SYNTHESIS, CHARACTERIZATION AND CHOLINESTERASE INHIBITORY EFFECTS OF IBUPROFEN-BASED SPIROTHIAZOLIDINONES

Year 2025, , 12 - 20, 20.01.2025

Çağla Begüm Apaydın , Gozde Hasbal Çelikok , Tuğba Yılmaz Özden

https://doi.org/10.33483/jfpau.1493082

Abstract

Objective: A novel class of spirothiazolidinone derivatives were designed, synthesized, and assessed as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors for Alzheimer's disease therapy.
Material and Method: In this study, novel spirocyclic compounds were synthesized by one-pot reaction. IR, 1H NMR, 13C NMR, LC-MS and elemental analysis techniques have all been used to clarify the chemical structures of the compounds. AChE and BuChE inhibitory effects of compounds (4a-e and, 5a-e) were assayed according to Ellman’s method using galantamine as reference.
Result and Discussion: According to the inhibition data, compound 4e demonstrated the most promising activity against AChE, with an IC50 value of 39.53±1.94 µM, while compound 4b exhibited the most potential against BuChE, with an IC50 value of 95.97±1.79 µM.

Keywords

Acetylcholinesterase, butyrylcholinesterase, ibuprofen, spirothiazolidinone, synthesis

İBUPROFEN TÜREVİ SPİROTHİAZOLİDİNONLARIN SENTEZİ, KARAKTERİZASYONU VE KOLİNESTERAZ İNHİBİTÖR ETKİLERİ

Abstract

Amaç: Alzheimer hastalığına karşı potansiyel asetilkolinesteraz (AChE) ve butirilkolinesteraz (BuChE) inhibitörleri olarak bir seri yeni spirotiyazolidinon türevi tasarlanmış, sentezlenmiş ve inhibisyon etkileri değerlendirilmiştir.
Gereç ve Yöntem: Bu çalışmadan kazanılan yeni spiro bileşikler tek kap yöntemi ile sentez edilmiştir. Bileşiklerin kimyasal yapılarını aydınlatmak için IR, 1H NMR, 13C NMR, LC-MS ve elementel analiz yöntemleri kullanılmıştır. Bileşiklerin (4a-e ve 5a-e), AChE ve BuChE enzimleri üzerindeki inhibisyon etkileri galantamin referans olarak kullanılarak Ellman yöntemine göre analiz edilmiştir.
Sonuç ve Tartışma: İnhibisyon sonuçlarına göre, en umut verici bileşik AChE'ye karşı IC50 değeri 39.53±1.94 µM olan 4e ve BuChE'ye karşı IC50 değeri 95.97±1.79 µM olan 4b bileşikleri olarak kaydedilmiştir.

