Rationale Design, Synthesis, and Pharmacological Evaluation of Isatin Analogues as Antiseizure Agents

Abstract

Background: Epilepsy is one of the most common and devastating neurological diseases affecting about 1% of the world’s population at any time. Herein, we have reported rationale design and synthesis of 5-acetyl-3-((4-substitutedphenyl)imino)indolin-2-one analogues 3(a-k) as antiseizure agents. Objective: These analogues were designed as four component pharmacophoric model by clubbing structural fragments of potent antiepileptic drugs. The Aim of this study is to synthesize structurally designed isatin analogues and screen them for anticonvulsant activity and neurotoxicity. Methods: The compound 3d have exhibited good anticonvulsant activity in preclinical seizure models with better toxicity profile when compared to standard drugs (3d: ED50 = 31.5 mg/kg, MES test; ED50 = 37.4 mg/kg, scPTZ test; TD50 = 384.3 mg/kg,). Compound 3d have also shown good binding affinity at crucial amino acids of GluN1 subunit of NMDAR (Docking score = -9.30) and fit adequately in the cavity of the receptor (Amino acids involved and H-bonding distance = GLY93: acetyl >C=O, 2.38Å; PHE92: acetyl >C=O, 2.22Å; and THR26: >C=O of isatin, 1.71Å). Results of molecular docking supported the structural features present over isatins to persuade potent antiseizure activity. Results: The compound 3d have exhibited good anticonvulsant activity in preclinical seizure models with better toxicity profile when compared to standard drugs (3d: ED50 = 31.5 mg/kg, MES test; ED50 = 37.4 mg/kg, scPTZ test; TD50 = 384.3 mg/kg,). Compound 3d have also shown good binding affinity at crucial amino acids of GluN1 subunit of NMDAR (Docking score = -9.30) and fit adequately in the cavity of the receptor (Amino acids involved and H-bonding distance = GLY93: acetyl >C=O, 2.38Å; PHE92: acetyl >C=O, 2.22Å; and THR26: >C=O of isatin, 1.71Å). Results of molecular docking supported the structural features present over isatins to persuade potent antiseizure activity. Conclusion: Rationale designing strategy, in-vivo pharmacological profile, and computational studies make us anticipate the emergence of these molecules as novel antiseizure agents, which can be further explored to develop probes for the treatment of epilepsy.