Yeni 4-Aminoantipirin Türevi Schiff Bazlarının Antioksidan ve Anti-Alzheimer Özelliklerinin Araştırılması

Year 2025, Volume: 13 Issue: 3, 707 - 722

Ercan Çınar

https://doi.org/10.33715/inonusaglik.1642420

Abstract

Bu çalışmada, 4-aminoantipirin(4AAP) türevi Schiff bazları sentezlendi ve bu moleküllerin yapıları spektroskopik yöntemlerle (1H- ve 13C-NMR) aydınlatıldı. Literatürde ilk kez sentezlenen bu moleküllerin antioksidan potansiyelleri, DPPH- (1,1-difenil-2-pikrilhidrazil) serbest radikal süpürücü etkisi, 2,2'-azino-bis(3-etilbenztiazolin-6-sülfonik asit) (ABTS) radikal süpürücü aktivitesi ve bakır iyon indirgeyici antioksidan kapasitesi (CUPRAC) analizi ile araştırıldı. Daha sonra kolinesterazlara (ChE) karşı inhibitör potansiyelleri incelendi. Enzim inhibisyon çalışmalarında, (4E)-4-(5-kloro-2-hidroksibenzilidenamino)-1,2-dihidro-2,3-dimetil-1-fenilpirazol-5-on (R3) bileşikleri, 27,05±0,13 µM inhibisyon değeriyle, standart inhibitör Neostigmin'in 33,3 ± 0,32 µM değerine kıyasla daha yüksek bir inhibisyon etkisi gösterdi. Daha sonra antioksidan yöntemler DPPH, ABTS ve CUPRAC analiz edildi. DPPH testinde, (4E)-4-(2-hidroksi-5-nitrobenzilidenamino)-1,2-dihidro-2,3-dimetil-1-fenilpirazol-5-on (R5) molekülü, 116,79±2,73 µM ile en iyi aktiviteyi gösterdi. Ancak bu deney yönteminde tüm moleküller standart antioksidanlardan (bütilhidroksianisol (BHA), bütillenmiş hidroksitoluen (BHT) ve alfa-tokoferol (α-TOC)) daha iyi sonuçlar vermedi. ABTS yönteminde sentezlenen tüm moleküller standart antioksidanlar BHA ve α-TOC ile karşılaştırıldığında iyi aktivite gösterdi. R3 molekülü en iyi aktiviteyi gösterdi. CUPRAC yönteminde ise tüm moleküller antioksidan aktivite göstermesine rağmen standart antioksidanlar kadar iyi değildi. (4E)-4-(2-hidroksibenzilidenamino)-1,2-dihidro-2,3-dimetil-1-fenilpirazol-5-on (R1) molekülü aktif molekül olarak en iyi aktiviteyi gösterdi.

Keywords

4-aminoantipirin , Alzheimer hastalığı , Antioksidanlar , Schiff bazı

INVESTIGATION OF ANTIOXIDANT AND ANTI-ALZHEIMER PROPERTIES OF NOVEL 4-AMINOANTIPYRINE-DERIVED SCHIFF BASES

Abstract

In this study, Schiff bases derived from 4-aminoantipyrine (4AAP) were synthesized and elucidated using spectroscopic methods (¹H- and ¹³C-NMR). DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical scavenging test, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity, and copper ion reducing antioxidant capacity (CUPRAC) analysis were used to evaluate Schiff bases’ antioxidant potentials. Furthermore, their inhibitory potentials against cholinesterase (ChE) enzymes were investigated. The compound (4E)-4-(5-chloro-2-hydroxybenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (R3) exhibited a higher inhibition effect with an inhibitory value of 27.05 ± 0.13 µM as compared to the standard inhibitor neostigmine (33.3 ± 0.32 µM). The synthesized compounds were subjected to antioxidant tests, including DPPH, ABTS, and CUPRAC, respectively. In the DPPH experiment, the compound (4E)-4-(2-hydroxy-5-nitrobenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (R5) exhibited activity with a value of 116.79 ± 2.73 µM. However, in this test, all compounds showed lower antioxidant activity as compared to standard antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and α-tocopherol (α-TOC). By contrast, in the ABTS assay, all compounds were active as compared to standard antioxidants, and the R3 compound showed high antioxidant activity. In the CUPRAC experiment, although the compounds showed antioxidant activity, it was not as high as that of the standard antioxidants. (4E) -4-(2-hydroxybenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (R1) compound was the most effective in the CUPRAC method.

Keywords

Alzheimer disease , 4-Aminoantipyrine , Antioxidants , Schiff base

Ethical Statement

There is no need for ethics committee approval for our research article.

