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 (GABAARs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N‐[1‐(4‐chlorophenyl)‐2‐(1H‐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 GABAAR and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABAAR in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABAAR is elucidated. N‐[1‐(4‐Chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethylidene]hydroxylamine esters were prepared and in vivo evaluated for their protective potentials against convulsions induced by the 6‐Hz, maximal electroshock, and subcutaneous metrazol methods. While most of the derivatives were active in at least one of the models, compound 4c stood out with an ED50 of 48.85 mg/kg in the 6‐Hz test at 0.25 h in mice administered via the intraperitoneal route.
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research