In silico SAR-Guided Discovery of Imidazole-Based Anticonvulsants with Optimized ADMET Profiles

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures caused by abnormal electrical activity in the brain. The development of novel anticonvulsant agents with improved efficacy and safety remains a significant therapeutic challenge. This study aimed to evaluate imidazole derivatives as potential anticonvulsant candidates through comprehensive in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis. Materials and Methods: A total of 29 imidazole derivatives were evaluated using SwissADME for physicochemical and drug-likeness properties. Based on favorable characteristics, the top eight compounds were selected for detailed pharmacokinetic and toxicity assessment using pkCSM and admetSAR. The clinically approved antiepileptic drug phenytoin was included as a reference compound for comparative analysis. Structure-Activity Relationship (SAR) and target prediction analyses were also performed to investigate the relationship between structural features and anticonvulsant activity. Results: All compounds complied with Lipinski’s rule of five, with molecular weights ranging from 217 to 438 Da. The selected compounds exhibited favorable Log p values (1.35-2.36) and Topological Polar Surface Area (TPSA) values (44.12-70.42 Ų), indicating good drug-likeness and excellent intestinal absorption (99.8-100%). Compound A21 demonstrated the highest Blood-Brain Barrier (BBB) permeability (log BB= 0.182) and Central Nervous System (CNS) penetration (log PS= -1.3). Compound A20 exhibited moderate BBB permeability (log BB = -0.898), a higher clearance rate (0.887 log mL/min/kg), lower predicted neurotoxicity (18.15%) than A21 (44.45%), and acceptable acute toxicity (LD₅₀=2.461 mol/kg). SAR analysis suggested that the imidazole core and ester substitutions contribute to enhanced BBB permeability and reduced neurotoxicity. Target prediction identified GABA-A receptors, GRM4/GRM5, and ADORA1/ADORA2A as potential molecular targets, indicating modulation of inhibitory and excitatory neurotransmission. Conclusion: Among the evaluated compounds, A20 demonstrated the most balanced pharmacokinetic and safety profile, highlighting its potential as a promising anticonvulsant candidate. These findings support further in vitro and in vivo investigations to validate its therapeutic efficacy and safety.