Synthesis and Anticonvulsant Activity or Novel Dihydroimidazole- 1 - Carbo(Thio) Hydrazide Derivatives

Abstract

Epilepsy is the third most widely spread neurological disorder found in the elderly after cerebrovascular disease and dementia. There is a significant unmet medical need for new, effective, and safe drugs. Extensive literature review revealed that two structures among the compounds studied for anticonvulsant activity are (thio) semicarbazone moiety and imidazolinone ring show potent anticonvulsant activity. Hence 1st series carbothioamide moiety with imidazolinone and 2nd series imidazolinone with carboxamide were designed using pharmacophore distance mapping techniques and synthesized. These title compounds in series-1 were prepared by condensation of substituted aryl carbothioamide with 4-benzylidene-2- methyloxazolone whereas in 2nd series, condensation of substituted aryl carboxamide with 4- benzylidene-2-methyloxazolone gave the designed molecule. Ultrasonication reaction was used to synthesize carbothioamide and carboxamide intermediates with better yield and purity. Structure elucidation of the synthesized compounds was done by spectral analysis. The anticonvulsant activity of the title compounds (100 mg/kg) was evaluated using scPTZ model (60mg/kg) and carbamazepine (reference standard) (100 mg/kg). All synthesized compounds of both series showed no sedation side effect as compared to reference standard. The present study indicated that hydroxy substituted compounds (RS-1 and RS-3) and chloro substituted derivatives (RS-6 and RS-7) showed significant protection against pentylenetetrazole induced convulsions as well as mortality within 24 h in mice and also decreased number of clonic convulsions and increased onset time for clonic convulsion which was statistically significant in comparison to control. These can be regarded as strong candidates for future investigations.