Bazı yeni hidrazon türevlerinin sentezi, anti-alzheimer aktivitelerinin araştırılması ve moleküler modelleme çalışmaları
Yükleniyor...
Dosyalar
Tarih
2021
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
İnönü Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Alzheimer hastalığı (AH) tedavisi için çoklu enzim hedeflerine yönelik olarak tasarlanan, AChE, MAO-A ve MAO-B inhibitörü etki göstermesi beklenen, (2-florofenil)piperazin yapısı içeren piridazinonların sentezi ve biyolojik değerlendirmesinin yapıldığı bu tez kapsamında 12 bileşiğin sentezinin yapılması amaçlanmıştır. Sentezlere hazır alınan 3,6-dikloropiridazin ile 2-florofenilpiperazinin reaksiyonuyla başlanmıştır. Elde edilen 3-kloro-6-[4-(2-florofenil)piperazin-1-il]piridazin molekülü glasiyel asetik asit içerisinde hidroliz edilerek 6-[4-(2-florofenil)piperazin-1-il]-3(2H)-piridazinon bileşiğine ulaşılmıştır. Sonrasında etil bromoasetatla muamelesinden ester türevine, bir sonraki basamakta da hidrazinhidratla reaksiyonundan son basamakta olan 6-[4-(2-florofenil)piperazin-1-il]-3(2H)-piridazinon-2-ilasetohidrazit bileşiğine ulaşılmıştır. Sonuç bileşikleri ise sübstitüe veya nonsübstitüe benzaldehitler ile asetohidrazit molekülünün reaksiyonuyla elde edilmiştir. Elde edilen bileşiklerin erime noktası tayinleri yapılmış, verimleri belirlenmiş, bileşiklerin yapıları 1H-NMR, 13C-NMR ve HRMS gibi çeşitli spektroskopik yöntemleriyle kanıtlanmıştır. AChE enzim inhibisyonu Ellman metodu ile tayin edilmiş, fakat bileşiklerin hiçbiri belirgin enzim inhibitörü aktivite göstermemiştir. Bileşiklerin rekombinant insan MAO-A ve MAO-B inhibitör aktiviteleri, sırasıyla kinuramin (0.06 mM) ve benzilamin (0.3 mM) kullanılarak test edilmiştir. T6'nın 0.013 µM IC50 değeri ile en güçlü MAO-B inhibitörü olduğu ve bunu 0.039 µM IC50 değeri ile T3 bileşiğinin takip ettiği bulunmuştur. MAO-B için inhibe edici güç, meta bromo sübstitüsyonu (T6) ile para bromo sübstitüsyonundan (T7) daha fazla artmıştır. T6 ve T3, 1.57 ve 4.19 µM'lık IC50 değerleri ile MAO-A'yı etkili bir şekilde inhibe etmiştir. MAO bağlama bölgeleri ile moleküler yerleştirme simülasyonları, MAO-B ile T6 ve T3 için MAO-A'ya göre daha yüksek yerleştirme skorları vermiştir. Sonuç: Bu sonuçlar, T3 ve T6'nın MAO-B'nin seçici, geri dönüşümlü ve yarışmalı inhibitörleri olduğunu ve AH gibi nörodejeneratif bozuklukların tedavisi için öncü adaylar olarak düşünülebileceğini göstermiştir.
