Pyridin-4-ylmethyl-5-bromothiophene-2-carboxylates as potential antiseizure molecules: Pd- catalyzed Suzuki–Miyaura synthesis, dual GABAA/SV2A targeting, EEG analysis and pharmacokinetic insights

Abstract

Epilepsy remains a serious neurological condition for which a large number of patients show resistance to current antiepileptic medications. In this study, a series of novel pyridin-4-ylmethyl-5-bromothiophene-2-carboxylate derivatives (5a-5h) were designed and synthesized using an efficient Suzuki–Miyaura cross-coupling approach to explore their anticonvulsant potential. The afforded compounds were structurally characterized using spectroscopic techniques and evaluated through multiple in vivo seizure models, including pentylenetetrazole (PTZ), maximal electroshock seizure (MES), and 6 Hz psychomotor assays. Among the tested compounds, derivative 5g demonstrated the most potent anticonvulsant activity, significantly delaying seizure onset, reducing seizure severity, and providing substantial protection against mortality in the PTZ model, along with partial efficacy in MES and 6 Hz models. Electroencephalography (EEG) analysis further confirmed its ability to attenuate epileptiform discharges and cortical hyperexcitability. Molecular docking studies demonstrated favorable binding interactions of active sites, particularly 5g, with SV2A and GABAA receptor targets, comparable to standard drugs. In silico ADMET profiling indicated good drug-like properties and high gastrointestinal absorption, although blood-brain barrier permeability varied across the series.

Graphical abstract