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

Abstract

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'-(benzylidene)propanehydrazide 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-(substitutedamino)propanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-(substitutedamino)propanoate 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 Cu(II), Fe(II), and Zn(II) ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

Keywords

• Acylhydrazone
• antioxidant
• Alzheimer’s disease
• cholinesterase inhibition
• metal-chelator

ALZHEİMER HASTALIĞI İÇİN MTDL OLARAK YENİ N'-PROPANHİDRAZİTLERİN TASARIMI, SENTEZİ VE BİYOLOJİK DEĞERLENDİRMESİ

Abstract

Amaç: Bu çalışmada, çoklu hedefe yönelik ligand (MTDL) stratejisi izlenerek ve nöroprotektif ferulik asit yapısından ilham alınarak, sekiz yeni N'-(benziliden)propanhidrazit 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-(amino)propanhidrazitler, metil 3-(sübstitüeamino)propanoat 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 Cu(II), Fe(II), ve Zn(II) iyonları için değişen oranlarda şelatör etkileri de gözlenmiştir. Ayrıca, final bileşikler, in-siliko tahminlere göre kabul edilebilir öncü benzeri özellikler göstermiştir.

Keywords

• Açilhidrazon
• Alzheimer hastalığı
• antioksidan
• kolinesteraz inhibisyonu
• metal-şelatör

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