Clinical drug-oriented design, synthesis, and pharmacological evaluation of novel dual-target antiepileptic hybrid molecules

Epilepsy is a common neurological disorder frequently complicated by drug resistance, underscoring the urgent need for novel therapeutic agents. Using a pharmacophore hybridization strategy, we designed and synthesized two series of novel hybrid compounds by conjugating memantine (an NMDA Receptor Antagonist) with levetiracetam (a modulator of synaptic vesicle glycoprotein 2 A, SV2A) and lacosamide (a Sodium Channel blocker), respectively. Cytotoxicity screening against four human cell lines at 100 μM identified 11 compounds with >70% cell viability. Among them, compound 11a-d lacosamide-memantine hybrid linked by a flexible alkyl chain-was selected as the most promising candidate based on in silico ADME profiling and safety evaluation. In mice, 11a exhibited no overt toxicity or neurotoxicity at doses up to 200 mg/kg. In the pentylenetetrazole (PTZ)-induced seizure model, administration of 11a at 50 mg/kg significantly prolonged the latency to first clonic seizure by 57% (from 76.3 s in the vehicle group to 179.0 s) and reduced the Racine score by 40% (from 5.25 to 3.13), achieving anticonvulsant efficacy comparable to lacosamide and levetiracetam. CETSA and DARTS assays confirmed that 11a simultaneously binds to voltage-gated sodium channels (Nav) and N-methyl-d-aspartate receptors (NMDAR), supporting its dual-target mechanism of action. Although passive blood-brain barrier permeability was predicted to be low, the potent central anticonvulsant activity of 11a suggests sufficient brain exposure, likely via active uptake transporters. Collectively, this study validates the dual-target hybridization strategy and identifies 11a as a promising lead for antiepileptic drug development.