New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage‐gated sodium channels (VGSCs) and enhance γ‐aminobutyric acid (GABA)‐mediated response. LRZ, a positive allosteric modulator of A‐type GABA receptors (GABA A Rs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N ‐[1‐(4‐chlorophenyl)‐2‐(1 H ‐imidazol‐1‐yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6‐Hz psychomotor seizure test, a model for therapy‐resistant partial seizure. We performed molecular docking studies for our active compounds using GABA A R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA A R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA A R is elucidated.