Araştırma Makalesi
BibTex RIS Kaynak Göster

Novel (p-tolyl)-3(2H)-pyridazinone derivatives containing substituted-1,2,3-triazole moiety as new anti-Alzheimer agents: Synthesis, in vitro and in silico assays

Yıl 2022, Cilt: 47 Sayı: 3, 355 - 368, 19.10.2022

İrem Bozbey Gülce Taşkor Önel Burçin Türkmenoğlu Şule Gürsoy Esra Dilek

https://doi.org/10.55262/fabadeczacilik.1128446
Cited By: 1

Öz

Alzheimer's disease (AD) is a chronic neurodegenerative disease that is the most common cause of dementia. The risk of developing the disease increases with age. When the histopathology of the disease is examined, senile amyloid plaques, neurofibrillary tangle formation, synapse-neuron loss and marked atrophy in the brain are detected. The decrease in the level of choline acetyltransferase, which is responsible for the synthesis of acetylcholine in Alzheimer's disease, is 58-90%. There is a great need for new drugs that target the basis of the cause of the disease, as existing drugs cannot stop the progression of the disease. In this study, triazole-pyridazinone derivative compounds showing acetylcholinesterase inhibition were synthesized and their inhibitions were investigated. Compound 6e exhibited the strongest inhibitory effect with a Ki value of 0.049 ± 0.014 µM (Tacrine Ki= 0.226 ± 0.025 µM). In addition, in silico studies were applied for all compounds.

Anahtar Kelimeler

3(2H)-pyridazinone Acetylcholinesterase molecular docking

Teşekkür

The authors would like to thank Erzincan Binali Yıldırım University, Basic Sciences Application and Research Center (EBYU-EUTAM) for the Schrödinger Maestro 2021-2 program.

Kaynakça

  • Anil, D. A., Aydin, B. O., Demir, Y., & Turkmenoglu, B. (2022). Design, synthesis, biological evaluation and molecular docking studies of novel 1H-1, 2, 3-Triazole derivatives as potent inhibitors of carbonic anhydrase, acetylcholinesterase and aldose reductase. Journal of Molecular Structure, 1257, 132613.
  • Arora, K., Alfulaij, N., Higa, J. K., Panee, J., & Nichols, R. A. (2013). Impact of sustained exposure to β-amyloid on calcium homeostasis and neuronal integrity in model nerve cell system expressing α4β2 nicotinic acetylcholine receptors. J Biol Chem, 288(16), 11175-11190. doi:10.1074/jbc.M113.453746
  • Birks, J. (2006). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev, 2006(1), Cd005593. doi:10.1002/14651858.Cd005593
  • Bozbey, İ., Özdemir, Z., Uslu, H., Özçelik, A. B., Şenol, F. S., Orhan İ, E., & Uysal, M. (2020). A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies. Mini Rev Med Chem, 20(11), 1042-1060. doi:10.2174/1389557519666191010154444
  • Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K. (2021). Alzheimer's disease drug development pipeline: 2021. Alzheimers Dement (N Y), 7(1), e12179. doi:10.1002/trc2.12179
  • ÇÖL, Ö. F., Bozbey, İ., Türkmenoğlu, B., & Uysal, M. (2022a). 3 (2H)-Pyridazinone Derivatives: Synthesis, In-Silico Studies, Structure-Activity Relationship and In-Vitro Evaluation for Acetylcholinesterase Enzyme İnhibition. Journal of Molecular Structure, 132970.
  • Çöl, Ö. F., Bozbey, İ., Türkmenoğlu, B., & Uysal, M. (2022b). 3(2H)-pyridazinone derivatives: Synthesis, in-silico studies, structure-activity relationship and in-vitro evaluation for acetylcholinesterase enzyme inhibition. Journal of Molecular Structure, 1261, 132970. doi:https://doi.org/10.1016/j.molstruc.2022.132970
  • Daulatzai, M. A. (2016). Fundamental role of pan-inflammation and oxidative-nitrosative pathways in neuropathogenesis of Alzheimer's disease in focal cerebral ischemic rats. American journal of neurodegenerative disease, 5(2), 102-130. Retrieved from https://pubmed.ncbi.nlm.nih.gov/27335702 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913220/
  • Fani Maleki, A., Cisbani, G., Plante, M.-M., Préfontaine, P., Laflamme, N., Gosselin, J., & Rivest, S. (2020). Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease. Journal of Neuroinflammation, 17(1), 218. doi:10.1186/s12974-020-01893-3
  • Harel, M., Schalk, I., Ehretsabatier, L., Bouet, F., Goeldner, M., Hirth, C., . . . Sussman, J. L. (1993). Quaternary Ligand-Binding to Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase. Proceedings of the National Academy of Sciences of the United States of America, 90(19), 9031-9035. doi:DOI 10.1073/pnas.90.19.9031
  • Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020). Clinical trials of new drugs for Alzheimer disease. Journal of biomedical science, 27(1), 18. doi:10.1186/s12929-019-0609-7
  • Koronyo-Hamaoui, M., Sheyn, J., Hayden, E. Y., Li, S., Fuchs, D.-T., Regis, G. C., . . . Rentsendorj, A. (2020). Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease. Brain, 143(1), 336-358. doi:10.1093/brain/awz364
  • Kumar, K., Kumar, A., Keegan, R. M., & Deshmukh, R. (2018). Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease. Biomed Pharmacother, 98, 297-307. doi:10.1016/j.biopha.2017.12.053
  • Özçelik, A. B., Özdemir, Z., Sari, S., Utku, S., & Uysal, M. (2019). A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies. Pharmacological Reports, 71(6), 1253-1263. doi:https://doi.org/10.1016/j.pharep.2019.07.006
  • Schrödinger Release 2021-2: Glide, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: LigPrep, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: Prime, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: Protein Preparation Wizard; Epik, S., LLC, New York, NY, 2021; Impact, Schrödinger, LLC, New York, NY; Prime, Schrödinger, LLC, New York, NY, 2021.
  • Srivastava, S., Ahmad, R., & Khare, S. K. (2021). Alzheimer's disease and its treatment by different approaches: A review. Eur J Med Chem, 216, 113320. doi:10.1016/j.ejmech.2021.113320
  • Taudorf, L., Nørgaard, A., Waldemar, G., & Laursen, T. M. (2021). Mortality in Dementia from 1996 to 2015: A National Registry-Based Cohort Study. Journal of Alzheimer's disease : JAD, 79(1), 289-300. doi:10.3233/JAD-200823
  • Zhang, W., Jiao, B., Xiao, T., Liu, X., Liao, X., Xiao, X., . . . Shen, L. (2020). Association of rare variants in neurodegenerative genes with familial Alzheimer's disease. Annals of clinical and translational neurology, 7(10), 1985-1995. doi:10.1002/acn3.51197

