Docking and Anticonvulsant Study of Benzothiazole-Pyrimidine-linked Analogues
Amol Kale, Smita Pawar, Vishal Jagtap, Srushti Jadhav, Rajendra Kakde, Ishwar KakdeIntroduction and Objectives:
Epilepsy is a neurological disorder characterized by recurrent seizures, and currently available antiepileptic drugs (AEDs) have had only limited success. This study was undertaken to design and synthesize a novel series of benzothiazole–pyrimidine-linked acetamide analogues and to evaluate their anticonvulsant potential through in vivo biological screening, neurochemical investigations, acute toxicity assessment, and molecular docking studies against the GABAA receptor. The study was based on the hypothesis that molecular hybridization of benzothiazole and pyrimidine pharmacophores could generate compounds with enhanced anticonvulsant efficacy and improved safety profiles.
Methods:
The compounds were synthesized through a three-step procedure and structurally confirmed using IR and ¹H NMR spectroscopy. Anticonvulsant activity was assessed in Swiss albino mice using the maximal electroshock (MES) and pentylenetetrazole (scPTZ) seizure models. Neurotoxicity was evaluated using the rotarod test, brain GABA levels were quantified by spectrophotometric analysis, and receptor-binding affinity was assessed by molecular docking against the GABAA receptor (PDB ID: 4COF). Acute toxicity studies were also conducted to determine safety.
Results:
Among the synthesized derivatives, CP-4 showed the highest level of anticonvulsant activity protection at a dose of 30 mg/kg (MES) and 100 mg/kg (scPTZ) without neurotoxicity at a dose of 300 mg/kg. Neurochemical analysis revealed a significant increase in GABA levels in the brain to 71.35 μmol/g tissue, only slightly lower than the reference standard, phenobarbital, at 74.58 μmol/g tissue. Acute toxicity studies showed safety at a dose of 300 mg/kg. However, death was recorded at a dose of ≥1000 mg/kg. Molecular docking analysis showed the formation of hydrogen bonds (THR96A), hydrophobic interactions (ASP95A, THR96A), and π-π interaction between the amino groups of CP-4 and the aromatic amino acid PHE98A with a docking score of -3.909 kcal/mol and a binding energy of -19.11 kcal/mol, indicating a favorable interaction within the receptor binding pocket.
Discussion:
The results of pharmacological and computational studies show that CP-4 exhibited promising anticonvulsant activity in both MES and scPTZ seizure models. This is due to its enhanced GABA activity and its significant interaction with the GABAA receptor. Also, its good safety profile supports its potential as a promising lead compound.
Conclusion:
CP-4 is a promising, safe anticonvulsant candidate with significant GABA-enhancing activity and strong receptor-binding properties. These results suggest that pyrimidine-acetamide structures may contribute significantly to the development of new AEDs. More studies on its pharmacokinetics (ADMET) and SAR are needed to improve its therapeutic use.