In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

BACKGROUND: The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action. METHODS: The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site. RESULT: Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively. CONCLUSION: Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

Recent Development in Substituted Benzothiazole as an Anticonvulsant Agent.

Heterocyclic compounds and their derivatives gained more attention due to their valuable biological and pharmacological properties. Benzothiazole is a heterocyclic structure containing a bicyclic ring system with a large panel of applications. The benzothiazole is present in many new products undergoing research hoping that it possesses various biological activities. Epilepsy is a diverse group of diseases marked by neuronal excitability and hypersynchronous neuronal activity of motor, sensory or autonomic events with or without loss of consciousness. Presently, many antiepileptic drugs like lamotrigine, stiripentol tiagabine, pregabalin, felbamate, and topiramate are available and effective towards 60-80% of patients only, along with undesirable side effects, such as hepatotoxicity, gastrointestinal disturbance, drowsiness, gingival hyperplasia, and hirsutism. Thus, many attempts are still on-going to develop antiepileptic drugs with a safer profile. This review is mainly focused on the compilation of reported scientific literature data in the recent one-decade on the anticonvulsant activity of benzothiazole compounds.