DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Burcu Kılıç

Makale detayları

DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Yazarlar:

Burcu Kılıç

Yayıncı:

Ankara University

Ana Başlıklar:

Farmasotik Kimya

Dergi:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 3, pp.840-852

Belge Tipi:

Makale

Yayın Tarihi:

10/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001319061

pISSN:

1015-3918

Anahtar kelimeler:

Özet:

 Objective: In this study, following the multi-target directed ligands MTDLs strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N-benzylidenepropanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-substitutedaminopropanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-substitutedaminopropanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a IC50  12.83 µM and 2d IC50  16.02 µM were identified as the most potent inhibitors for acetylcholinesterase AChE and butyrylcholinesterase BChE, respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for CuII, FeII, and ZnII ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

 Objective: In this study, following the multi-target directed ligands MTDLs strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N-benzylidenepropanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-substitutedaminopropanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-substitutedaminopropanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a IC50  12.83 µM and 2d IC50  16.02 µM were identified as the most potent inhibitors for acetylcholinesterase AChE and butyrylcholinesterase BChE, respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for CuII, FeII, and ZnII ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

 Objective: In this study, following the multi-target directed ligands MTDLs strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N-benzylidenepropanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-substitutedaminopropanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-substitutedaminopropanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a IC50  12.83 µM and 2d IC50  16.02 µM were identified as the most potent inhibitors for acetylcholinesterase AChE and butyrylcholinesterase BChE, respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for CuII, FeII, and ZnII ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

 Amaç: Bu çalışmada, çoklu hedefe yönelik ligand MTDL stratejisi izlenerek ve nöroprotektif ferulik asit yapısından ilham alınarak, sekiz yeni N-benzilidenpropanhidrazit türevleri tasarlandı, sentezlendi, kolinesteraz inhibitör ve antioksidan kapasitelerini değerlendirmek üzere test edildi. Gereç ve Yöntem: Sonuç bileşiklerin eldesi için ilk olarak, kilit ara ürünler olan 3-aminopropanhidrazitler, metil 3-sübstitüeaminopropanoat ara ürünlerinin hidrazin hidrat ile hidrolizinden hazırlandı. Bu ara ürünler ise metil akrilat ve ticari olarak mevcut tersiyer amin türevlerinin Michael katım tepkimesinden hazırlanmıştır. Hazırlanan kilit ara ürünlerin, seri hareket bileşikleri olan 4-hidroksibenzaldehit veya 4-metoksibenzaldehit ile katım tepkimesinden sonuç bileşikler sentezlenmiştir. Sentezlenen ve saflaştırılan bileşiklerin 1H-NMR, 13C-NMR ve HRMS analizleri ile yapı kontrolleri gerçekleştirilmiştir. Ardından, sonuç bileşiklerin modifiye Ellman yöntemiyle kolinesteraz inhibitör etki, DPPH ve ORAC yöntemleriyle antioksidan etki ve UV-spektroskopisi analiziyle de metal şelatör etki incelemeleri yapılmıştır. Ayrıca tüm bileşiklerin ilaç olabilirliklerini değerlendirebilmek amacıyla QikProp Schrodinger Suite 2023 kullanılarak fizikokimyasal parametreleri hesaplanmıştır. Sonuç ve Tartışma: Sekiz sonuç bileşikten yedisinin değişen oranlarda kolinesteraz inhibisyonu oluşturdukları bulunmuştur. Bileşik 2a IC50  12.83 µM ve 2d IC50  16.02 µM sırasıyla en iyi asetilkolinesteraz AChE ve bütirilkolinesteraz BChE inhibitörü olarak belirlenmiştir. Bununla birlikte, ORAC testinde tüm bileşikler antioksidan etki göstermiştir. Tüm bileşiklerin CuII, FeII, ve ZnII iyonları için değişen oranlarda şelatör etkileri de gözlenmiştir. Ayrıca, final bileşikler, in-siliko tahminlere göre kabul edilebilir öncü benzeri özellikler göstermiştir.

Makale detayları

DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Yazarlar:

Burcu Kılıç

Yayıncı:

Ankara University

Ana Başlıklar:

Farmasotik Kimya

Dergi:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 3, pp.840-852

Belge Tipi:

Makale

Yayın Tarihi:

10/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001319061

pISSN:

1015-3918

Acylhydrazone

antioxidant

Alzheimer’s disease

cholinesterase inhibition

metal-chelatorAçilhidrazon

Alzheimer hastalığı

antioksidan

kolinesteraz inhibisyonu

metal-şelatör

Sayı

Makale detayları

Yazarlar: Burcu Kılıç

Yayıncı: Ankara University

Ana Başlıklar: Farmasotik Kimya

Dergi: Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 3, pp.840-852

Belge Tipi: Makale

Yayın Tarihi: 10/2024

Belge Dili: İngilizce

Document ID (Org No.): 2001319061

pISSN: 1015-3918

Sayı

Yazarlar:

Burcu Kılıç

Yayıncı:

Ankara University

Ana Başlıklar:

Farmasotik Kimya

Dergi:

Ankara Üniversitesi Eczacılık Fakültesi Dergisi Vol.48 Issue 3, pp.840-852

Belge Tipi:

Makale

Yayın Tarihi:

10/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001319061

pISSN:

1015-3918