ALZHEİMER HASTALIĞINA KARŞI YENİ PİPERAZİN TÜREVLERİNİN SENTEZİ VE BİYOLOJİK AKTİVİTELERİNİN DEĞERLENDİRİLMESİ

Year 2022, Volume: 31 Issue: 3, 330 - 335, 26.12.2022

Derya Osmaniye , Zafer Asım Kaplancıklı

https://doi.org/10.34108/eujhs.979093

Cited By: 2

Abstract

Alzheimer hastalığı dünyada en sık görülen nörodejeneratif hastalıklardan biridir. Dünya nüfusunun yaş ortalamasının artması ile artan hasta sayısı, radikal bir tedavinin mevcut olmaması yeni bileşiklerin geliştirilmesine ihtiyaç oluşturmaktadır. Hastalığa karşı kolinesteraz inhibitörleri sıklıkla kullanılmaktadır. Bilinen iki kolinesteraz, asetilkolinesteraz (AChE) ve butirilkolinesteraz (BChE)’dır. AH'dan etkilenen beyinlerde, normal koşullar altında ACh hidrolizinden sorumlu ana enzim olan AChE miktarı azalırken, BChE konsantrasyonu korunur, hatta yükselebilmektedir.Bu çalışma kapsamında8 yeni bileşikten oluşan 6-(2-(4-sübstitüepiperazin-1-il) asetil)-2H-benzo[b] [1,4] oksazin-3(4H)-on (1a-1h) serisi sentezlenmiştir. Elde edilen bileşiklerin yapıları 1H-NMR, 13C-NMR ve HRMS spektroskopisi verileri kullanılarak aydınlatılmıştır. Bileşiklerin in vitrokolinesteraz (ChE) inhibitör aktivitesi Elmann metodu kullanılarak değerlendirilmiştir. Sentezlenen bileşikler içerisinde 1b ve 1e kodlu bileşikler asetilkolinesteraza (AChE) karşı önemli düzeyde inhibitor etkinlik göstermiştir. Sentezlenen bileşiklerin asetilkolinesteraz inhibitör potansiyelleri incelendiğinde umut verici sonuçlara ulaşıldığı görülmektedir. Ayrıca aktif türevler ile gerçekleştirilen in siliko moleküler doklama çalışmaları ile aktif bileşiklerin enzim aktif bölgesine oturduğu ve bu bölgedeki aminoasitler ile etkileştiği görülmektedir. Elde edilen bileşikler üzerinde yapılan modifikasyonlar ile daha etkili yeni bileşiklere ulaşılması planlanmaktadır.

Keywords

Piperazin, Asetilkolin, Alzheimer

SYNTHESIS AND EVALUATION OF BIOLOGICAL ACTIVITIES OF NEW PIPERAZINE DERIVATIVES AGAINST ALZHEIMER'S DISEASE

Abstract

Alzheimer's disease is one of the most common neurodegenerative diseases in the world. The increasing number of patients with the aging of the world population and the absence of a radical treatment create a need for the development of new compounds. Cholinesterase inhibitors are frequently used against the disease. The two known cholinesterase’s are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In AD-affected brains, the amount of AChE, the main enzyme responsible for ACh hydrolysis, is reduced under normal conditions, while the concentration of BChE is maintained or even increased.The 6-(2-(4-substitutedpiperazin-1-yl) acetyl)-2H-benzo[b][1,4] oxazin-3(4H)-one (1a-1h) series consisting of 8 new compounds was synthesized. The structures of the obtained compounds were elucidated using 1H-NMR, 13C-NMR and HRMS spectroscopy data. The in vitro cholinesterase (ChE) inhibitory activity of the compounds was evaluated using the Ellman's method. Among the synthesized compounds, the compounds 1b and 1e showed significant inhibitory activity against acetylcholinesterase (AChE). When the acetylcholinesterase inhibitory potentials of the synthesized compounds are examined, it is seen that promising results have been achieved. Additionally, in silico molecular docking studies with active derivatives show that active compounds have settled in the enzyme active site and interact with amino acids in this region. It is planned to reach more effective new compounds with the modifications made on the obtained compounds.

Keywords

Piperazine, Acetylcholine, Alzheimer

References

• Chen Y, Dang M, Zhang Z. Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and–specific lesion patterns. Mol Neurodegener 2021; 16(1):1-22.
• Zhang L, Zhang G, Xu S, Song Y. Recent Advances of Quinones as a Privileged Structure in Drug Discovery. Eur J Med Chem 2021; 113632.
• Michalska P, Buendia I, Barrio LD, Leon R. Novel multitarget hybrid compounds for the treatment of Alzheimer’s disease. Curr Top Med Chem 2017; 17(9):1027-1043.
• Ferreira JP, Albuquerque HM, Cardoso SM, Silva AM, Silva VL. Dual-target compounds for Alzheimer’s disease: natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur J Med Chem 2021; 113492.
• Srivastava S, Ahmad R, Khare SK. Alzheimer’s disease and its treatment by different approaches: a review. Eur J Med Chem 2021; 113320.
• Mohamed T, PN Rao P. Alzheimer's disease: emerging trends in small molecule therapies. Curr Med Chem 2011; 18(28):4299-4320.
• Thapa S, Lv M, Xu H. Acetylcholinesterase: a primary target for drugs and insecticides. Mini Rev Med Chem 2017; 17(17):1665-1676.
• Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013; 11(3):315-335.
• Zimmerman G, Soreq H. Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission. Cell Tissue Res 2006; 326(2):655-669.
• Saxena M, Dubey R. Target enzyme in Alzheimer’s disease: Acetylcholinesterase inhibitors. Curr Top Med Chem 2019; 19(4):264-275.
• Nachon F, Carletti E, Ronco C, et.al. Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl-and butyryl-cholinesterase. Biochem J 2013; 453(3):393-399.
• Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2):88-95.
• Acar Cevik U, Saglik BN, Levent S, et al. Synthesis and AChE-inhibitory activity of new benzimidazole derivatives. Molecules 2019; 24(5):861.
• Osmaniye D, Sağlık BN, Acar Çevik U, et. al. Synthesis and AChE inhibitory activity of novel thiazolylhydrazone derivatives. Molecules 2019; 24(13):2392.
• Cheung J, Rudolph MJ, Burshteyn F, et. al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 2012; 55(22):10282-10286.
• Maestro, Version 10.6, Schrödinger, LLC: New York, NY, USA, 2021.
• Schrödinger, Version 2021-2, LLC: New York, NY, USA, 2021.
• LigPrep, Version 3.8, Schrödinger, LLC: New York, NY, USA, 2021.
• Glide, Version 7.1, Schrödinger, LLC: New York, NY, USA, 2021