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

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 (GABA Rs), 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 GABA R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA R is elucidated.

Synthesis, anticonvulsant screening, and molecular modeling studies of new arylalkylimidazole oxime ether derivatives

“…Anticonvulsant activities of some compounds containing imidazole and pyrazole as azole group and naphthalene ring as aryl group were investigated in our previous studies. Derivatives prepared in this study were more active than the nafimidone oxime derivatives with aromatic ester and those bearing ester/ether groups with 1–3 carbon as the small oxygen functional group, according to our previous studies (Karakurt et al, , , ; Sari et al, , ; Özdemir et al, 2015). In this study, more active compounds were achieved by increasing the carbon chain of the ether moiety (4–7 carbon lengths).…”

“…1‐(2‐Naphthyl)‐2‐bromoethanone ( 2 ), 1‐(2‐naphthyl)‐2‐(1 H ‐imidazol‐1‐yl)ethanone ( 3 ), and 1‐(2‐naphthyl)‐2‐(1 H ‐imidazol‐1‐yl)ethanone oxime ( 4 ) were prepared according to the previously reported methods (Scheme ; Immediata & Day, ; Karakurt et al, , , , ; Ozdemir et al, ; Sari et al, , ; Walker, Wallach, & Hirschfeld, ).…”

“…(Arylalkyl)azoles (AAAs) emerged as a class of antiepileptic compounds with nafimidone and denzimol. Various chemical modifications on AAAs have shown that those containing oxygen groups on the alkyl chain between the naphthalene and the azole rings are the most active (Karakurt, Alagöz, Sayoğlu, Calıs, & Dalkara, ; Karakurt et al, , ; Karakurt, Özalp, Işık, Stables, & Dalkara, ; Ozdemir et al, ; Robertson et al, ; Sari et al, , ). As seen in Figure , the title compounds, 1‐(2‐naphthyl)‐2‐(1 H ‐imidazol‐1‐yl)ethanone oxime ether derivatives, were designed to provide the structural requirements for anticonvulsant activity.…”

“…(Arylalkyl)azoles (AAAs) emerged as a class of antiepileptic compounds with nafimidone and denzimol. Various chemical modifications on AAAs have shown that those containing oxygen groups on the alkyl chain between the naphthalene and the azole rings are the most active (Karakurt, Alagöz, Sayo glu, Calıs, & Dalkara, 2012;Karakurt et al, 2001Karakurt et al, , 2006Karakurt, Özalp, Işık, Stables, & Dalkara, 2010;Ozdemir et al, 2015;Robertson et al, 1986;Sari et al, 2016Sari et al, , 2017.…”

“…Significant anticonvulsant activity was found in some (arylalkyl) imidazole oxime ester and ether derivatives previously synthesized by our research group (Karakurt et al, 2006(Karakurt et al, , 2010Ozdemir et al, 2015;Sari et al, 2016Sari et al, , 2017. In addition, the ester derivatives containing long alkyl chain attached to nafimidone alcohol, the active metabolite of nafimidone, were prepared and especially isovaleric, valeric, and valproic acid derivatives were found effective (Karakurt et al, 2010Sari et al, 2016Sari et al, , 2017.…”