References

• Alam, M. S., Lee, D. U. (2021). Molecular structure, spectral (FT-IR, FT-Raman, Uv-Vis, and fluorescent) properties and quantum chemical analyses of azomethine derivative of 4-aminoantipyrine. Journal of Molecular Structure, 1227, 129512.
• Aljamali, N. M. (2014). Review in cyclic compounds with heteroatom. Asian Journal of Research in Chemistry, 7(11), 975-1006.
• Al-Mulla, A. (2017). A review: biological importance of heterocyclic compounds. Der Pharma Chem, 9(13), 141-147. Apak, R., Güçlü, K., Özyürek, M., Karademir, S. E. (2004). Novel total antioxidant capacity index for dietary polyphenols and vitamins C and E, using their cupric ion reducing capability in the presence of neocuproine: CUPRAC method. Journal of agricultural and food chemistry, 52(26), 7970-7981.
• Arora, R., Sharma, R., Tageza, A., Grewal, A. S., Saini, B., Arora, S., Kaur, R. (2021). Design and synthesis of novel 4-aminophenazone Schiff bases by grinding technique as prospective anti-inflammatory agents. Journal of Applied Pharmaceutical Science, 11(1), 048-053.
• Ashraf, M. A., Mahmood, K., Wajid, A., Maah, M. J., Yusoff, I. (2011). Synthesis, characterization and biological activity of Schiff bases. IPCBEE, 10(1), 185.
• Benzi, G., Moretti, A. (1998). Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease?. European journal of pharmacology, 346(1), 1-13.
• Bernard, G. R., Wheeler, A. P., Arons, M. M., Morris, P. E., Paz, H. L., Russell, J. A., Wright, P.E., Antioxidant in ARDS Study Group. (1997). A trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest, 112(1), 164-172.
• Blois, M. S. (1958). Antioxidant determinations by the use of a stable free radical. Nature, 181(4617), 1199-1200.
• Castro, A., Martinez, A. (2006). Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Current pharmaceutical design, 12(33), 4377-4387.
• Ceramella, J., Iacopetta, D., Catalano, A., Cirillo, F., Lappano, R., Sinicropi, M. S. (2022). A review on the antimicrobial activity of Schiff bases: Data collection and recent studies. Antibiotics, 11(2), 191.
• Chen, Z. R., Huang, J. B., Yang, S. L., Hong, F. F. (2022). Role of cholinergic signaling in Alzheimer’s disease. Molecules, 27(6), 1816.
• Çakmak, R., Başaran, E., Boğa, M., Erdoğan, Ö., Çınar, E., Çevik, Ö. (2022). Schiff base derivatives of 4-aminoantipyrine as promising molecules: synthesis, structural characterization, and biological activities. Russian Journal of Bioorganic Chemistry, 48(2), 334-344.
• Çınar, E., Başaran, E., Erdoğan, Ö., Çakmak, R., Boğa, M., Çevik, Ö. (2021). Heterocyclic Schiff base derivatives containing pyrazolone moiety: Synthesis, characterization, and in vitro biological studies. Journal of the Chinese Chemical Society, 68(12), 2355-2367.
• Dhalla, N. S., Temsah, R. M., Netticadan, T. (2000). Role of oxidative stress in cardiovascular diseases. Journal of hypertension, 18(6), 655-673.
• Ellman, G. L., Courtney, K. D., Andres Jr, V., Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, 7(2), 88-95. Esmer, Y. İ., Çınar, E., & Başaran, E. (2022). Design, docking, synthesis and biological evaluation of novel nicotinohydrazone derivatives as potential butyrylcholinesterase enzyme inhibitor. ChemistrySelect, 7(33), e202202771.
• Farlow, M. R., Miller, M. L., & Pejovic, V. (2008). Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations. Dementia and geriatric cognitive disorders, 25(5), 408-422. Fathima, S. S. A., Paulpandiyan, R., & Nagarajan, E. R. (2019). Expatiating biological excellence of aminoantipyrine derived novel metal complexes: Combined DNA interaction, antimicrobial, free radical scavenging studies and molecular docking simulations. Journal of Molecular Structure, 1178, 179-191.
• Finkel, T. (1998). Oxygen radicals and signaling. Current opinion in cell biology, 10(2), 248-253. Finkel, T., & Holbrook, N. J. (2000). Oxidants, oxidative stress and the biology of ageing. nature, 408(6809), 239-247.
• Forman, H. J., Augusto, O., Brigelius-Flohe, R., Dennery, P. A., Kalyanaraman, B., Ischiropoulos, H., Mann, G.E., Radi, R., Roberts, L.J., Vina, J., & Davies, K. J. (2015). Even free radicals should follow some rules: a guide to free radical research terminology and methodology. Free Radical Biology and Medicine, 78, 233-235.
• Gella, A., & Durany, N. (2009). Oxidative stress in Alzheimer disease. Cell adhesion & migration, 3(1), 88-93.
• Goedert, M., & Spillantini, M. G. (2006). A century of Alzheimer's disease. science, 314(5800), 777-781.
