Research Article
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
Abstract
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.
Thanks
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.
References
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- 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
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- 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
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- 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
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- 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
Year 2022,
Volume: 47 Issue: 3, 355 - 368, 19.10.2022
Abstract
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.
References
- 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
There are 21 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Pharmacology and Pharmaceutical Sciences |
| Journal Section | Research Article |
| Authors | |
| Publication Date | October 19, 2022 |
| Submission Date | June 9, 2022 |
| Published in Issue | Year 2022 Volume: 47 Issue: 3 |