SYNTHESIS OF SOME BENZOXAZOLE-2(3H)-ONE/BENZOTHIAZOLE-2(3H)-ONE DERIVATIVES AND INVESTIGATION OF THEIR EFFECTS AGAINST ALZHEIMER'S DISEASE

Yıl 2024, Cilt: 48 Sayı: 1, 226 - 241, 20.01.2024

Merve Bardakkaya Burcu Kılıç Deniz Doğruer

https://doi.org/10.33483/jfpau.1387244

Öz

Objective: In this study, 28 new acetamide derivatives bearing benzoxazole/benzothiazole rings were synthesized and their effects against Alzheimer's disease were tested in vitro.
Material and Method: Amine derivatives (5 and 6) used in the synthesis of final compounds were synthesized by the methylation of commercially available 1,3-benzoxazol-2(3H)-one or 1,3-benzothiazol-2(3H)-one rings with dimethyl sulfate followed by nitration with nitric acid and then reduction with tin chloride. In order to synthesize acetamide derivatives, 5 and 6 was first acylated with bromoacetyl bromide to obtain intermediates 7 and 8. Then, these compounds was reacted with appropriate secondary amines to get the title compounds (9a-n and 10a-n). The structure of the synthesized compounds was elucidated by spectroscopic methods, HRMS and elemental analysis. After the cholinesterase inhibitor activities of all title compounds were determined by the modified Ellman method, their antioxidant activities were measured by the DPPH and ORAC method. Finally, the metal chelator properties of the title compounds were determined.
Result and Discussion: New 2-substituted-N-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol/1,3- benzothiazol-6-yl)acetamide derivative compounds were synthesized. Their cholinesterase inhibitory effects and structure activity relationships were determined. Compound 10g (IC50: 52.90 µM) was identified as the most potent acetylcholinesterase (AChE) inhibitor, and also compound 10h (IC50: 51.03 µM) was determined as the most active derivative for the butyrylcholinesterase (BChE). In the ORAC antioxidant activity test, compounds carrying phenylpiperazine derivatives in their side chains were found to show 3-5 times higher antioxidant activity than the reference trolox. Additionally, the metal chelator activity results of the title compounds showed that the majority of them had metal chelator properties.

Anahtar Kelimeler

Alzheimer’s disease, benzoxazolone, benzothiazolone, cholinesteraze inhibition, metal-chelating

Proje Numarası

TÜBİTAK 115S192

BAZI BENZOKSAZOL-2(3H)-ON/BENZOTİYAZOL-2(3H)-ON TÜREVLERİNİN SENTEZİ VE ALZHEİMER HASTALIĞINA KARŞI ETKİLERİNİN İNCELENMESİ

Öz

Amaç: Bu çalışmada benzoksazolon/benzotiyazolon halkası taşıyan asetamit türevi 28 yeni bileşik sentez edilmiş ve Alzheimer hastalığına karşı etkileri in vitro olarak test edilmiştir.
Gereç ve Yöntem: Sonuç bileşiklerin sentezinde kullanılan amin türevleri (5 ve 6), öncelikle ticari olarak mevcut 1,3-benzoksazol-2(3H)-on ve 1,3-benzotiyazol-2(3H)-on halkalarının metillenmesi, nitrik asit ile nitrolanması ve ardından kalay klorürle indirgenmesi ile sentez edilmiştir. Daha sonra, amin türevi 5 ve 6’nın bromoasetil bromür ile açilasyonundan hazırlanan ara ürünlerin (7 ve 8) uygun amin türevleri ile tepkimesinden sonuç bileşikler (9a-n ve 10a-n) elde edilmiştir. Sentezlenen bileşiklerin kimyasal yapıları spektroskopik yöntemler, HRMS ve elementel analiz ile aydınlatılmıştır. Tüm sonuç bileşiklerin modifiye Ellman yöntemiyle kolinesteraz inhibitör aktiviteleri belirlendikten sonra DPPH ve ORAC yöntemiyle antioksidan aktiviteleri ölçülmüştür. Son olarak sonuç bileşiklerin metal şelatör özellikleri tayin edilmiştir.
Sonuç ve Tartışma: Yeni 2-sübstitüe-N-(3-metil-2-okso-2,3-dihidro-1,3-benzoksazol/1,3-benzotiyazol-6-il)asetamit türevi bileşikler sentez edilmiştir. Kolinesteraz inhibitör etkileri ve yapı aktivite ilişkileri belirlenmiştir. Asetilkolinesteraz (AKE) inhibisyonu için bileşik 10g’nin (IC50: 52.90 µM), butirilkolinesteraz BKE inhibisyonu için bileşik 10h’nin (IC50: 51.03 µM ) en yüksek aktiviteye sahip olduğu bulunmuştur. ORAC testi ile yapılan antioksidan aktivite tayininde ise yan zincirinde fenilpiperazin türevleri taşıyan bileşiklerin referans trolokstan daha yüksek antioksidan aktivite gösterdikleri bulunmuştur. Ayrıca sonuç bileşiklerin metal şelatör etkileri incelendiğinde büyük çoğunluğunun metal şelatör özellik taşıdığı belirlenmiştir.

Anahtar Kelimeler

Alzheimer hastalığı, benzoksazolon, benzotiyazolon, kolinesteraz inhibisyonu, metal şelasyonu

Proje Numarası

TÜBİTAK 115S192

Kaynakça

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