New Anti-Seizure (Arylalkyl)azole Derivatives: Synthesis,In VivoandIn SilicoStudies: Anti-Seizure (Arylalkyl)azole Derivatives

Sari, Suat; Dalkara, Sevim; Kaynak, Filiz Betül; Reynisson, Jóhannes; Saraç, Selma; Karakurt, Arzu

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 (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.

Citation

Sari, S., Dalkara, S., Kaynak, F. B., Reynisson, J., Saraç, S., & Karakurt, A. (2017). New Anti-Seizure (Arylalkyl)azole Derivatives: Synthesis,In VivoandIn SilicoStudies: Anti-Seizure (Arylalkyl)azole Derivatives. Archiv der Pharmazie / Chemistry in Life Sciences, 350(6), Article e201700043. https://doi.org/10.1002/ardp.201700043

• Journal Article Type: Article
• Online Publication Date: May 2, 2017
• Publication Date: 2017-06
• Deposit Date: Jun 12, 2023
• Journal: Archiv der Pharmazie
• Print ISSN: 0365-6233
• Publisher: Wiley-VCH Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 350
• Issue: 6
• Article Number: e201700043
• DOI: https://doi.org/10.1002/ardp.201700043
• Keywords: Drug Discovery; Pharmaceutical Science