Yeni Tiyazolil-Hidrazin Türevlerinin Sentezi ve Asetilkolinesteraz (AChE) ve Bütirilkolinesteraz (BuChE) Aktivite Çalışmaları

Year 2022, , 277 - 285, 30.06.2022

Ayşen Işık , Ulviye Acar Çevik , Tugba Ercetin , Ahmet Koçak

https://doi.org/10.35193/bseufbd.1017849

Abstract

Alzheimer hastalığı (AH), zamanla beyin hücrelerinin ölümüne bağlı olarak bilişsel işlevlerde azalma, hafıza kaybı ve bunama ile ilişkilendirilmiştir. Alzheimer hastalığının tedavisinde sınırlayıcı uygulamaların mevcut oluşu, hastalığın sağlık harcamalarında kanser ve kalp hastalıklardan sonra dünyada üçüncü sırada oluşu araştırmacıları AH üzerinde erken evrede tanıma ve yeni tedavi yöntemlerine yönlendirmektedir. Günümüzde kolinerjik anomalikler ile AH arasında doğrudan bir ilişki olduğu düşünülmektedir. Çalışmalar, asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) inhibisyonunun asetilkolin (ACh) seviyesinde meydana gelen artışların Alzheimer hastalığının başlangıç evrelerindeki bilişsel yetmezliği iyileştirebileceğini kanıtlamıştır. Dolayısıyla ACh düzeylerini arttırmak için uygulanacak en iyi metot ise, ACh’yi yıkan AChE veya BuChE enzimlerinin baskılanmasıdır. Dolayısıyla yapılan bu çalışmada, sübstitüe edilmiş tiyazolilhidrazin türevleri tasarlanmış, sentezlenmiş ve AH’ ye karşı asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) kolinesteraz enzimlerinin inhibisyon potansiyelleri araştırılmıştır. Hedef bileşiklerin yapıları 1H NMR/13C NMR analiz yöntemleri ile aydınlatılmıştır. Hedef bileşiklerin AChE ve BuChE enzimleri üzerindeki inhibisyon etkileri Ellman yöntemiile değerlendirilmiş ve hedef bileşiklerin enzim inhibisyon çalışmaları sonucunda 3d bileşiğinin orta düzeyde bütirilkolinesteraz enzimini inhibe ettiği tespit edilmiştir.

Keywords

Alzheimer Hastalığı, Tiyazolilhidrazin, Ellman Metot

Synthesis of Novel Thiazolyl-Hydrazine Derivatives and Activity Studies of Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE)

Abstract

Alzheimer's disease (AD) has been associated with ecreased cognitive function, memory loss, and dementia due to the death of brain cells over time. Existence of limiting practices in the treatment of AD, and the fact that the disease ranks third in health expenditures in the world after cancer and heart diseases, directs researchers to early diagnosis and new treatment methods on AD. Today, it is thought that there is a direct relationship between cholinergic abnormalities and AD. Studies have shown that acetylcholine (ACh) level increases due to acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition can improve cognitive impairment in the initial stages of Alzheimer's disease. The best method to increase these ACh levels is to suppress the AChE or BuChE enzymes that break down ACh. Therefore, in this study, substituted thiazolylhydrazine derivatives were designed, synthesized and their cholinesterase inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes against AD were investigated. The structures of the target compounds were illuminated by 1H NMR/13C NMR analysis methods. The effects of the target compounds on the on AChE and BuChE enzymes were evaluated using the Ellman process and as a result of the enzyme inhibiton studies of the target compounds, it was determined that the 3d compound showed moderate butyrylcholinesterase activity.

