Zafer Asım KAPLANCIKLI, Leyla YURTTAŞ, Carine MASQUEFA, Gülhan TURAN-ZİTOUN, Ahmet ÖZDEMİR

Bazı İmidazo[1,2-a]pirazin Türevlerinin Sentezi ve Antinosiseptif Aktivitelerinin Değerlendirilmeleri

Amaç: İmidazopirazin halkası biyolojik olarak aktif bir heterosiklik halkadır. Bir dizi hidrazid-hidrazon türevi bileşiğin antibakteryial-antifungal, antikonvülzan, antiinflamatuvar, antitüberkülotik ve analjezik aktiviteye sahip olduğu belirtilmiştir. Aroilhidrazid-hidrazon yapısını içeren piridin, indol, imidazo [2,1-b]piridin ve imidazo[1,2-a]pirazin gibi hetero halkalar özel ilgi çekmektedir. N-(4-Sübstitüe benziliden)imidazo[1,2-a]pirazin-2-karbohidrazit (2a-j) türevi bileşikler daha önce belirtilen iki farmakoforik grup kullanılarak önceki çalışmamızda yapılan sentez prosedürüne göre tasarlanmış ve elde edilmiştir. Bütün sonuç bileşiklerinin antinosiseptif aktiviteleri incelenmiştir.Yöntemler: Bileşiklerin yapıları 1H-NMR, 13C-NMR ve Kütle spektroskopisi gibi spektroskopik metodlarla aydınlatılmıştır. On adet sonuç bileşiği potansiyel in vivo antinosiseptif aktiviteleri sıcak taban ve asetik asitle indüklenmiş kıvranma testi kullanılarak araştırılmıştır. Ayrıca bu bileşiklerin potansiyel antikonvülzan aktiviteleri Pentilentetrazol (PTZ) ile uyarılmış nöbetlere karşı değerlendirilmiştir. Rota-Rod testi bileşiklerin muhtemel nörolojik hasarlarını incelemek amacıyla yapılmıştır.Bulgular: Serideki bileşiklerden hiçbiri sıcak tabaka testinde belirgin bir etki gösterememiştir. Bununla birlikte 2f bileşiği asetik asitle indüklenmiş kıvranma testinde 100 mg/kg dozla bileşiğin antinosiseptif etkisini gösteren bir biçimde kıvranma davranışının sayısında göze çarpan bir düşüşe neden olmuştur. Farelerin Rota-Rod gecikme süreleri test bileşikleri tarafından değiştirilememiştir. Ayrıca, test bileşikleri PTZ ile indüklenen nöbet testlerinde de etkisizdir.Sonuç: Benziliden kalıntısı taşıyan 2f bileşiği en aktif türev olarak belirlendi.

Anahtar Kelimeler:

Antinosiseptif, hidrazon, imidazopirazin, sıcak taban testi, kıvranma testi

Synthesis of Some Imidazo[1,2-a]pyrazine Derivatives and Evaluation of Their Antinociceptive Activity

Objective: The imidazopyrazine ring is a biologically active heterocyclic ring. Many hydrazide–hydrazone-possessing compounds have been reported to have interesting bioactivity, such as antibacterial, antifungal, anticonvulsant, anti-inflammatory, antituberculosis, and analgesic activities. In particular, aroyl hydrazides/hydrazone-containing hetero-rings, such as indole, pyridine, and imidazo[2,1-b]pyridine, and imidazo[1,2-a]pyrazine, have attracted special attention. We designed and synthesized N-(4-substitutedbenzylidene)imidazo[1,2-a]pyrazine-2-carbohydrazide (2a-j) derivatives using the two aforementioned pharmacophoric units based on the synthetic procedure indicated in our previous study.Methods: The structures of the compounds were elucidated using 1H-NMR, 13C-NMR, and mass spectroscopy. Ten final compounds were screened for their possible in vivo antinociceptive activity using a hot plate and acetic acid-induced writhing tests. In addition, the potential anticonvulsant activities of these compounds were evaluated using the PTZ-induced seizure test. A rotarod test was performed to examine probable neurological deficits because of the test compounds.Results: In the hot plate tests, none of the test compounds in the series demonstrated a significant effect. However, compound 2f, which was administrated at 100 mg/kg, significantly decreased the number of writhing behaviors in the acetic acid-induced writhing tests, indicating the antinociceptive activity of this compound. The rotarod latencies of mice were not changed by the test compounds. Furthermore, the tested compounds were ineffective in the PTZ-induced seizure tests.Conclusion: Compound 2f bearing 5-benzylidene moiety was determined as the most active compound.

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