 H-NMR and 13 C-NMR spectral analysis, FAB/ESI mass spectrometry. (-)-Carvone hydrazones were proven to exist as Z/E geometrical isomers about C=N bond using ion mobility-tandem mass spectrometry (IM-MS/MS). Single crystal X-ray diffraction study was applied to determine molecular and crystal structure of compound 3e. Hydrazones 3a-3e were evaluated as potential anticonvulsant agents after their oral administration against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in mice. Analgesic activity of compounds was investigated by topical application on models of capsaicin and AITC-induced pain. The present findings indicate that (-)-carvone derivatives afforded seizure protection both at short (1 h) and long (24 h) time period by blocking electroshock-and chemical-induced convulsions.Hydrazones binding to TRPA1/TRPV1 ion channels was proposed as possible mechanism explaining significant analgesic effect of compounds.

Terpenoid Hydrazones as Biomembrane Penetration Enhancers: FT-IR Spectroscopy and Fluorescence Probe Studies

“…In this manner, the results of the investigation of hydrazones as biomembrane penetration enhancers using fluorescence probe studies and FT-IR spectroscopy indicated the increased permeability of these compounds across membranes. These data further substantiate the high pharmacological effect of terpenoid derivatives and fully correlate with previously published data [ 21 , 22 , 23 ] regarding the analgesic and anticonvulsant activity of the abovementioned compounds. According to our study, the higher antinociceptive and antiseizure potency after topical delivery and oral administration, respectively, was displayed by terpenoid derivatives with H, Cl or Br atoms in the para -position of the benzene ring.…”

“…The aforementioned terpenoid derivatives were found to exhibit anticonvulsant activity on pentylenetetrazole and maximal electroshock seizure test results, along with analgesic potency on chemically and thermally-induced pain models [ 21 , 22 , 23 ]. Expanding the concept of polypharmacology, we attempted to design molecules capable of modulating different types of receptors and enhancing self-permeability across biological barriers after their oral administration or transdermal/topical delivery.…”

“…All organic solvents and other chemicals used were of analytical grade. Terpenoid hydrazones 1 – 15 were synthesized and fully characterized in our previous studies [ 21 , 22 , 23 ]. Pure terpenoids were used as obtained from their commercial supplier: (–)-verbenone, (–)-menthone and (–)-carvone (TCI, Philadelphia, PA, USA).…”

“…In this respect, oxygen-containing terpenes, as agonists of transient receptor potential (TRP) channels and allosteric modulators of GABA A receptors [ 17 , 18 ], were conjugated with para -substituted phenoxyacetic acid hydrazides that also manifest anticonvulsant and nociceptive potentialities [ 19 , 20 ]. Therefore, hydrazones based on carvone, menthone and verbenone were obtained and tested in vivo as potential antiseizure and analgesic agents with prolonged action due to the enzymatically degraded azomethine –NH–N=C– group in their structure [ 21 , 22 , 23 ]. Bearing in mind the high pharmacological effect of the aforementioned terpenoid derivatives with oral administration and topical applications, studies of their impact on lipid molecular organization are feasible.…”

Design, synthesis and pharmacological profile of (−)-verbenone hydrazones

“…The synthesis of (−)-verbenone hydrazones 3a-3e was performed via condensation of 4,6,6-trimethylbicyclo Here, we have to notice that condensation of bicyclic terpenoid verbenone with hydrazides requires more harsh reaction conditions (reflux for 12 h in n-PrOH), whereas monocyclic terpenoids (such as menthone or carvone [18,19]) react under mild conditions (reflux for 4 h in MeOH).…”