Anticonvulsant activity, organotypic hippocampal neuroprotection assay and in-silico sodium channel blocking potential of 2-amino-6-nitrobenzothiazole derived semicarbazones

Abstract

Epilepsy is one of the dreadful neurodegenerative disorder characterized by recurrent, unprovoked seizures. Currently available antiepileptic drugs are still associated with enormous side effects resulting in search of newer, more effective and safer agents. In view of this, we have investigated anticonvulsant activity of 2-amino-6-nitrobenzothiazole derived semicarbazones (7–32) in various in-vivo animal seizure models viz. maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6Hz psychomotor seizure model. Neurotoxicity was estimated by rotarod test. The compounds were also assessed for their neuroprotective potential from excitotoxic insult using organotypic hippocampal slice culture neuroprotection assay. Several compounds exhibited excellent anticonvulsant activity in MES and scPTZ models compared to reference drugs, phenytoin and levetiracetam. The results of kainic acid (KA) – induced neuroprotection assay indicated that compounds 26 and 24 were found to be most potent with IC50 of 99.54±1.27 and 101.00±1.20μM respectively. Both the compounds attenuated KA-mediated cell death in organotypic hippocampal slice cultures. Some of the compounds were found to be good antidepressants, better than the reference drug citalopram, when analyzed in forced swim test. Since semicarbazones exhibited profile resembling phenytoin, an attempt was made to screen them against human neuronal sodium channel isoform (hNav1.2) by performing computational molecular docking using AutoDock 4.2. Compound 30, 1-(5-Chloro-2-oxoindolin-3-ylidene)-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as lead candidate possessing excellent in-vivo MES activity and high binding affinity computationally, better than the reference drug phenytoin and also exhibited neuroprotection from excitotoxic insult in KA-induced neuroprotection assay (IC50=126.80±1.24μM). However, some of the active compounds were neurotoxic at their anticonvulsant doses. Further optimization studies are needed to reduce toxicity and develop them as novel therapeutic agents for epilepsy.