Yıl 2022, Cilt: 47 Sayı: 3, 355 - 368, 19.10.2022

İrem Bozbey Gülce Taşkor Önel Burçin Türkmenoğlu Şule Gürsoy Esra Dilek

https://doi.org/10.55262/fabadeczacilik.1128446
Cited By: 1

Öz

Alzheimer hastalığı (AH), demansın en yaygın nedeni olan kronik nörodejeneratif bir hastalıktır. Hastalığa yakalanma riski yaşla birlikte artar. Hastalığın histopatolojisi incelendiğinde senil amiloid plakları, nörofibriler yumak oluşumu, sinaps-nöron kaybı ve beyinde belirgin atrofi saptanır. Alzheimer hastalığında asetilkolin sentezinden sorumlu olan kolin asetil transferaz düzeyindeki azalma %58-90'dır. Mevcut ilaçlar hastalığın ilerlemesini durduramadığından, hastalığın temel nedenini hedef alan yeni ilaçlara büyük ihtiyaç vardır. Bu çalışmada asetilkolinesteraz inhibisyonu gösteren triazol-piridazinon türevi bileşikler sentezlenmiştir ve enzim inhibisyonları araştırılmıştır. Bileşik 6e, 0.049 ± 0.014 µM Ki değeri ile en güçlü inhibitör etkiyi göstermiştir (Takrin Ki= 0.226 ± 0.025 µM). Ayrıca sentezlenen tüm bileşikler için in-silico çalışmalar yapıldı.

