Design, synthesis, in vivo and in silico evaluation of novel benzothiazole-hydrazone derivatives as new antiepileptic agents

In humans, epilepsy becomes a serious health problem due to scarcity of effective medications against it. Most of the available anti-epileptic drugs have severe adverse effects with little efficacy along with long duration of treatment. As there are constant increases in the number of epileptic patient, new and more potent anticonvulsant medications are constantly sought after. After taking into the consideration of structural requirements (pharmacophore model) of antiepileptic drugs, some new (5-benzothiazol-2-yl-2-methoxy-phenoxy)-acetic acid (1-substituted-ethylidene)-hydrazides (6a-o) have been designed and synthesized. All the synthesized compounds have been evaluated for anticonvulsant potential by utilizing maximal electroshock (MES) and subcutaneous pentylenetetrazole ( sc PTZ) models. Neurotoxicity of the synthesized compounds was also checked using rotarod performance test. Among all of the synthesized compounds, compound 6c, 6g, 6n , and 6o have been found with significant anticonvulsant potential as compared with phenytoin with no neurotoxicity. Subsequently, antidepressant activities (motor impairment screening) of the active antiepileptic compounds have been checked by actophotometer following standard protocol. All the compounds have also shown good antidepressant activity. In silico studies (molecular docking and physicochemical parameters calculations) of the synthesized compounds was also carried on different targets to determine the possible mechanism of action. The obtained results of In silico studies also backs the antiepileptic potential of the synthesized compounds. The study also established that the synthesized compounds have exerted their antiepileptic action via voltage gated sodium channels (VGSCs). Graphical abstract