Keywords

Alzheimer, Thiazolylhydrazine, Ellman Method

References

• Prince, M., Guerchet, M. & Prina, M. (2013). Policy brief for heads of government: the global impact of dementia. The Global Impact of Dementia, 8, 2013-2050.
• Shah, H., Albanase, E. & Duggan, C. (2016). Research priorities to reduce the global burden of dementia by 2025. The Lancet Neurology, 15, 1285-1294.
• Li, Y., Zhang, X. X., Jiang, L.J., Yuan, L., Cao, T., Li, X., Dong, L., Li, Y., & Yin, S.F. (2015). Inhibition of acetylcholinesterase (AChE): A potential therapeutic target to treat Alzheimer’s disease. Chemical Biology & Drug Design, 86, 776-782.
• Kumar, G.P. & Khanum, F. (2012). Neuroprotective potential of phytochemicals. Pharmacognosy Reviews, 6, 81-90.
• Kocaelli, H., Yaltirik, M., Yargic, L.I., & Ozbas, H. (2002). Alzheimer’s disease and dental management. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 93, 521-4.
• Hofman, A., Ott, A., Breteler, M. M., Bots, M. L., Slooter, A. J., Van Harskamp, F., Van Duijin, C.N., Van Broeckhoven, C., & Grobbee, D.E. (1997). Atherosclerosis, apolipoprotein E. and prevalance of dementia and Alzheimer’s disease in the Rotterdam Study. The Lancet, 349, 151-4.
• Parihar, M. S., & Hemnani, T. (2004). Experimental excitotoxicity provokes oxidative damage in mice brain and attenuation by extract of Asparagus racemosus. Journal of Neural Transmission, 111, 1–12.
• Shidore M., Machhi, J., Shingala, K., Murumkar, P., Sharma, M. K., Agrawal, N., Tripathi, A., Parikh, Z., Pillai, P. & Yadav, M. R. (2016). Benzylpiperidine-linked Diarylthiazoles as Potential Anti-alzheimer’s Agents: Synthesis and Biological Evaluation. Journal of Medicinal Chemistry, 59, 5823–5846.
• Das, U. N. (2012). Acetylcholinesterase and butyrylcholinesterase as markers of low-grade systemic inflammation, Annals of hepatology, 11, 409-411.
• Tripathi, A. (2008). Acetylcholinsterase: A Versatile Enzyme of Nervous System. Annals of Neuroscience, 15, 106-111.
• Barta, C., Sasvari-Szekely, M., Devai, A., Kovacs, E., Staub, M. & Enyedi, P. (2001). Analysis of mutations in the plasma cholinesterase gene of patients with a history of prolonged neuromuscular block during anesthesia. Molecular Genetics and Metabolism, 74, 484-488.
• Silman, I. & Sussman J.L. (2005). Acetylcholinesterase: 'classical' and 'non-classical' functions and pharmacology, Current Opinion in Pharmacology, 5, 293-302.
• Greig, N. H., Utsuki, T., Yu, Q., Zhu, X., Holloway, H. W., Perry, T., Lee, B., Ingram, D. K. & Lahiri, D. K. (2001). A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase, Current Medical Research and Opinion, 17, 159-165.
• Bartus, R. T., Dean, R. L., Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408-414.
• Bartus, R. T. (2000). On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Journal of Experimental Neurology, 163, 495-529.
• Hasselmo, M. E. (2006). The role of acetylcholine in learning and memory. Current Opinion in Neurobiology, 16, 710-715.
• Rees, T. M., & Brimijoin, S. (2003). The role of acetylcholine in the pathogenesis of Alzheimer’s disease. Drugs of Today, 39, 75-83.
• Quinn, D. M. (1987). Acetylcholinesterase: Enzyme structure, reaction dynamics, and virtual transition states. Chemical Reviews, 87, 955-979.
• Wang, Q., Wang, C., Zuo, Y., Wang, Z., Yang, B., & Kuang, H. (2012). Compounds from the roots and rhizomes of Valerianaamurensis protectagainst neurotoxicity in PC12 cells. Molecules, 17, 15013-15021.
• Massoulie, J., Pezzementi, L., Bon, S., Krejci, E., & Valette, F. M. (1993). Molecular and cellular biology of cholinesterases. Progress in Neurobiology, 41,31-91.
• Reid, G. A., Chilukuri, N., & Darvesh, S. (2013). Butyrylcholinesterase and the cholinergic system. Journal of Neuroscience, 234, 53-68.
• Masson, P., & Lockridge, O. (2010). Butyrylcholinesterase for protection from organophosphorus poisons: Catalytic complexities and hysteretic behavior. Archives of Biochemistry and Biophysics, 494, 107-120.
• Becker, R. E. (1991). Therapy of the Cognitive Deficit in Alzheimer’s Disease: the Cholinergic System. In Cholinergic Basis for Alzheimer Therapy, 1-22. Birkhäuser, Boston, MA.
• Robinson, D. M., & Keating, G.M. (2006). Memantine: : a review of its use in Alzheimer's disease. Drugs, 66(11), 1515–1534.
• Heinrich, M. (2010). Galanthamine from galanthus and other amaryllidaceae—Chemistry and biology based on traditional use. The Alkaloids: Chemistry and Biology, 68, 157-165.
• Thomsen, T., & Kewitz, H. (1990). Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Science Journal, 46, 1553-1558.
• Grossberg, G. T. (2003). Cholinesterase inhibitors for the treatment of Alzheimer’s disease: Getting on and staying on. Current Therapeutic Research, 64, 216-235.
• Arendt, T., Brückner, M. K., Lange, M., & Bigl, V. (1992). Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s diseaseresemble embryonic development—A study of molecular forms. Neurochemistry International, 21, 381-396.
• Soyer, Z., Uysal, S., Parlar, S., Tarikogullari Dogan, A. H., & Alptuzun, V. (2017). Synthesis and molecular docking studies of some 4- phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1), 13-19.
• Özkay, Ü. D., Can, Ö. D., Özkay, Y., & Öztürk, Y. (2012). Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocininduced cognitive deficits. Pharmacological Reports, 64(4), 834-847.
• Siddiqui, N., Arshad, M. F., Ahsan, W., & Alam, M. S. (2009). Thiazoles: a valuable insight into the recent advances and biological activities. International Journal of Pharmaceutical Sciences and Drug Research, 1, 136–143.
• Matsunaga, Y., Tanaka, T., Yoshinaga, K., Ueki, S., Hori, Y., & Eta, R. (2011). Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitör enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride. Journal of Pharmacology and Experimental Therapeutics, 336, 791–800.
• Alptüzün, V., Prinz, M., & Hörr, V. (2010). Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with β-amyloid, acetylcholine, and butyrylcholine esterases. Bioorganic & Medicinal Chemistry, 18, 2049–59.
• Ellman, G. L., Courtney, K. D., Andres, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7, 88-95.
• Özkay, Y., Yurttaş, L., Abu Mohsen, U., Sever, B., Hussein, W., Ozturk, O., ... & Kaplancikli, Z. (2014). Study on thiazolyl-hydrazone derivatives as acetylcholinesterase inhibitors. Clinical and Experimental Health Sciences, 4, 1.