ABSTRACT
(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 (GABAA Rs), was reported to be sensitive to Asn265 of the ß2/ß3 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 GABAA R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABAA R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABAA R is elucidated.
Subject(s)
Anticonvulsants/therapeutic use , Azoles/therapeutic use , Molecular Docking Simulation , Seizures/drug therapy , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Azoles/administration & dosage , Azoles/chemical synthesis , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Male , Mice , Mice, Inbred Strains , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.