• Gulcan, H. O., Mavideniz, A., Sahin, M. F., & Orhan, I. E. (2019). Benzimidazole-derived compounds designed for different targets of Alzheimer’s disease. Current Medicinal Chemistry, 26(18), 3260-3278. Halliwell, B., & Gutteridge, J. M. (2015). Free radicals in biology and medicine. Oxford university press.
• Jaganjac, M., Milkovic, L., Zarkovic, N., & Zarkovic, K. (2022). Oxidative stress and regeneration. Free Radical Biology and Medicine, 181, 154-165.
• Kazancioglu, E. A., & Senturk, M. (2020). Synthesis of N-phenylsulfonamide derivatives and investigation of some esterase enzymes inhibiting properties. Bioorganic Chemistry, 104, 104279.
• Maresova, P., Mohelska, H., Dolejs, J., & Kuca, K. (2015). Socio-economic aspects of Alzheimer's disease. Current Alzheimer Research, 12(9), 903-911.
• Marucci, G., Buccioni, M., Dal Ben, D., Lambertucci, C., Volpini, R., & Amenta, F. (2021). Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology, 190, 108352.
• Mathew, B. B., Tiwari, A., & Jatawa, S. K. (2011). Free radicals and antioxidants: A review. Journal of Pharmacy Research, 4(12), 4340-4343.
• Monroe, T., Carter, M., Feldt, K., Tolley, B., & Cowan, R. L. (2012). Assessing advanced cancer pain in older adults with dementia at the end‐of‐life. Journal of advanced nursing, 68(9), 2070-2078.
• Nordberg, A., & Svensson, A. L. (1998). Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug safety, 19, 465-480.
• Okey, N.C., Obasi, N. L., Ejikeme, P.M., Ndinteh, D.T., Ramasami, P., Sherif, E.S.M., Akpan, E.D., and Ebenso, E.E., (2020). Evaluation of some amino benzoic acid and 4-aminoantipyrine derived Schiff bases as corrosion inhibitors for mild steel in acidic medium: Synthesis, experimental and computational studies. Journal of Molecular Liquids, 315, 113773.
• Pohanka, M. (2014). Alzheimer s disease and oxidative stress: a review. Current medicinal chemistry, 21(3), 356-364.
• Re, R., Pellegrini, N., Proteggente, A., Pannala, A., Yang, M., & Rice-Evans, C. (1999). Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free radical biology and medicine, 26(9-10), 1231-1237.
• Sakthivel, A., Jeyasubramanian, K., Thangagiri, B., & Raja, J. D. (2020). Recent advances in Schiff base metal complexes derived from 4-aminoantipyrine derivatives and their potential applications. Journal of Molecular Structure, 1222, 128885.
• Salamizadeh, A., Mirzaei, T., & Ravari, A. (2017). The impact of spiritual care education on the self-efficacy of the family caregivers of elderly people with Alzheimer’s disease. International Journal of Community Based Nursing and Midwifery, 5(3), 231.
• Shoaib, M., Rahman, G., Shah, S. W. A., & Umar, M. N. (2015). Synthesis of 4-aminoantipyrine derived Schiff bases and their evaluation for antibacterial, cytotoxic and free radical scavenging activity. Bangladesh Journal of Pharmacology, 10(2), 332-336.
• Sies, H., Belousov, V. V., Chandel, N. S., Davies, M. J., Jones, D. P., Mann, G. E., Murphy, M.P., Yamamoto, M., & Winterbourn, C. (2022). Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nature reviews Molecular cell biology, 23(7), 499-515. Stanciu, G. D., Luca, A., Rusu, R. N., Bild, V., Beschea Chiriac, S. I., Solcan, C., Bild, W., & Ababei, D. C. (2019). Alzheimer’s disease pharmacotherapy in relation to cholinergic system involvement. Biomolecules, 10(1), 40.
• Szabo, C., Zingarelli, B., O'Connor, M., & Salzman, AL. (1996). DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proceedings of the National Academy of Sciences, 93(5), 1753-1758.
• Tabet, N. (2006). Acetylcholinesterase inhibitors for Alzheimer’s disease: anti-inflammatories in acetylcholine clothing!. Age and ageing, 35(4), 336-338.
• Teran, R., Guevara, R., Mora, J., Dobronski, L., Barreiro-Costa, O., Beske, T., Pérez-Barrera, J., Araya-Maturana, R., Rojas-Silva, P., Poveda, A., & Heredia-Moya, J. (2019). Characterization of antimicrobial, antioxidant, and leishmanicidal activities of Schiff base derivatives of 4-aminoantipyrine. Molecules, 24(15), 2696.
• Terry, R. D., Gonatas, N. K., & Weiss, M. (1964). Ultrastructural studies in Alzheimer's presenile dementia. The American journal of pathology, 44(2), 269.
• Topal, G., Tombak, A., Yigitalp, E., Batibay, D., Kilicoglu, T., & Ocak, Y. S. (2017). Diester Molecules for Organic-Based Electrical and Photoelectrical Devices. Journal of Electronic Materials, 46, 3958-3964.
• Upadhyay, A., Kar, P. K., & Dash, S. (2020). A spectrophotometric study of impact of solvent, substituent and cross-conjugation in some 4-aminoantipyrine based Schiff bases. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 233, 118231. Yiannopoulou, K. G., & Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer’s disease. Therapeutic advances in neurological disorders, 6(1), 19-33.