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

Mariia Nesterkina,Dmytro Barbalat,Iryna Kravchenko

doi:10.1515/chem-2020-0103

Abstract

AbstractA series of novel (−)-verbenone hydrazones was designed and synthesized via condensation of terpenoid with hydrazides derived from phenoxyacetic acid. The structure of target compounds was confirmed by 1H-NMR and 13C-NMR analysis, Raman and FT-IR spectroscopy, electrospray ionization method and fast atom bombardment (FAB) mass spectrometry. Thermal properties of (−)-verbenone hydrazones 3a–3e were estimated by differential scanning calorimetry and their purity by HPLC coupled to mass spectrometry. Verbenone hydrazones were revealed to exist as Z/E geometrical isomers about C═N bond and cis/trans amide conformers. Verbenone derivatives were estimated as potential anticonvulsant agents after their oral administration against pentylenetetrazole and maximal electroshock-induced seizures in mice. Analgesic effect of hydrazones was studied by topical application on models of allyl isothiocyanate and capsaicin-induced pain. The present findings indicate that verbenone hydrazones contribute to seizure protection both at short (6 h) and long (24 h) time periods by blocking chemical- and electroshock-induced convulsions. Binding of compounds 3a–3e to TRPA1/TRPV1 ion channels was suggested as a feasible mechanism explaining their significant analgesic activity.

Highlights

A series of novel (−)-verbenone hydrazones was designed and synthesized via condensation of terpenoid with hydrazides derived from phenoxyacetic acid
The formation of verbenone derivatives was elucidated by mass spectrometry – molecular ion peaks of target compounds 3a–3e correspond to their molecular formulas (FAB and electrospray ionization method (ESI))
The synthesis of (−)-verbenone hydrazones 3a–3e was performed via condensation of 4,6,6-trimethylbicyclo

Summary

Introduction

Abstract: A series of novel (−)-verbenone hydrazones was designed and synthesized via condensation of terpenoid with hydrazides derived from phenoxyacetic acid. Verbenone derivatives were estimated as potential anticonvulsant agents after their oral administration against pentylenetetrazole and maximal electroshock-induced seizures in mice. Terpenoids are unique scaffold that might be used for further chemical modification aimed at synthesizing the compounds simultaneously affecting the central and peripheral nervous systems. In this context, substantial attention is concentrated on hydrazones comprising their structure azomethine group ‒NH‒N═C‒ and undergoing hydrolytic reactions both in vitro and in vivo [8,9].

General

Anticonvulsant activity

Analgesic action

Statistical analysis

Chemistry

Conclusion