Discovery of 1,4-diaryl-1,3-dihydro-2H-imidazole-2-thione anticonvulsants integrating AMPA receptor antagonism, Nav1.2 channel blockade, redox modulation, and favorable pharmacokinetic properties.

A series of 1,4-diaryl-1,3-dihydro-2H-imidazole-2-thione derivatives was designed and synthesized as anticonvulsant candidates, integrating AMPAR antagonism, neuronal Nav1.2 channel blockade, and antioxidant neuroprotection. Biological screening identified compound 6a as the lead analogue, producing complete protection in the MES model at 100 mg/kg and 80% protection in the PTZ model, with a 24-fold prolongation of seizure-onset latency compared to PTZ-group. Quantitative evaluation showed an MES ED50 of 11.03 mg/kg, close to phenytoin, but with a markedly wider protective index (45.3 vs 6.89) and no neurotoxicity up to (TD50 > 500 mg/kg). Mechanistically, 6a inhibited AMPARs more potently than phenytoin and comparable to GYKI-52466 (IC50 = 12.7 ± 0.4 vs 30.0 ± 4.0 μM, 8.7 ± 0.4 μM, respectively) and blocked Nav1.2 channels with higher potency than phenytoin (IC50 = 7.01 ± 1.1 vs 13.2 ± 2.0 μM), while showing negligible NMDAR liability. Compound 6a also showed excellent PAMPA-BBB permeability, minimal CYP3A4, CYP2D6, and CYP2C9 inhibition, and improved hepatic safety. Importantly, oral/i.p. PK profiling established its oral CNS exposure advantage: orally administered 6a reached serum Cmax 4-fold faster than phenytoin, increased brain Cmax by 3.16-fold, elevated brain AUC by 1.92-fold, and improved the brain/serum AUC ratio by 2.28-fold. Oral brain exposure exceeded the AMPAR and VGSC IC50 values by 6.38- and 11.57-fold, respectively, confirming pharmacologically relevant target coverage. Together, these findings identify compound 6a as a brain-penetrant AMPAR/Nav1.2-modulating anticonvulsant lead.