Facile Synthesis of Thiophen‐2‐ylmethyl 5‐Phenylfuran‐2‐Carboxylates Through SMC Reaction: Assessing Their Anti‐Seizure Potential and Molecular Docking Studies

Abstract The anticonvulsant efficacy of a novel series of thiophen‐2‐ylmethyl 5‐phenylfuran‐2‐carboxylate derivatives (5a–5h) was evaluated through in vivo and in silico investigations. The in vivo anticonvulsant activity was tested using acute pentylenetetrazol (PTZ) seizure and 6 Hz psychomotor models. The molecular docking analysis established that all the investigated ligands showed promising inhibiting activity towards the epileptic target macromolecules; GABA a receptor from mice and SV2A protein in outward open state. In addition, lipophilicity profile analysis confirms the BBB of all the studied ligands. Compounds 3 and 5g were shown to be the most effective out of all the synthesized compounds (5a–5h) through in silico and in vivo studies. In comparison to standard drugs (levetiracetam and diazepam), these compounds show no neurotoxicity. In silico analysis also revealed that synthesized compounds (5a–5h) had multiple binding affinities to localize binding receptors. Molecular docking studies against GABA a receptor and SV2A transporter proteins was conducted for their mechanistic relevance to seizure suppression and functional compatibility with the ligand's hydrophobic scaffolds which revealed strong binding affinities, supporting multi‐target anticonvulsant action. Among the series, 3 and 5g were found to be potent anticonvulsant molecules, which can act as a lead scaffold for further drug development.