Synthesis and characterization of novel conjugates of 4-[3-(aryl/heteroaryl)-3-oxo-propenyl]-benzaldehyde with thiazole and thiazolidinones as possible voltage-gated sodium channel blockers

Abstract

A series of chalcones of thiazole and thiazolidinone (3a–3j) were synthesized, characterized and evaluated for anticonvulsant activity. The structures of all the new synthesized compounds were established by spectral and elemental analysis. The anticonvulsant activity was performed by maximal electroshock seizure (MES) in mice, and all the derivatives were found to be active. The compounds investigated for their ability to prevent chemically (isoniazid) induced seizures, when compared with phenytoin and diazepam. Results of the anticonvulsant activity revealed that among all the synthesized compounds, naphthalene and halo (4-fluoro-phenyl)-substituted ring serves as the lipophilic aryl portion. Thus, compound 3c (95.61 % inhibition of the convulsions) and 3b (66.07 % inhibition of the convulsions), with log P values of 3.40 and 2.70, respectively, exhibited potential anticonvulsant activity in MES and isoniazid-induced convulsion model at a dose of 50 mg/kg, respectively. Compound 3c was also found to be least hydrolysed (1.92 %) in simulated gastric fluid (SGF). Thus, hydrolysis and most lipophilic character of compound 3c made it a potent member of the series. Results showed that all the derivatives were more effective against MES model than isoniazid (INH) model. It can be promulgated that these compounds may act bind preferentially to the inactive form of the voltage-gated sodium channels (VGSCs) through blocking sustained high-frequency repetitive firing of action potentials, similar to phenytoin. Compound 3-(4-{[4-(4-methoxy-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenyl)-1-naphthalen-2-yl-propenone (3c) was found to be almost equipotent to phenytoin (97.32 % inhibition of the convulsions) in the MES model.