Anahtar Kelimeler

3(2H)-piridazinon Asetilkolinesteraz moleküler docking

Kaynakça

  • Anil, D. A., Aydin, B. O., Demir, Y., & Turkmenoglu, B. (2022). Design, synthesis, biological evaluation and molecular docking studies of novel 1H-1, 2, 3-Triazole derivatives as potent inhibitors of carbonic anhydrase, acetylcholinesterase and aldose reductase. Journal of Molecular Structure, 1257, 132613.
  • Arora, K., Alfulaij, N., Higa, J. K., Panee, J., & Nichols, R. A. (2013). Impact of sustained exposure to β-amyloid on calcium homeostasis and neuronal integrity in model nerve cell system expressing α4β2 nicotinic acetylcholine receptors. J Biol Chem, 288(16), 11175-11190. doi:10.1074/jbc.M113.453746
  • Birks, J. (2006). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev, 2006(1), Cd005593. doi:10.1002/14651858.Cd005593
  • Bozbey, İ., Özdemir, Z., Uslu, H., Özçelik, A. B., Şenol, F. S., Orhan İ, E., & Uysal, M. (2020). A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies. Mini Rev Med Chem, 20(11), 1042-1060. doi:10.2174/1389557519666191010154444
  • Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K. (2021). Alzheimer's disease drug development pipeline: 2021. Alzheimers Dement (N Y), 7(1), e12179. doi:10.1002/trc2.12179
  • ÇÖL, Ö. F., Bozbey, İ., Türkmenoğlu, B., & Uysal, M. (2022a). 3 (2H)-Pyridazinone Derivatives: Synthesis, In-Silico Studies, Structure-Activity Relationship and In-Vitro Evaluation for Acetylcholinesterase Enzyme İnhibition. Journal of Molecular Structure, 132970.
  • Çöl, Ö. F., Bozbey, İ., Türkmenoğlu, B., & Uysal, M. (2022b). 3(2H)-pyridazinone derivatives: Synthesis, in-silico studies, structure-activity relationship and in-vitro evaluation for acetylcholinesterase enzyme inhibition. Journal of Molecular Structure, 1261, 132970. doi:https://doi.org/10.1016/j.molstruc.2022.132970
  • Daulatzai, M. A. (2016). Fundamental role of pan-inflammation and oxidative-nitrosative pathways in neuropathogenesis of Alzheimer's disease in focal cerebral ischemic rats. American journal of neurodegenerative disease, 5(2), 102-130. Retrieved from https://pubmed.ncbi.nlm.nih.gov/27335702 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913220/
  • Fani Maleki, A., Cisbani, G., Plante, M.-M., Préfontaine, P., Laflamme, N., Gosselin, J., & Rivest, S. (2020). Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease. Journal of Neuroinflammation, 17(1), 218. doi:10.1186/s12974-020-01893-3
  • Harel, M., Schalk, I., Ehretsabatier, L., Bouet, F., Goeldner, M., Hirth, C., . . . Sussman, J. L. (1993). Quaternary Ligand-Binding to Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase. Proceedings of the National Academy of Sciences of the United States of America, 90(19), 9031-9035. doi:DOI 10.1073/pnas.90.19.9031
  • Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020). Clinical trials of new drugs for Alzheimer disease. Journal of biomedical science, 27(1), 18. doi:10.1186/s12929-019-0609-7
  • Koronyo-Hamaoui, M., Sheyn, J., Hayden, E. Y., Li, S., Fuchs, D.-T., Regis, G. C., . . . Rentsendorj, A. (2020). Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease. Brain, 143(1), 336-358. doi:10.1093/brain/awz364
  • Kumar, K., Kumar, A., Keegan, R. M., & Deshmukh, R. (2018). Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease. Biomed Pharmacother, 98, 297-307. doi:10.1016/j.biopha.2017.12.053
  • Özçelik, A. B., Özdemir, Z., Sari, S., Utku, S., & Uysal, M. (2019). A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies. Pharmacological Reports, 71(6), 1253-1263. doi:https://doi.org/10.1016/j.pharep.2019.07.006
  • Schrödinger Release 2021-2: Glide, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: LigPrep, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: Prime, S., LLC, New York, NY, 2021.
  • Schrödinger Release 2021-2: Protein Preparation Wizard; Epik, S., LLC, New York, NY, 2021; Impact, Schrödinger, LLC, New York, NY; Prime, Schrödinger, LLC, New York, NY, 2021.
  • Srivastava, S., Ahmad, R., & Khare, S. K. (2021). Alzheimer's disease and its treatment by different approaches: A review. Eur J Med Chem, 216, 113320. doi:10.1016/j.ejmech.2021.113320
  • Taudorf, L., Nørgaard, A., Waldemar, G., & Laursen, T. M. (2021). Mortality in Dementia from 1996 to 2015: A National Registry-Based Cohort Study. Journal of Alzheimer's disease : JAD, 79(1), 289-300. doi:10.3233/JAD-200823
  • Zhang, W., Jiao, B., Xiao, T., Liu, X., Liao, X., Xiao, X., . . . Shen, L. (2020). Association of rare variants in neurodegenerative genes with familial Alzheimer's disease. Annals of clinical and translational neurology, 7(10), 1985-1995. doi:10.1002/acn3.51197
Toplam 21 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri
Bölüm Araştırma Makalesi
Yazarlar

İrem Bozbey 0000-0002-9290-938X

Gülce Taşkor Önel 0000-0002-9375-2329

Burçin Türkmenoğlu 0000-0002-5770-0847

Şule Gürsoy 0000-0001-5236-5974

Esra Dilek 0000-0002-3629-5168

Yayımlanma Tarihi 19 Ekim 2022
Gönderilme Tarihi 9 Haziran 2022
Yayımlandığı Sayı Yıl 2022 Cilt: 47 Sayı: 3

Kaynak Göster

APA Bozbey, İ., Taşkor Önel, G., Türkmenoğlu, B., Gürsoy, Ş., vd. (2022). Novel (p-tolyl)-3(2H)-pyridazinone derivatives containing substituted-1,2,3-triazole moiety as new anti-Alzheimer agents: Synthesis, in vitro and in silico assays. Fabad Journal of Pharmaceutical Sciences, 47(3), 355-368. https://doi.org/10.55262/fabadeczacilik.1128446

Cited By

1,2,3-Triazolo[4,5-b]aminoquinolines: Design, synthesis, structure, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, and molecular docking of novel modified tacrines
Bioorganic Chemistry
https://doi.org/10.1016/j.bioorg.2023.106704