Synthesis and Structure Activity Relationship of New Aryl and Heteroaryl Semicarbazones as Anticonvulsants

Abstract

In the present thesis, six series of aryl and heteroaryl semicarbazones and their analogues were designed and synthesized based on 3-dimenstional four point pharmacophore model using both CHARMM (ACD 3D views) and MM3 (Alchemy 2000) force fields. The structure of the synthesized compounds was confirmed by spectral (IR, 1H-NMR, Mass) and elemental analysis. The synthesized compounds were preliminary evaluated for their anticonvulsant activity by MES and scPTZ tests. Compounds which showed promising activity, were further tested in scPTZ and scPIC screens. The synthesized compounds were also evaluated for various CNS side effects i.e. neurotoxicity, depression and behavioral despair effect. Neurochemical study has also been done on some selective compounds to discover the mechanism behind their anticonvulsant activity. The synthesized compounds were tested for their effect on the GABA level in the rat brain tissues/whole brains. Quantum mechanical modeling and structure activity relationship studies were also carried out on these compounds to understand the structural features essential for activity. The effect of EHOMO, ELUMO and and#916;E on anticonvulsant activity was studied. The higher the and#916;E values, greater was the activity profile. Along with this HOMO surface analysis was also done, to confirm the pharmacophoric requirement for anticonvulsant activity. Most of the synthesized compounds exhibited broad spectrum of activity i.e. exhibited protection in more than one seizure model. The most potent compound with broad spectrum of activity was found to be compound TR-18 (4-(4-fluorophenyl)-5-(4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one), which exhibited protection in all the four seizure models with lesser neurotoxicity and behavioral side effects. The compound resulted in a 10-fold increase in the GABA level in rat brain when compared to the control.