Within the scope of this thesis, the synthesis of 12 compounds is aimed, in which the synthesis and biological evaluation of pyridazinones containing (2-fluorophenyl) piperazine structure, designed for multiple enzyme targets and expected to act as an AChE, MAO-A and MAO-B inhibitor. Synthesis started with the reaction of commercially available 3,6-dichloropyridazine with 2-fluorophenylpiperazine. The obtained 3-chloro-6- [4-(2-fluorophenyl) piperazin-1-yl]pyridazine molecule is hydrolyzed in glacial acetic acid and 6-[4-(2fluorophenyl) piperazin-1-yl]-3(2H)pyridazinone compound was reached. Then, from the treatment with ethyl bromoacetate, the ester derivative was obtained, and in the next step, the last step of the starting materials, 6- [4- (2-fluorophenyl) piperazin-1-yl] -3 (2H) -pyridazinone-2-ylacetohydrazide, was obtained from the reaction with hydrazine hydrate. Result compounds were obtained by the reaction of substituted or nonsubstituted benzaldehydes and acetohydrazide molecule. The melting point of the obtained compounds were determined, their percentage yields were determined, the structures of the compounds were proved by various spectroscopic methods such as 1H-NMR, 13C-NMR and HRMS. AChE enzyme inhibition was determined by the Ellman method, but none of the compounds showed significant enzyme inhibitory activity. The recombinant human MAO-A and MAO-B inhibitory activities of the compounds were tested using kinuramine (0.06 mM) and benzylamine (0.3 mM), respectively. T6 was found to be the strongest MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 compound with an IC50 value of 0.039 µM. The inhibitory power for MAO-B increased more than para bromo substitution (T7) with meta bromo substitution (T6). T6 and T3 effectively inhibited MAO-A with IC50 values of 1.57 and 4.19 µM. Molecular insertion simulations with MAO binding sites gave higher insertion scores for T6 and T3 with MAO-B than for MAO-A. Conclusion: These results show that T3 and T6 are selective, reversible and competitive inhibitors of MAO-B and can be considered as leading candidates for the treatment of neurodegenerative disorders such as Alzheimer's disease.
Within the scope of this thesis, the synthesis of 12 compounds is aimed, in which the synthesis and biological evaluation of pyridazinones containing (2-fluorophenyl) piperazine structure, designed for multiple enzyme targets and expected to act as an AChE, MAO-A and MAO-B inhibitor. Synthesis started with the reaction of commercially available 3,6-dichloropyridazine with 2-fluorophenylpiperazine. The obtained 3-chloro-6- [4-(2-fluorophenyl) piperazin-1-yl]pyridazine molecule is hydrolyzed in glacial acetic acid and 6-[4-(2fluorophenyl) piperazin-1-yl]-3(2H)pyridazinone compound was reached. Then, from the treatment with ethyl bromoacetate, the ester derivative was obtained, and in the next step, the last step of the starting materials, 6- [4- (2-fluorophenyl) piperazin-1-yl] -3 (2H) -pyridazinone-2-ylacetohydrazide, was obtained from the reaction with hydrazine hydrate. Result compounds were obtained by the reaction of substituted or nonsubstituted benzaldehydes and acetohydrazide molecule. The melting point of the obtained compounds were determined, their percentage yields were determined, the structures of the compounds were proved by various spectroscopic methods such as 1H-NMR, 13C-NMR and HRMS. AChE enzyme inhibition was determined by the Ellman method, but none of the compounds showed significant enzyme inhibitory activity. The recombinant human MAO-A and MAO-B inhibitory activities of the compounds were tested using kinuramine (0.06 mM) and benzylamine (0.3 mM), respectively. T6 was found to be the strongest MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 compound with an IC50 value of 0.039 µM. The inhibitory power for MAO-B increased more than para bromo substitution (T7) with meta bromo substitution (T6). T6 and T3 effectively inhibited MAO-A with IC50 values of 1.57 and 4.19 µM. Molecular insertion simulations with MAO binding sites gave higher insertion scores for T6 and T3 with MAO-B than for MAO-A. Conclusion: These results show that T3 and T6 are selective, reversible and competitive inhibitors of MAO-B and can be considered as leading candidates for the treatment of neurodegenerative disorders such as Alzheimer's disease.
Açıklama
Anahtar Kelimeler
Eczacılık ve Farmakoloji, Pharmacy and Pharmacology
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Çeçen, M. (2021). Bazı yeni hidrazon türevlerinin sentezi, anti-alzheimer aktivitelerinin araştırılması ve moleküler modelleme çalışmaları. Yayınlanmış Doktora Tezi, İnönü Üniversitesi.