Keywords

Asetilkolinesteraz, butirilkolinesteraz, ibuprofen, sentez, spirotiyazolidinon

References

• 1. Querfurth, H.W., Laferla, F.M. (2010). Alzheimer’s disease. The New England Journal of Medicine, 362(4), 329-344. [CrossRef]
• 2. Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C.E., Cummings, J., van der Flier, W. (2021). Alzheimer’s disease. Lancet, 397, 1577-1590. [CrossRef]
• 3. Vaz, M., Silvestre, S. (2020). Alzheimer’s disease: Recent treatment strategies. European Journal of Pharmacology, 887, 173554. [CrossRef]
• 4. Davies, N.M. (1998). Clinical pharmacokinetics of ibuprofen. The first 30 years. Clinical Pharmacokinetics, 34, 101-154. [CrossRef]
• 5. Halford, G.M., Lordkipanidzé, M., Watson, S.P. (2012) 50th anniversary of the discovery of ibuprofen: An interview with Dr Stewart Adams. Platelets, 23, 415-422. [CrossRef]
• 6. McGeer, P.L., Guo, J.P., Lee, M., Kennedy, K., McGeer, E.G. (2018). Alzheimer’s disease can be spared by nonsteroidal anti-inflammatory drugs. Journal of Alzheimer's Disease, 62, 1219-1222. [CrossRef]
• 7. Wilkinson, B.L., Cramer, P.E., Varvel, N.H., Reed-Geaghan, E., Jiang, Q., Szabo, A., Herrup, K., Lamb B.T., Landreth, G.E. (2012). Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer’s disease. Neurobiology of Aging, 33, 197, e21-32. [CrossRef]
• 8. Cihan-Üstündağ, G., Naesens, L., Şatana, D., Erköse-Genç, G., Mataracı-Kara, E., Çapan, G. (2019). Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives. Monatshefte Fur Chemie, 150, 1533-1544. [CrossRef]
• 9. Look, G.C., Schullek, J.R., Holmes, C.P., Chinn, J.P., Gordon, E.M., Gallop, M. (1996). The identification of cyclooxygenase-1 inhibitors from 4-thiazolidinone combinatorial libraries. Bioorganic & Medicinal Chemistry Letters, 6, 707-712. [CrossRef]
• 10. Tahmasvand, R., Bayat, P., Mahmood, S., Dehghani, S. (2020). Design and synthesis of novel 4-thiazolidinone derivatives with promising anti-breast cancer activity: Synthesis, characterization, in vitro and in vivo results. Bioorganic and Medicinal Chemistry, 104, 104276. [CrossRef]
• 11. Suthar, S.K., Jaiswal, V., Lohan, S., Bansal, S., Chaudhary, A., Tiwari A, Alex A.T., Joesph, A. (2013). Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening. European Journal of Medicinal Chemistry, 63, 589-602. [CrossRef]
• 12. Liu, Z., Chai, Q., Li, Y.Y., Shen, Q., Ma, L.P., Zhang, L., Wang, X., Sheng, Li., Li, J., Li, J., Shen, J. (2010). Discovery of novel PTP1B inhibitors with antihyperglycemic activity. Acta Pharmacologica Sinica, 31, 1005-1012. [CrossRef]
• 13. Almasirad, A., Ghadimi, M., Mirahmadi, S., Ahmadian Kodakan, P., Jahani, R., Nazari, M., Rezaee, E., Azizian, H., Rabizadeh, P., Tabatabai, S.A., Faizi, M. (2022). Design, synthesis, and preliminary pharmacological evaluation of novel thiazolidinone derivatives as potential benzodiazepine agonists. Molecular Diversity, 26, 769-780. [CrossRef]
• 14. Cihan-Üstündağ, G., Zopun, M., Vanderlinden, E., Ozkirimli, E. (2020). Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones, Bioorganic and Medicinal Chemistry, 28, 115130. [CrossRef]
• 15. Ashraf, M., Hussain, R., Khan, S., Rehman, W., Khan, Y., Sardar, A., Aziz, T., Khowdiary, M.M. (2024). In vitro and in silico correlation of benzoxazole-based thiazolidinone hybrids derivatives: A promising acetylcholinesterase and butyrylcholinesterase inhibitors. Journal of Molecular Structure, 1301, 137317. [CrossRef]
• 16. Bilgicli, H.G., Taslimi, P., Akyuz, B., Tuzun, B., Gulcin, İ. (2020). Synthesis, characterization, biological evaluation, and molecular docking studies of some piperonyl‐based 4‐thiazolidinone derivatives. Archiv der Pharmazie, 353(1), e1900304. [CrossRef]
• 17. Kocabalkanli, A., Cihan-Ustundag, G., Naesens, L., Mataraci-Kara, E., Nassozi, M., Capan, G., (2017). Diclofenac-based hydrazones and spirothiazolidinones: Synthesis, characterization, and antimicrobial properties. Archiv der Pharmazie, 350(5), e1700010. [CrossRef]
• 18. Goktas, F., Vanderlinden, E., Naesens, L., Cesur, N., Cesur, Z., (2012). Microwave assisted synthesis and anti-influenza virus activity of 1-adamantyl substituted N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives. Bioorganic and Medicinal Chemistry, 20(24), 7155–7159. [CrossRef]
• 19. Yousefi, M., Mohammadi, M., Habibi, Z. (2014). Enantioselective resolution of racemic ibuprofen esters using different lipases immobilized on octyl sepharose. Journal of Molecular Catalysis B: Enzymatic, 104, 87-94. [CrossRef]
• 20. Kumsi, M., Poojary, B., Lobo, P.L., Kumari, N.S., Chullikana, A. (2010). Synthesis, characterization and biological studies of some bioactive thiazolotriazole derivatives. Zeitschrift Fur Naturforsch, 65, 1509-1515. [CrossRef]
• 21. 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. [CrossRef]