SavedAdd your journal

Journals / Journal of Gazi University Health Sciences Institute / 2022 / Cilt: 4 Sayı: 2

Novel 2,6-disubstituted-3-(2H)-pyridazones as Cholinesterase Inhibitors: In vitro Enzyme Inhibition and In silico Molecular Modelling and Dynamic Studies

Azime Berna ÖZÇELİK
Hasan Erkan RÜZGAR
Fatma Sezer ŞENOL DENİZ
İlkay ERDOĞAN ORHAN
Mehmet Abdullah ALAGÖZ
Zeynep ÖZDEMİR
Pages
80–95
Publication Date
2022-08-31
DOI
—
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

The obtained results suggest that new pyridazinone derivatives can act as BChE inhibitory agents.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:The approach proposed as the cholinergic hypothesis for Alzheimer's Disease contributed significantly to the explanation of cognitive decline observed in the elderly and Alzheimer's patients due to dysfunction of neurons containing acetylcholine in the brain.
📊
Key Findings & Data:To date, this notion has formed the basis of most of the treatment strategies and drug development approaches for Alzheimer Disease.
💡
Conclusion & Impact:The obtained results suggest that new pyridazinone derivatives can act as BChE inhibitory agents.
🔬Design:Modeling & Simulation
📍Scope:Comprehensive Sample
⚙️Variables:Alzheimer · AChE · BChE

Abstract

The approach proposed as the cholinergic hypothesis for Alzheimer's Disease contributed significantly to the explanation of cognitive decline observed in the elderly and Alzheimer's patients due to dysfunction of neurons containing acetylcholine in the brain. To date, this notion has formed the basis of most of the treatment strategies and drug development approaches for Alzheimer Disease. Within the scope of this study, in which the synthesis and biological evaluation of pyridazinones, which are designed for multi-enzyme targets and expected to act as AChE and BChE inhibitors, were performed, 12 new compounds were synthesized, their in vitro enzyme inhibitor activities were evaluated and molecular modeling studies were carried out. While the compounds did not show significant AChE inhibition, they showed a high degree of BChE inhibition. D2e was determined as the most potent BChE inhibitor and molecular modeling and molecular dynamics simulation studies were also carried out for D2e and tacrine. The obtained results suggest that new pyridazinone derivatives can act as BChE inhibitory agents. Although the synthesized compounds are less effective than the reference drugs, it has been concluded that it is possible to reach the precursor compounds as a result of suitable modifications.

🔖

Cite This Article

ÖZÇELİK, A. B., RÜZGAR, H. E., DENİZ, F. S. Ş., ORHAN, İ. E., ALAGÖZ, M. A., ÖZDEMİR, Z. (2022). Novel 2,6-disubstituted-3-(2H)-pyridazones as Cholinesterase Inhibitors: In vitro Enzyme Inhibition and In silico Molecular Modelling and Dynamic Studies. Journal of Gazi University Health Sciences Institute, Cilt: 4 Sayı: 2, 80–95. https://ajindex.com/articles/906224

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (10)

  1. Ahmed, E. M., Hassan, M. S., El-Malah, A. A., Kassab, A. E. (2020). New pyridazine derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents; design, synthesis and biological evaluation., Bioorganic Chemistry, 95, 103497. https://doi.org/10.1016/j.bioorg.2019.103497
  2. Alagöz, M. A., Özdemir, Z., Özçelik, A. B. (2019). Molecular Modelling Studies of Pyridazinone Derivatives as Antibutyrylcholinesterases. International Journal of Pharmacy and Chemistry, 5(3), 26-30. https://doi.org/10.11648/j.ijpc.20190503.11
  3. Anand, P. & P. Singh,P. (2013). A review on cholinesterase inhibitors for Alzheimer’s disease. Archives of Pharmacal Research, 36, 375-399. https://doi.org/10.1007/s12272-013-0036-3
  4. Banerjee, P. S. (2011). Various Biological Activities of Pyridazinone Ring Derivatives. Asian Journal of Chemistry, 23, 1905-1910.
  5. Bozbey, İ., Özdemir, Z., Uslu, H., Özçelik, A. B., Şenol, F. S., Orhan-Erdoğan, İ., Uysal, M. (2020). A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies. Mini-Reviews in Medicinal Chemistry, 20(11), 1042-1060. https://doi.org/10.2174/1389557519666191010154444 Çeçen,M., Oh, J. M., Özdemir, Z., Büyüktuncel, S. E. Uysal, M., Abdelgawad, M. A.,. Musa,A., Gambacorta, N., Nicolotti, O., Mathew, B., Kim H. (2020).
  6. Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors. Molecules, 25(22), 5371. https://doi.org/10.3390/molecules25225371
  7. Chatonnet, A. & Lockridge, O. (1989). Comparison of butyrylcholinesterase and acetylcholinesterase. Biochemical Journal, 260(3), 625-634. https://doi.org/10.1042/bj2600625
  8. Ciftci, O., Özdemir, Z., Acar, C., Sözen, M., Basak-Türkmen, N., Ayhan, I., Gözükara, H. (2018). The Novel Synthesized Pyridazinone Derivates had the Antiproliferative and Apoptotic Effects in SHSY5Y and HEP3B Cancer Cell Line. Letters in Organic Chemistry, 15(4), 323-331. https://doi.org/10.2174/1570178614666170707154210
  9. Costas-Lago, M. C., Besada, P., Rodrıguez-Enrıquez, F., Viña, D., Vilar, S., Uriarte, E., Borges, F., Terán, C. (2017).Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors. European Journal of Medicinal Chemistry., 139, 1-11. https://doi.org/10.1016/j.ejmech.2017.07.045
  10. Dvir, H., Silman, I., Harel, M., Rosenberry, T. L., Sussmana, J. L. (2010). Acetylcholinesterase: fro