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

Merve Bardakkaya; Burcu Kılıç; Deniz Doğruer

Article Details

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

Authors:

Merve Bardakkaya | Burcu Kılıç | Deniz Doğruer

Publisher:

Ankara University

Main Topics:

Farmasotik Kimya

Journal:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 1, pp.226-241

Document Type:

Article

Publication Date:

1/2024

Document Language:

Turkish

Document ID (Org No.):

2001300957

pISSN:

1015-3918

Keywords:

Abstract:

 Objective: In this study, 28 new acetamide derivatives bearing benzoxazolebenzothiazole rings were synthesized and their effects against Alzheimers 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-23H-one or 1,3-benzothiazol-23H-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-benzoxazol1,3- benzothiazol-6-ylacetamide 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.

 Objective: In this study, 28 new acetamide derivatives bearing benzoxazolebenzothiazole rings were synthesized and their effects against Alzheimers 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-23H-one or 1,3-benzothiazol-23H-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-benzoxazol1,3- benzothiazol-6-ylacetamide 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.

 Objective: In this study, 28 new acetamide derivatives bearing benzoxazolebenzothiazole rings were synthesized and their effects against Alzheimers 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-23H-one or 1,3-benzothiazol-23H-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-benzoxazol1,3- benzothiazol-6-ylacetamide 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.

 Amaç: Bu çalışmada benzoksazolonbenzotiyazolon 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-23H-on ve 1,3-benzotiyazol-23H-on halkalarının metillenmesi, nitrik asit ile nitrolanması ve ardından kalay klorürle indirgenmesi ile sentez edilmiştir. Daha sonra, amin türevi 5 ve 6nın 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-benzoksazol1,3-benzotiyazol-6-ilasetamit türevi bileşikler sentez edilmiştir. Kolinesteraz inhibitör etkileri ve yapı aktivite ilişkileri belirlenmiştir. Asetilkolinesteraz AKE inhibisyonu için bileşik 10gnin IC50: 52.90 µM, butirilkolinesteraz BKE inhibisyonu için bileşik 10hnin 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.

Article Details

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

Authors:

Merve Bardakkaya | Burcu Kılıç | Deniz Doğruer

Publisher:

Ankara University

Main Topics:

Farmasotik Kimya

Journal:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 1, pp.226-241

Document Type:

Article

Publication Date:

1/2024

Document Language:

Turkish

Document ID (Org No.):

2001300957

pISSN:

1015-3918

Alzheimer’s disease

benzoxazolone

benzothiazolone

cholinesteraze inhibition

metal-chelatingAlzheimer hastalığı

benzoksazolon

benzotiyazolon

kolinesteraz inhibisyonu

metal şelasyonu

Issues

Article Details

Authors: Merve Bardakkaya | Burcu Kılıç | Deniz Doğruer

Publisher: Ankara University

Main Topics: Farmasotik Kimya

Journal: Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 1, pp.226-241

Document Type: Article

Publication Date: 1/2024

Document Language: Turkish

Document ID (Org No.): 2001300957

pISSN: 1015-3918

Issues

Authors:

Merve Bardakkaya | Burcu Kılıç | Deniz Doğruer

Publisher:

Ankara University

Main Topics:

Farmasotik Kimya

Journal:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 1, pp.226-241

Document Type:

Article

Publication Date:

1/2024

Document Language:

Turkish

Document ID (Org No.):

2001300957

pISSN:

1015-3918