Abstract
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•Benzothiazoles contain an extended π-delocalized system that binds to DNA molecules via π–π interactions and demonstrates complex biological properties such as antimicrobial, anticancer, anti-inflammatory, antidiabetic, anticonvulsant, vasorelaxant, and larvicidal activities.•Antagonism of GABAergic inhibition in healthy brain results in acute epileptic discharges, and blockers of GABA receptors, including penicillin, pentylenetetrazole (PTZ), and bicuculline, are widely used as experimental epilepsy models.•The titled compounds consist of all essential pharmacophoric elements that are necessary for a molecule to show anticonvulsant activity.
In this paper, we report the synthesis of 2-[(6-substituted benzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothiourea derivatives (4a-y) carrying active pharmacophores essential for anticonvulsant activity. The anticonvulsant activity was evaluated in vivo by maximal electroshock (MES) test and subcutaneous pentylenetetrazole (scPTZ) test in mice. Most of the compounds showed promising anticonvulsant activity. The most active compounds 4b and 4q were found active in both MES and scPTZ models, without signs of neurotoxicity. Compound 4b showed the moderate change in SGOT and alkaline phosphatase level as compared to control. Compounds 4b and 4w were also found to elevate GABA levels in the olfactory lobe, mid brain, medulla oblongata and cerebellum regions of rat brain. In molecular docking study, the title compounds exhibited good binding properties with epilepsy molecular targets such as GABA-A. Structure-activity relationships are also elaborated along with the analysis of lipophilicity. The results suggested that compound 4b is likely to have varied mechanisms of action including voltage-gated ion channel inhibition and modulating GABAergic action.